RET fusions in a small subset of advanced colorectal cancers at risk of being neglected

Abstract

Background

Recognition of rare molecular subgroups is a challenge for precision oncology and may lead to tissue-agnostic approval of targeted agents. Here we aimed to comprehensively characterize the clinical, pathological and molecular landscape of RET rearranged metastatic colorectal cancer (mCRC).

Patients and methods

In this case series, we compared clinical, pathological and molecular characteristics of 24 RET rearranged mCRC patients with those of a control group of 291 patients with RET negative tumors. RET rearranged and RET negative mCRCs were retrieved by systematic literature review and by taking advantage of three screening sources: 1) Ignyta's phase 1/1b study on RXDX-105 (NCT01877811); 2) cohorts screened at two Italian and one South Korean Institutions; 3) Foundation Medicine Inc. database. Next generation sequencing data were analyzed for RET rearranged cases.

Results

RET fusions were more frequent in older patients (median age of 66 vs. 60 years, p = 0.052), with ECOG PS 1-2 (90% vs. 50%, p = 0.02), right-sided (55% vs. 32%, P=0.013), previously unresected primary tumors (58% vs. 21%, P<0.001), RAS and BRAF wild-type (100% vs. 40%, p < 0.001) and MSI-high (48% vs. 7%, P<0.001). Notably, 11 (26%) out of 43 patients with right-sided, RAS and BRAF wild-type tumors harbored a RET rearrangement.At a median follow-up of 45.8 months, patients with RET fusion-positive tumors showed a significantly worse OS when compared with RET-negative ones (median OS 14.0 vs. 38.0 months, HR: 4.59; 95% CI, 3.64-32.66; P<0.001). In the multivariable model, RET rearrangements were still associated with shorter OS [HR: 2.97; 95% CI, 1.25-7.07; P=0.014], while primary tumor location, RAS and BRAF mutations and MSI status were not.

Conclusions

Though very rare, RET rearrangements define a new subtype of mCRC that shows poor prognosis with conventional treatments and is therefore worth of a specific management.

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RET fusions in a small subset of advanced colorectal cancers at risk of being neglected

Abstract

Background

Recognition of rare molecular subgroups is a challenge for precision oncology and may lead to tissue-agnostic approval of targeted agents. Here we aimed to comprehensively characterize the clinical, pathological and molecular landscape of RET rearranged metastatic colorectal cancer (mCRC).

Patients and methods

In this case series, we compared clinical, pathological and molecular characteristics of 24 RET rearranged mCRC patients with those of a control group of 291 patients with RET negative tumors. RET rearranged and RET negative mCRCs were retrieved by systematic literature review and by taking advantage of three screening sources: 1) Ignyta's phase 1/1b study on RXDX-105 (NCT01877811); 2) cohorts screened at two Italian and one South Korean Institutions; 3) Foundation Medicine Inc. database. Next generation sequencing data were analyzed for RET rearranged cases.

Results

RET fusions were more frequent in older patients (median age of 66 vs. 60 years, p = 0.052), with ECOG PS 1-2 (90% vs. 50%, p = 0.02), right-sided (55% vs. 32%, P=0.013), previously unresected primary tumors (58% vs. 21%, P<0.001), RAS and BRAF wild-type (100% vs. 40%, p < 0.001) and MSI-high (48% vs. 7%, P<0.001). Notably, 11 (26%) out of 43 patients with right-sided, RAS and BRAF wild-type tumors harbored a RET rearrangement.At a median follow-up of 45.8 months, patients with RET fusion-positive tumors showed a significantly worse OS when compared with RET-negative ones (median OS 14.0 vs. 38.0 months, HR: 4.59; 95% CI, 3.64-32.66; P<0.001). In the multivariable model, RET rearrangements were still associated with shorter OS [HR: 2.97; 95% CI, 1.25-7.07; P=0.014], while primary tumor location, RAS and BRAF mutations and MSI status were not.

Conclusions

Though very rare, RET rearrangements define a new subtype of mCRC that shows poor prognosis with conventional treatments and is therefore worth of a specific management.

http://ift.tt/2oXz9YO

Focal immune-related pancreatitis occurring after treatment with programmed cell death 1 inhibitors: a distinct form of autoimmune pancreatitis?

Publication date: Available online 9 March 2018
Source:European Journal of Cancer
Author(s): Gabriele Capurso, Livia Archibugi, Laura Tessieri, Maria Chiara Petrone, Andrea Laghi, Paolo Giorgio Arcidiacono




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Immune checkpoint therapy in proteinuric kidney disease

Publication date: Available online 9 March 2018
Source:European Journal of Cancer
Author(s): Tsuneo Takenaka, Yohko Kawai, Takahiro Amano




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CREB promotes laryngeal cancer cell migration via MYCT1/NAT10 axis

http://ift.tt/2oWVtBA

Do checkpoint inhibitors provide new hope for management of metastatic penile carcinoma?

Future Oncology, Ahead of Print.


http://ift.tt/2txGwL7

CD59: a promising target for tumor immunotherapy

Future Oncology, Ahead of Print.


http://ift.tt/2oYZ3vf

Biological imaging for individualized therapy in radiation oncology: part II medical and clinical aspects

Future Oncology, Ahead of Print.


http://ift.tt/2HmJ5BE

Biological imaging for individualized therapy in radiation oncology: part I physical and technical aspects

Future Oncology, Ahead of Print.


http://ift.tt/2FDDWZ4

MGMT pyrosequencing-based cut-off methylation level and clinical outcome in patients with glioblastoma multiforme

Future Oncology, Ahead of Print.


http://ift.tt/2tvf7JP

Do checkpoint inhibitors provide new hope for management of metastatic penile carcinoma?

Future Oncology, Ahead of Print.


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CD59: a promising target for tumor immunotherapy

Future Oncology, Ahead of Print.


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Biological imaging for individualized therapy in radiation oncology: part II medical and clinical aspects

Future Oncology, Ahead of Print.


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Biological imaging for individualized therapy in radiation oncology: part I physical and technical aspects

Future Oncology, Ahead of Print.


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MGMT pyrosequencing-based cut-off methylation level and clinical outcome in patients with glioblastoma multiforme

Future Oncology, Ahead of Print.


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Loss of FFAR2 promotes colon cancer by epigenetic dysregulation of inflammation suppressors

Abstract

Free fatty acid receptor 2 (FFAR2, also named GPR43), is activated by short-chain fatty acids (SCFAs), such as butyrate, that are produced when gut bacteria ferment dietary fiber. FFAR2 has been suggested to regulate colonic inflammation, which is a major risk factor for the development of colon cancer and is also linked to epigenetic dysregulation in colon carcinogenesis. The current study assessed whether FFAR2, acting as an epigenetic regulator, protects against colon carcinogenesis. To mimic the mild inflammation that promotes human colon cancer, we treated mice with dextran sodium sulfate (DSS) overnight, which avoids excessive inflammation but induces mild inflammation that promotes colon carcinogenesis in the Apc^Min/+ and the azoxymethane (AOM)-treated mice. Our results showed that FFAR2 deficiency promotes the development of colon adenoma in the Apc^Min/+/DSS mice and the progression of adenoma to adenocarcinoma in the AOM/DSS mice. FFAR2's downstream cAMP–PKA–CREB pathway was enhanced, leading to overexpression of histone deacetylases (HDACs) in the FFAR2-deficient mice. ChIP-qPCR analysis revealed differential binding of H3K27me3 and H3K4me3 histone marks onto the promoter regions of inflammation suppressors (e.g., sfrp1, dkk3, socs1), resulting in decreased expression of these genes in the FFAR2-deficient mice. Also, more neutrophils infiltrated into tumors and colon lamina propria of the FFAR2-deficient mice. Depletion of neutrophils blocked the progression of colon tumors. In addition, FFAR2 is required for butyrate to suppress HDAC expression and hypermethylation of inflammation suppressors. Therefore, our results suggest that FFAR2 is an epigenetic tumor suppressor that acts at multiple stages of colon carcinogenesis. This article is protected by copyright. All rights reserved.

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Lifetime and baseline alcohol intakes and risk of pancreatic cancer in the European Prospective Investigation into Cancer and Nutrition study

Abstract

Recent evidence suggested a weak relationship between alcohol consumption and pancreatic cancer (PC) risk. In this study, the association between lifetime and baseline alcohol intakes and the risk of PC was evaluated, including the type of alcoholic beverages and potential interaction with smoking. Within the European Prospective Investigation into Cancer and Nutrition (EPIC) study, 1,283 incident PC (57% women) were diagnosed from 476,106 cancer-free participants, followed up for 14 years. Amounts of lifetime and baseline alcohol were estimated through lifestyle and dietary questionnaires, respectively. Cox proportional hazard models with age as primary time variable were used to estimate PC hazard ratios (HR) and their 95% confidence interval (CI). Alcohol intake was positively associated with PC risk in men. Associations were mainly driven by extreme alcohol levels, with HRs comparing heavy drinkers (>60 g/day) to the reference category (0.1-4.9 g/day) equal to 1.77 (95% CI: 1.06, 2.95) and 1.63 (95% CI: 1.16, 2.29) for lifetime and baseline alcohol, respectively. Baseline alcohol intakes from beer (>40 g/day) and spirits/liquors (>10 g/day) showed HRs equal to 1.58 (95% CI: 1.07, 2.34) and 1.41 (95% CI: 1.03, 1.94), respectively, compared to the reference category (0.1-2.9 g/day). In women, HR estimates did not reach statistically significance. The alcohol and PC risk association was not modified by smoking status. Findings from a large prospective study suggest that baseline and lifetime alcohol intakes were positively associated with PC risk, with more apparent risk estimates for beer and spirits/liquors than wine intake. This article is protected by copyright. All rights reserved.

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MRI background parenchymal enhancement, breast density and serum hormones in postmenopausal women

ABSTRACT

Background parenchymal enhancement (BPE) is the degree to which normal breast tissue enhances on contrast-enhanced magnetic resonance imaging (MRI). MRI-density is a volumetric measure of breast density that is highly correlated with mammographic density, an established breast cancer risk factor. Endogenous estrogen concentrations are positively associated with postmenopausal breast cancer risk and BPE has been shown to be sensitive to hormonal exposures. The objective of this study was to examine the relationship between BPE and MRI-density and serum hormone concentrations in postmenopausal women.

This was a study of cancer-free postmenopausal women undergoing contrast-enhanced breast MRI (N=118). At the time of MRI all women completed a self-administered questionnaire and blood samples were collected for hormone analyses. Serum concentrations of estrone (E1), estradiol (E2) and bioavailable E2 were examined by category of BPE and MRI-density.

Compared to women with 'minimal' BPE, those who had 'marked' BPE had significantly higher serum concentrations of E1, E2 and bioavailable E2 (90% increase, p_trend across all categories=0.001; 150% increase, p_trend=0.001; and 158% increase, p_trend=0.001 respectively). These associations were only affected to a minor extent by adjustment for BMI and other variables. After adjustment for BMI, no significant associations between MRI-density and serum E1, E2 and bioavailable E2 were observed.

Serum estrogen concentrations were significantly positively associated with BPE. This study provides further evidence of the hormone-sensitive nature of BPE, indicating a potential role for BPE as an imaging marker of endogenous and exogenous hormonal exposures in the breast. This article is protected by copyright. All rights reserved.

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Caveolin-1, cancer and therapy resistance

Abstract

Resistance of solid tumors to chemo- and radiotherapy remains a major obstacle in anti-cancer treatment. Herein, the membrane protein Caveolin-1 (CAV1) came into focus as it is highly expressed in many tumors and high CAV1 levels were correlated with tumor progression, invasion and metastasis, and thus, a worse clinical outcome. Increasing evidence further indicates that the heterogeneous tumor microenvironment, also known as the tumor stroma, contributes to therapy resistance resulting in poor clinical outcome. Again, CAV1 seems to play an important role in modulating tumor host interactions by promoting tumor growth, metastasis, therapy resistance and cell survival. However, the mechanisms driving stroma-mediated tumor growth and radiation resistance remain to be clarified. Understanding these interactions and thus, targeting CAV1 may offer a novel strategy for preventing cancer therapy resistance and improving clinical outcomes. In this review, we will summarize the resistance-promoting effects of CAV1 in tumors, and emphasize its role in the tumor-stroma communication as well as the resulting malignant phenotype of epithelial tumors. This article is protected by copyright. All rights reserved.

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Clinical Evaluation of Human Papillomavirus 16/18 Oncoprotein Test for Cervical Cancer Screening and HPV Positive Women Triage

Abstract

HPV-16 and -18 account for about 80% of cervical cancers. We evaluated the performance of HPV-16/18 oncoprotein to predict precancer and cancer in corresponding tissue biopsy specimens. 1008 women attending cervical cancer screening program and 638 women referred to colposcopy with biopsy-confirmed cervical intraepithelial neoplasia grade 2 or worse (CIN2+) from 4 hospitals were recruited (1646 in total). All women were tested OncoE6 (AVC), Liquid Based Cytology (Hologic) and cobas HPV test (Roche). Colposcopy was performed on women with any abnormal results. The final diagnoses were based on a consensus panel review of the histology. There were 919 normal, 69 CIN1, 53 CIN2, 91 CIN3,474 squamous cell carcinoma(SCC) and 40 adenocarcinoma (ADC) cases, the prevalence of OncoE6 was 1.7%, 10.1%, 13.2%, 44.0%, 80.4% and 65.0%, respectively. The percent positive for cobas was higher than that of OncoE6 in detection of HPV16/18 in entire population (P<0.001). However, the disparity of positive rate between these two tests became tiny among cervical cancer patients (CIN2: 26.4% vs. 13.2%, CIN3: 73.6% vs. 44.0%, SCC: 84.0% vs. 80.4%, ADC: 67.5% vs. 65.0%). OncoE6 was less sensitive than cobas (73.9% versus 93.6%, P<0.001), but more specific (97.1% versus 75.4%, P<0.001) for CIN3+ in entire population; OncoE6 yielded a sensitivity of 77.7% and a specificity of 91.0% for CIN3+ among cobas positive women, which can reduce nearly half of the colposcopy referral numbers. OncoE6 can be considered as a useful tool for cervical cancer screening and a potential powerful biomarker for HPV positive triage. This article is protected by copyright. All rights reserved.

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Loss of FFAR2 promotes colon cancer by epigenetic dysregulation of inflammation suppressors

Abstract

Free fatty acid receptor 2 (FFAR2, also named GPR43), is activated by short-chain fatty acids (SCFAs), such as butyrate, that are produced when gut bacteria ferment dietary fiber. FFAR2 has been suggested to regulate colonic inflammation, which is a major risk factor for the development of colon cancer and is also linked to epigenetic dysregulation in colon carcinogenesis. The current study assessed whether FFAR2, acting as an epigenetic regulator, protects against colon carcinogenesis. To mimic the mild inflammation that promotes human colon cancer, we treated mice with dextran sodium sulfate (DSS) overnight, which avoids excessive inflammation but induces mild inflammation that promotes colon carcinogenesis in the Apc^Min/+ and the azoxymethane (AOM)-treated mice. Our results showed that FFAR2 deficiency promotes the development of colon adenoma in the Apc^Min/+/DSS mice and the progression of adenoma to adenocarcinoma in the AOM/DSS mice. FFAR2's downstream cAMP–PKA–CREB pathway was enhanced, leading to overexpression of histone deacetylases (HDACs) in the FFAR2-deficient mice. ChIP-qPCR analysis revealed differential binding of H3K27me3 and H3K4me3 histone marks onto the promoter regions of inflammation suppressors (e.g., sfrp1, dkk3, socs1), resulting in decreased expression of these genes in the FFAR2-deficient mice. Also, more neutrophils infiltrated into tumors and colon lamina propria of the FFAR2-deficient mice. Depletion of neutrophils blocked the progression of colon tumors. In addition, FFAR2 is required for butyrate to suppress HDAC expression and hypermethylation of inflammation suppressors. Therefore, our results suggest that FFAR2 is an epigenetic tumor suppressor that acts at multiple stages of colon carcinogenesis. This article is protected by copyright. All rights reserved.

http://ift.tt/2FtjQxb

Lifetime and baseline alcohol intakes and risk of pancreatic cancer in the European Prospective Investigation into Cancer and Nutrition study

Abstract

Recent evidence suggested a weak relationship between alcohol consumption and pancreatic cancer (PC) risk. In this study, the association between lifetime and baseline alcohol intakes and the risk of PC was evaluated, including the type of alcoholic beverages and potential interaction with smoking. Within the European Prospective Investigation into Cancer and Nutrition (EPIC) study, 1,283 incident PC (57% women) were diagnosed from 476,106 cancer-free participants, followed up for 14 years. Amounts of lifetime and baseline alcohol were estimated through lifestyle and dietary questionnaires, respectively. Cox proportional hazard models with age as primary time variable were used to estimate PC hazard ratios (HR) and their 95% confidence interval (CI). Alcohol intake was positively associated with PC risk in men. Associations were mainly driven by extreme alcohol levels, with HRs comparing heavy drinkers (>60 g/day) to the reference category (0.1-4.9 g/day) equal to 1.77 (95% CI: 1.06, 2.95) and 1.63 (95% CI: 1.16, 2.29) for lifetime and baseline alcohol, respectively. Baseline alcohol intakes from beer (>40 g/day) and spirits/liquors (>10 g/day) showed HRs equal to 1.58 (95% CI: 1.07, 2.34) and 1.41 (95% CI: 1.03, 1.94), respectively, compared to the reference category (0.1-2.9 g/day). In women, HR estimates did not reach statistically significance. The alcohol and PC risk association was not modified by smoking status. Findings from a large prospective study suggest that baseline and lifetime alcohol intakes were positively associated with PC risk, with more apparent risk estimates for beer and spirits/liquors than wine intake. This article is protected by copyright. All rights reserved.

http://ift.tt/2Gcu1rf

MRI background parenchymal enhancement, breast density and serum hormones in postmenopausal women

ABSTRACT

Background parenchymal enhancement (BPE) is the degree to which normal breast tissue enhances on contrast-enhanced magnetic resonance imaging (MRI). MRI-density is a volumetric measure of breast density that is highly correlated with mammographic density, an established breast cancer risk factor. Endogenous estrogen concentrations are positively associated with postmenopausal breast cancer risk and BPE has been shown to be sensitive to hormonal exposures. The objective of this study was to examine the relationship between BPE and MRI-density and serum hormone concentrations in postmenopausal women.

This was a study of cancer-free postmenopausal women undergoing contrast-enhanced breast MRI (N=118). At the time of MRI all women completed a self-administered questionnaire and blood samples were collected for hormone analyses. Serum concentrations of estrone (E1), estradiol (E2) and bioavailable E2 were examined by category of BPE and MRI-density.

Compared to women with 'minimal' BPE, those who had 'marked' BPE had significantly higher serum concentrations of E1, E2 and bioavailable E2 (90% increase, p_trend across all categories=0.001; 150% increase, p_trend=0.001; and 158% increase, p_trend=0.001 respectively). These associations were only affected to a minor extent by adjustment for BMI and other variables. After adjustment for BMI, no significant associations between MRI-density and serum E1, E2 and bioavailable E2 were observed.

Serum estrogen concentrations were significantly positively associated with BPE. This study provides further evidence of the hormone-sensitive nature of BPE, indicating a potential role for BPE as an imaging marker of endogenous and exogenous hormonal exposures in the breast. This article is protected by copyright. All rights reserved.

http://ift.tt/2FtjKpj

Caveolin-1, cancer and therapy resistance

Abstract

Resistance of solid tumors to chemo- and radiotherapy remains a major obstacle in anti-cancer treatment. Herein, the membrane protein Caveolin-1 (CAV1) came into focus as it is highly expressed in many tumors and high CAV1 levels were correlated with tumor progression, invasion and metastasis, and thus, a worse clinical outcome. Increasing evidence further indicates that the heterogeneous tumor microenvironment, also known as the tumor stroma, contributes to therapy resistance resulting in poor clinical outcome. Again, CAV1 seems to play an important role in modulating tumor host interactions by promoting tumor growth, metastasis, therapy resistance and cell survival. However, the mechanisms driving stroma-mediated tumor growth and radiation resistance remain to be clarified. Understanding these interactions and thus, targeting CAV1 may offer a novel strategy for preventing cancer therapy resistance and improving clinical outcomes. In this review, we will summarize the resistance-promoting effects of CAV1 in tumors, and emphasize its role in the tumor-stroma communication as well as the resulting malignant phenotype of epithelial tumors. This article is protected by copyright. All rights reserved.

http://ift.tt/2FoS2Ot

Clinical Evaluation of Human Papillomavirus 16/18 Oncoprotein Test for Cervical Cancer Screening and HPV Positive Women Triage

Abstract

HPV-16 and -18 account for about 80% of cervical cancers. We evaluated the performance of HPV-16/18 oncoprotein to predict precancer and cancer in corresponding tissue biopsy specimens. 1008 women attending cervical cancer screening program and 638 women referred to colposcopy with biopsy-confirmed cervical intraepithelial neoplasia grade 2 or worse (CIN2+) from 4 hospitals were recruited (1646 in total). All women were tested OncoE6 (AVC), Liquid Based Cytology (Hologic) and cobas HPV test (Roche). Colposcopy was performed on women with any abnormal results. The final diagnoses were based on a consensus panel review of the histology. There were 919 normal, 69 CIN1, 53 CIN2, 91 CIN3,474 squamous cell carcinoma(SCC) and 40 adenocarcinoma (ADC) cases, the prevalence of OncoE6 was 1.7%, 10.1%, 13.2%, 44.0%, 80.4% and 65.0%, respectively. The percent positive for cobas was higher than that of OncoE6 in detection of HPV16/18 in entire population (P<0.001). However, the disparity of positive rate between these two tests became tiny among cervical cancer patients (CIN2: 26.4% vs. 13.2%, CIN3: 73.6% vs. 44.0%, SCC: 84.0% vs. 80.4%, ADC: 67.5% vs. 65.0%). OncoE6 was less sensitive than cobas (73.9% versus 93.6%, P<0.001), but more specific (97.1% versus 75.4%, P<0.001) for CIN3+ in entire population; OncoE6 yielded a sensitivity of 77.7% and a specificity of 91.0% for CIN3+ among cobas positive women, which can reduce nearly half of the colposcopy referral numbers. OncoE6 can be considered as a useful tool for cervical cancer screening and a potential powerful biomarker for HPV positive triage. This article is protected by copyright. All rights reserved.

http://ift.tt/2FuosDc

SHP2 Inhibition May Resensitize NSCLC Tumors to ALK Inhibitors [Research Watch]

Targeting SHP2 suppresses ALK inhibitor resistance caused by tyrosine kinase reactivation.

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SS18-SSX Induces the Expression of Neurogenic Genes to Drive Synovial Sarcoma [Research Watch]

SS18–SSX usurps the PRC1.1 repressive complex to drive expression of a synovial sarcoma gene signature.

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DNA Damage Response Alterations Predict Responses to Anti-PD-1/PD-L1 [Research Watch]

DNA damage response alterations are linked to improved responses to anti–PD-1/PD-L1 in urothelial carcinoma.

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Engineered IL2/IL2R{beta} Pairs May Enhance the Efficacy of T-cell Therapy [Research Watch]

Orthogonal IL2/IL2Rβ pairs allow selective targeting of engineered autologously transferred T cells.

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Peli1 modulates the subcellular localization and activity of Mdmx

Mdm2 and Mdmx, both major repressors of p53 in human cancers, are predominantly localized to the nucleus and cytoplasm, respectively. The mechanism by which subcellular localization of Mdmx is regulated remains unclear. In this study, we identify the E3 ligase Peli1 as a major binding partner and regulator of Mdmx in human cells. Peli1 bound Mdmx in vitro and in vivo and promoted high levels of ubiquitination of Mdmx. Peli1-mediated ubiquitination was degradation-independent, promoting cytoplasmic localization of Mdmx which in turn resulted in p53 activation. Consistent with this, knockdown or knockout Peli1 in human cancer cells induced nuclear localization of Mdmx and suppressed p53 activity. Myc-induced tumorigenesis was accelerated in Peli1-null mice and associated with downregulation of p53 function. Clinical samples of human cutaneous melanoma had decreased Peli1 expression which was associated with poor overall survival. Together, these results demonstrate that Peli1 acts as a critical factor for the Mdmx-p53 axis by modulating the subcellular localization and activity of Mdmx, thus revealing a novel mechanism of Mdmx deregulation in human cancers.

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Tumor-derived TGF-{beta} alters the ability of plasmacytoid dendritic cells to respond to innate immune signaling

A growing number of observations has suggested that plasmacytoid dendritic cells (pDC) play a critical role in tumor biology. In patients, infiltration of tumors by pDC generally correlates with a poor prognosis, suggesting that pDC may play an important role in the host-tumor relationship. Here we analyze the influence of pDC in solid tumor development using two different tumor models: TC-1 and B16-OVA. Phenotypic and functional gene profiling analysis of tumor-associated pDC showed that the tumor microenvironment affected their activation status and ability to produce cytokines and chemokines. In addition, tumor cells secreted factors that inhibit the ability of pDC to produce type I IFN. Among the various cytokines and chemokines produced by the tumor cells, we demonstrate that TGF-β is the main factor responsible for this inhibition. Using a mouse model deficient for pDCs, we also show that pDCs promote TC-1 tumor growth and that NK cells and regulatory T cells are involved in the protumoral effect of pDCs. Overall, our results evidence the crosstalk among pDCs, NK and regulatory T cells in the promotion of tumor growth and their role in the development of anti-tumor immune responses.

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Peli1 modulates the subcellular localization and activity of Mdmx

Mdm2 and Mdmx, both major repressors of p53 in human cancers, are predominantly localized to the nucleus and cytoplasm, respectively. The mechanism by which subcellular localization of Mdmx is regulated remains unclear. In this study, we identify the E3 ligase Peli1 as a major binding partner and regulator of Mdmx in human cells. Peli1 bound Mdmx in vitro and in vivo and promoted high levels of ubiquitination of Mdmx. Peli1-mediated ubiquitination was degradation-independent, promoting cytoplasmic localization of Mdmx which in turn resulted in p53 activation. Consistent with this, knockdown or knockout Peli1 in human cancer cells induced nuclear localization of Mdmx and suppressed p53 activity. Myc-induced tumorigenesis was accelerated in Peli1-null mice and associated with downregulation of p53 function. Clinical samples of human cutaneous melanoma had decreased Peli1 expression which was associated with poor overall survival. Together, these results demonstrate that Peli1 acts as a critical factor for the Mdmx-p53 axis by modulating the subcellular localization and activity of Mdmx, thus revealing a novel mechanism of Mdmx deregulation in human cancers.

http://ift.tt/2tsmSA4

Tumor-derived TGF-{beta} alters the ability of plasmacytoid dendritic cells to respond to innate immune signaling

A growing number of observations has suggested that plasmacytoid dendritic cells (pDC) play a critical role in tumor biology. In patients, infiltration of tumors by pDC generally correlates with a poor prognosis, suggesting that pDC may play an important role in the host-tumor relationship. Here we analyze the influence of pDC in solid tumor development using two different tumor models: TC-1 and B16-OVA. Phenotypic and functional gene profiling analysis of tumor-associated pDC showed that the tumor microenvironment affected their activation status and ability to produce cytokines and chemokines. In addition, tumor cells secreted factors that inhibit the ability of pDC to produce type I IFN. Among the various cytokines and chemokines produced by the tumor cells, we demonstrate that TGF-β is the main factor responsible for this inhibition. Using a mouse model deficient for pDCs, we also show that pDCs promote TC-1 tumor growth and that NK cells and regulatory T cells are involved in the protumoral effect of pDCs. Overall, our results evidence the crosstalk among pDCs, NK and regulatory T cells in the promotion of tumor growth and their role in the development of anti-tumor immune responses.

http://ift.tt/2oX3w1E

Goldilocks Dosing of TKIs: A Dose that is Just Right Leads to Optimal Outcomes

Higher concentrations of TKIs such as pazopanib are associated with improved outcomes in advanced RCC. A phase 3 trial failed to show disease-free survival benefit to pazopanib in the adjuvant setting, but improved DFS was seen in patients with higher Ctrough levels, supporting adequate drug exposure for optimal clinical outcome.

http://ift.tt/2FrxgOt

U.S. Food and Drug Administration Approval: Neratinib for the Extended Adjuvant Treatment of Early Stage HER2-Positive Breast Cancer

On July 17, 2017, the Food and Drug Administration (FDA) approved neratinib (NERLYNX, Puma Biotechnology, Inc) for the extended adjuvant treatment of adult patients with early-stage HER2-overexpressed/amplified breast cancer, to follow adjuvant trastuzumab-based therapy. Approval was based on data from ExteNET, a randomized, double-blind, placebo-controlled multicenter trial. Women with early-stage HER2-positive breast cancer and within two years of completing adjuvant trastuzumab were randomized to neratinib (n=1420) or placebo (n=1420) for one year. The primary endpoint was invasive disease-free survival (iDFS) defined as the time between randomization date to first occurrence of invasive recurrence (local/regional, ipsilateral or contralateral breast cancer), distance recurrence, or death from any cause, with two years and 28 days of follow up. The trial showed a statistically significant treatment effect favoring neratinib with a stratified hazard ratio of 0.66 (95% CI: 0.49, 0.90, p=0.008). Estimated iDFS rate at 2-years was 94.2% (95% CI: 92.6%, 95.4%) in patients treated with neratinib vs. 91.9% (95% CI: 90.2%, 93.2%) in those receiving placebo. Diarrhea was the most common adverse event (AE) with a 40% incidence of Grade 3 or 4 diarrhea and represents the most common AE leading to treatment discontinuation. Other frequent AEs (>10% incidence) were nausea, abdominal pain, fatigue, vomiting, rash, stomatitis, decreased appetite, and muscle spasms. Other than diarrhea, neratinib is associated with a low incidence of severe AEs; toxicities are generally reversible and manageable with dose interruptions, dose reductions, and/or standard medical care. This article summarizes FDA decision-making and data supporting the neratinib approval.

http://ift.tt/2Fy3uUc

Goldilocks Dosing of TKIs: A Dose that is Just Right Leads to Optimal Outcomes

Higher concentrations of TKIs such as pazopanib are associated with improved outcomes in advanced RCC. A phase 3 trial failed to show disease-free survival benefit to pazopanib in the adjuvant setting, but improved DFS was seen in patients with higher Ctrough levels, supporting adequate drug exposure for optimal clinical outcome.

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U.S. Food and Drug Administration Approval: Neratinib for the Extended Adjuvant Treatment of Early Stage HER2-Positive Breast Cancer

On July 17, 2017, the Food and Drug Administration (FDA) approved neratinib (NERLYNX, Puma Biotechnology, Inc) for the extended adjuvant treatment of adult patients with early-stage HER2-overexpressed/amplified breast cancer, to follow adjuvant trastuzumab-based therapy. Approval was based on data from ExteNET, a randomized, double-blind, placebo-controlled multicenter trial. Women with early-stage HER2-positive breast cancer and within two years of completing adjuvant trastuzumab were randomized to neratinib (n=1420) or placebo (n=1420) for one year. The primary endpoint was invasive disease-free survival (iDFS) defined as the time between randomization date to first occurrence of invasive recurrence (local/regional, ipsilateral or contralateral breast cancer), distance recurrence, or death from any cause, with two years and 28 days of follow up. The trial showed a statistically significant treatment effect favoring neratinib with a stratified hazard ratio of 0.66 (95% CI: 0.49, 0.90, p=0.008). Estimated iDFS rate at 2-years was 94.2% (95% CI: 92.6%, 95.4%) in patients treated with neratinib vs. 91.9% (95% CI: 90.2%, 93.2%) in those receiving placebo. Diarrhea was the most common adverse event (AE) with a 40% incidence of Grade 3 or 4 diarrhea and represents the most common AE leading to treatment discontinuation. Other frequent AEs (>10% incidence) were nausea, abdominal pain, fatigue, vomiting, rash, stomatitis, decreased appetite, and muscle spasms. Other than diarrhea, neratinib is associated with a low incidence of severe AEs; toxicities are generally reversible and manageable with dose interruptions, dose reductions, and/or standard medical care. This article summarizes FDA decision-making and data supporting the neratinib approval.

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Managing Your Anesthesiology Practice for the Future

Publication date: Available online 9 March 2018
Source:Anesthesiology Clinics
Author(s): Amr E. Abouleish, Stanley W. Stead




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Case-series of paraneoplastic Cushing syndrome in small-cell lung cancer

Summary

The objective of this study is to report three cases of paraneoplastic or ectopic Cushing syndrome, which is a rare phenomenon of the adrenocorticotropic hormone (ACTH)-dependent Cushing syndrome. Three cases are reported in respect of clinical presentation, diagnosis and treatment in addition to relevant literature review. The results showed that ectopic ACTH secretion can be associated with different types of neoplasm most common of which are bronchial carcinoid tumors, which are slow-growing, well-differentiated neoplasms with a favorable prognosis and small-cell lung cancer, which are poorly differentiated tumors with a poor outcome. The latter is present in two out of three cases and in the remaining one, primary tumor could not be localized, representing a small fraction of patients with paraneoplastic Cushing. Diagnosis is established in the setting of high clinical suspicion by documenting an elevated cortisol level, ACTH and doing dexamethasone suppression test. Treatment options include management of the primary tumor by surgery and chemotherapy and treating Cushing syndrome. Prognosis is poor in SCLC. We concluded that in front of a high clinical suspicion, ectopic Cushing syndrome diagnosis should be considered, and identification of the primary tumor is essential.

Learning points:

Learning how to suspect ectopic Cushing syndrome and confirm it among all the causes of excess cortisol.

Distinguish between occult and severe ectopic Cushing syndrome and etiology.

Providing the adequate treatment of the primary tumor as well as for the cortisol excess.

Prognosis depends on the differentiation and type of the primary malignancy.

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Case-series of paraneoplastic Cushing syndrome in small-cell lung cancer

Summary

The objective of this study is to report three cases of paraneoplastic or ectopic Cushing syndrome, which is a rare phenomenon of the adrenocorticotropic hormone (ACTH)-dependent Cushing syndrome. Three cases are reported in respect of clinical presentation, diagnosis and treatment in addition to relevant literature review. The results showed that ectopic ACTH secretion can be associated with different types of neoplasm most common of which are bronchial carcinoid tumors, which are slow-growing, well-differentiated neoplasms with a favorable prognosis and small-cell lung cancer, which are poorly differentiated tumors with a poor outcome. The latter is present in two out of three cases and in the remaining one, primary tumor could not be localized, representing a small fraction of patients with paraneoplastic Cushing. Diagnosis is established in the setting of high clinical suspicion by documenting an elevated cortisol level, ACTH and doing dexamethasone suppression test. Treatment options include management of the primary tumor by surgery and chemotherapy and treating Cushing syndrome. Prognosis is poor in SCLC. We concluded that in front of a high clinical suspicion, ectopic Cushing syndrome diagnosis should be considered, and identification of the primary tumor is essential.

Learning points:

Learning how to suspect ectopic Cushing syndrome and confirm it among all the causes of excess cortisol.

Distinguish between occult and severe ectopic Cushing syndrome and etiology.

Providing the adequate treatment of the primary tumor as well as for the cortisol excess.

Prognosis depends on the differentiation and type of the primary malignancy.

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Impact of rectal distension on prostate CBCT-based positioning assessed with 6 degrees of freedom couch

Publication date: Available online 9 March 2018
Source:Practical Radiation Oncology
Author(s): Julien Charret, Julia Salleron, Magali Quivrin, Frédéric Mazoyer, Paul Lesueur, Etienne Martin, Didier Peiffert, Gilles Créhange
IntroductionProstate requires a daily correction of its 3D position in relation with rectal distension. In this study, we sought to determine whether rectal distension with respect to the rectal behavior might have an impact on prostate translations and/or rotations during prostate IGRT using a 6 degrees of freedom (DOF) couch.MethodsWe reviewed the data from 39 patients with localized prostate cancer patients treated with protracted external radiotherapy using a 6 DOF couch. Before each fraction, a kV-CBCT was performed. The automatic fusion algorithm was set to fuse on soft tissue and it allowed correction for translations in three dimensions and rotations in the longitudinal axis ("roll") and lateral axis ("pitch"). After contouring the rectum on each kV-CBCT, we determined the Cross Sectional Area (CSA) and relative CSA (CSArel) by dividing with the CSA of planning CT. The standard deviation of CSArel per patient was used to classify the patients in two groups: patients with a stable rectum and patients with an unstable rectum. The CSArel was compared between these two groups with a linear mixed model with group as fixed effect and patient as random effect.ResultsSix hundred and sixteen kV-CBCT were analyzed and 2 subgroups of patients could be defined a posteriori: 19 patients had a stable rectum: mean CSArel (1.06±0.08). The other 20 patients had an unstable rectum: mean CSArel (1.43±0.08). The average pitch in the group with a stable rectum was 0.36° (+/-0.21) versus 0.40° (+/-0.20) (p=0.898). The pitch was not correlated with the CSA rel (p=-0.065, r=0.119). The average roll in the group with a stable rectum was 0.27° (+/-0.16) versus 0.05° (+/-0.16) (p=0.137). The roll was not correlated with the CSA (p=0.094, r=0.068). The average CSArel was higher (p=0.0013) and more variable (p=0.035) in the unstable group.ConclusionRectal distension had neither impact on the pitch nor on the roll, which suggest that a 6 DOF couch has little interest in daily practice for prostate IGRT.



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Impact of rectal distension on prostate CBCT-based positioning assessed with 6 degrees of freedom couch

Publication date: Available online 9 March 2018
Source:Practical Radiation Oncology
Author(s): Julien Charret, Julia Salleron, Magali Quivrin, Frédéric Mazoyer, Paul Lesueur, Etienne Martin, Didier Peiffert, Gilles Créhange
IntroductionProstate requires a daily correction of its 3D position in relation with rectal distension. In this study, we sought to determine whether rectal distension with respect to the rectal behavior might have an impact on prostate translations and/or rotations during prostate IGRT using a 6 degrees of freedom (DOF) couch.MethodsWe reviewed the data from 39 patients with localized prostate cancer patients treated with protracted external radiotherapy using a 6 DOF couch. Before each fraction, a kV-CBCT was performed. The automatic fusion algorithm was set to fuse on soft tissue and it allowed correction for translations in three dimensions and rotations in the longitudinal axis ("roll") and lateral axis ("pitch"). After contouring the rectum on each kV-CBCT, we determined the Cross Sectional Area (CSA) and relative CSA (CSArel) by dividing with the CSA of planning CT. The standard deviation of CSArel per patient was used to classify the patients in two groups: patients with a stable rectum and patients with an unstable rectum. The CSArel was compared between these two groups with a linear mixed model with group as fixed effect and patient as random effect.ResultsSix hundred and sixteen kV-CBCT were analyzed and 2 subgroups of patients could be defined a posteriori: 19 patients had a stable rectum: mean CSArel (1.06±0.08). The other 20 patients had an unstable rectum: mean CSArel (1.43±0.08). The average pitch in the group with a stable rectum was 0.36° (+/-0.21) versus 0.40° (+/-0.20) (p=0.898). The pitch was not correlated with the CSA rel (p=-0.065, r=0.119). The average roll in the group with a stable rectum was 0.27° (+/-0.16) versus 0.05° (+/-0.16) (p=0.137). The roll was not correlated with the CSA (p=0.094, r=0.068). The average CSArel was higher (p=0.0013) and more variable (p=0.035) in the unstable group.ConclusionRectal distension had neither impact on the pitch nor on the roll, which suggest that a 6 DOF couch has little interest in daily practice for prostate IGRT.



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High lymphocyte count during neoadjuvant chemoradiotherapy is associated with improved pathologic complete response in esophageal cancer

Neoadjuvant chemoradiation (nCRT) can reduce tumor infiltrating lymphocytes. We examined absolute lymphocyte count (ALC) nadir during nCRT for esophageal cancer (EC) and pathologic complete response (pCR).

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Inter-institutional analysis demonstrates the importance of lower than previously anticipated dose regions to prevent late rectal bleeding following prostate radiotherapy

To investigate whether inter-institutional cohort analysis uncovers more reliable dose–response relationships exemplified for late rectal bleeding (LRB) following prostate radiotherapy.

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Letter to the Editor: Who's Watching the Kids?

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Genomic Testing in Lung Cancer: Past, Present, and Future

Precision medicine commonly refers to the selection of the most effective cancer treatments based on the presence of specific biomarkers (eg, genomic abnormalities) in a patient's tumor. Therefore, genomic testing is used to identify patients whose tumors harbor the vulnerability that is sensitive to corresponding targeted therapies. This approach allows for the selection of patients who have the greatest chance of deriving benefit from the treatments, reduces toxicity, and significantly improves outcome; precision medicine is recommended for advanced non–small cell lung cancer. This article reviews the evolution of genomic testing in lung cancer, from its development, including first success and failures, to its current use in the care of patients with lung cancer, and addresses future considerations, such as the expected increase of targetable abnormalities, the need to follow the genomic profile over time, and tumor heterogeneity.

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Oncology Research Program

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Trends in Outcomes of Patients With Metastatic Cancer Undergoing Intubation and Mechanical Ventilation: Results of the National Hospital Discharge Survey

Background: There has been an overall decline in intensive care unit mortality over the past 2 decades, including in patients undergoing intubation and mechanical ventilation (MV). Whether this decline extends to patients with metastatic cancer remains unknown. We analyzed the outcomes of patients with metastatic cancer undergoing intubation/MV using the National Hospital Discharge Survey (NHDS) database from 2001 to 2010. Methods: Diagnosis and procedure codes were used to identify patients with metastatic cancer who underwent intubation/MV. Demographics, diagnoses, length of stay (LOS), and discharge information were abstracted. Multivariate linear and logistic regression models with weighted analysis were conducted to study trends in outcomes. Results: During the 10-year study period, 200,350 patients with metastatic cancer and who underwent intubation/MV were identified; the mean age was 65.3 years and 46.2% were men. There was an increase in the total number of patients with metastatic cancer who underwent intubation/MV during the study period, from 36,881 in 2001–2002 to 51,003 in 2009–2010 (P<.001). The overall inpatient mortality rate was 57.3%, discharge to a care facility (DTCF) rate was 40.9% among patients alive at discharge, and mean LOS was 11.1 days. No significant trends were seen in rates of mortality, DTCF, or LOS from 2001 to 2010. Conclusions: In this national database, there was an increase in the number of patients with metastatic cancer who underwent intubation/MV. These patients had high rates of inpatient mortality and DTCF, which did not improve during the study period. Therefore, novel solutions are required to improve outcomes for these patients.

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Molecular Diagnostics: Another Battle Brewing

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Patient-Reported Distress in Myelodysplastic Syndromes and Its Association With Clinical Outcomes: A Retrospective Cohort Study

Background: NCCN defines distress as a multifactorial, unpleasant emotional experience of a psychological nature that may interfere with patients' ability to cope with cancer symptoms and treatment. Patients with myelodysplastic syndromes (MDS) are at risk for distress due to the largely incurable nature of this hematopoietic malignancy and its symptom burden, yet associations with clinical outcomes are unknown. Methods: We retrospectively reviewed patient-reported distress data from adult ambulatory patients with MDS visiting a single, tertiary care medical center from July 2013 to September 2015. Demographic, diagnostic, treatment, and comorbidity information were abstracted from records along with NCCN Distress Thermometer (DT) and Problem List (PL) scores. Survival was analyzed using the Kaplan-Meier method and Cox proportional hazards regression. Results: We abstracted 376 DT scores (median, 1; range, 0–10) from 606 visits and 110 patients (median, 2 DT scores/patient; range, 1–16). NCCN Guidelines suggest that patients with DT scores ≥4 should be evaluated for referral to specialty services to address unmet needs. A total of 54 patients (49%) had at least 1 DT score ≥4 and 20 (18%) had 2 or more DT scores ≥4; 98 patients (89.1%) reported 1,379 problems during 23,613 person-days of follow-up (median, 4 problems/patient/visit; range, 1–23). The 5 most frequently reported problems were fatigue (181 times; 78 patients), pain (95 times; 46 patients), worry (80 times; 45 patients), sleep (78 times; 41 patients), and tingling hands/feet (68 times; 33 patients). After adjustment for risk stratification at diagnosis, a single point increase on the DT was associated with an increased risk of death (hazard ratio, 1.18; 95% CI, 1.01–1.36). Conclusions: Patients with MDS experience a high burden of distress, and patient-reported distress is associated with clinical outcomes. Distress should be further studied as a prognostic variable and a marker of unmet needs in MDS.

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Community Oncologists' Decision-Making for Treatment of Older Patients With Cancer

Background: This study's objectives were to describe community oncologists' beliefs about and confidence with geriatric care and to determine whether geriatric-relevant information influences cancer treatment decisions. Methods: Community oncologists were recruited to participate in 2 multisite geriatric oncology trials. Participants shared their beliefs about and confidence in caring for older adults. They were also asked to make a first-line chemotherapy recommendation (combination vs single-agent vs no chemotherapy) for a hypothetical vignette of an older patient with advanced pancreatic cancer. Each oncologist received one randomly chosen vignette that varied on 3 variables: age (72/84 years), impaired function (yes/no), and cognitive impairment (yes/no). Other patient characteristics were held constant. Logistic regression models were used to identify associations between oncologist/vignette-patient characteristics and treatment decisions. Results: Oncologist response rate was 61% (n=305/498). Most oncologists agreed that "the care of older adults with cancer needs to be improved" (89%) and that "geriatrics training is essential" (72%). However, <25% were "very confident" in recognizing dementia or conducting a fall risk or functional assessment, and only 23% reported using the geriatric assessment in clinic. Each randomly varied patient characteristic was independently associated with the decision to treat: younger age (adjusted odds ratio [aOR], 5.01; 95% CI, 2.73–9.20), normal cognition (aOR, 5.42; 95% CI, 3.01–9.76), and being functionally intact (aOR, 3.85; 95% CI, 2.12–7.00). Accounting for all vignettes across all scenarios, 161 oncologists (52%) said they would offer chemotherapy. All variables were independently associated with prescribing single-agent over combination chemotherapy (older age: aOR, 3.22; 95% CI 1.43–7.25, impaired cognition: aOR, 3.13; 95% CI, 1.36–7.20, impaired function: aOR, 2.48; 95% CI, 1.12–5.72). Oncologists' characteristics were not associated with decisions about providing chemotherapy. Conclusion: Geriatric-relevant information, when available, strongly influences community oncologists' treatment decisions.

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Letter to the Editor: No Evidence to Promote Interim FDG-PET Adapted Therapy in the NCCN Guidelines for Hodgkin Lymphoma

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NCCN News

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Idelalisib and Rituximab in 17p Deletion-Positive Splenic Marginal Zone Lymphoma

Splenic marginal zone lymphoma (SMZL) is a rare indolent B-cell malignancy involving the spleen and bone marrow. Various cytogenetic abnormalities with prognostic value have been identified in SMZL. Complexity of karyotype, 14q aberrations, and TP53 deletions have been found to be poor prognostic indicators. We report an unusual case of SMZL with a complex karyotype including 17p deletion, primarily refractory to 2 chemoimmunotherapy regimens, that responded well to treatment with phosphatidylinositol-3-kinase delta (PI3K) inhibitors idelalisib and rituximab.

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Adherence to the World Cancer Research Fund/American Institute for Cancer Research Guideline Is Associated With Better Health-Related Quality of Life Among Chinese Patients With Breast Cancer

Background: The 2007 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) guideline provides recommendations for cancer prevention among cancer survivors. Limited data have examined whether guideline adherence is related to health-related quality of life (HRQoL) among Chinese patients with breast cancer. Methods: An ongoing prospective cohort study involving 1,462 Chinese women with early-stage breast cancer assessed exercise, diet, and body mass index (BMI) at baseline and at 18-months follow-up after diagnosis. Each assessment recorded patient habits within the previous 12 months. HRQoL was evaluated by the EORTC Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30). We first compared the level of adherence to WCRF/AICR recommendations before and after cancer diagnosis. We then examined whether adherence to these recommendations after diagnosis was associated with HRQoL at 18 months. Results: The mean adherence score significantly increased from baseline (3.2; SD, 1.1) to 18-month follow-up (3.9; SD, 1.1; P<.001). Overall, increasing adherence to the WCRF/AICR guideline was associated with higher scores of global health status/quality of life (QoL; P_trend=.011), physical (P_trend<.001) and role functioning (P_trend=.024), and lower scores for fatigue (P_trend=.016), nausea and vomiting (P_trend<.001), pain (P_trend=.004), dyspnea (P_trend=.030), loss of appetite (P_trend=.007), and diarrhea (P_trend=.020). Patients with cancer who met the BMI recommendation had higher scores for physical functioning (P=.001) and lower scores for fatigue (P=.024), pain (P<.001), and dyspnea (P=.045). Adherence to physical activity recommendation was associated with better scores of global health status/QoL (P<.001), physical functioning (P=.003), fatigue (P=.002), pain (P=.018), and dyspnea (P=.021). Higher adherence to diet recommendation was associated with lower scores of nausea and vomiting (P_trend=.005), loss of appetite (P_trend=.026), constipation (P_trend=.040), and diarrhea (P_trend=.031). Conclusions: Chinese patients with breast cancer made positive lifestyle changes early after cancer diagnosis. Increased adherence to WCRF/AICR recommendations after cancer diagnosis may improve HRQoL. Our data suggest that Chinese patients with breast cancer should follow the WCRF/AICR guideline to improve overall well-being.

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A Novel PRKAR1B-BRAF Fusion in Gastrointestinal Stromal Tumor Guides Adjuvant Treatment Decision-Making During Pregnancy

Gastrointestinal stromal tumors (GISTs) are rare in pregnancy, with only 11 reported cases. Adjuvant imatinib therapy, which targets the most common driver mutations in GIST (KIT and PDGFRA), is recommended for patients with high-risk GIST, but it has known teratogenicity in the first trimester. A 34-year-old G3P2 woman underwent exploratory laparotomy at 16 weeks' gestation for a presumed adnexal mass. Surgical findings included normal adnexa and a 14-cm solid small bowel mass. The mass was resected en bloc with a segment of jejunum followed by a primary anastomosis. Histopathology and genomic analyses demonstrated a GIST with high-risk features but lack of KIT/PDGFRA mutations and identified the presence of a previously unreported, pathogenic PRKAR1B-BRAF gene fusion. Given her tumor profile, adjuvant therapy with imatinib was not recommended. GIST is rare in pregnancy, but can masquerade as an adnexal mass in women of childbearing age. Because neoadjuvant/adjuvant imatinib has risks of teratogenicity, tumor molecular profiling is critical as we identified a previously unreported gene fusion of PRKAR1B with BRAF that is predicted to be imatinib-resistant. In this case, testing provided the rationale for not offering adjuvant imatinib to avoid unnecessary toxicity to the patient and fetus.

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Ten-Year Trends in Antiemetic Prescribing in Patients Receiving Highly Emetogenic Chemotherapy

Purpose: Prevention of chemotherapy-induced nausea and vomiting is essential to preserve quality of life in patients with cancer receiving highly emetogenic chemotherapy (HEC). Recently, new drugs (eg, fosaprepitant, and the newer neurokinin-1 receptor antagonists [NK1RAs] rolapitant and netupitant) and updated antiemetic guidelines have emerged. However, trends in real-world antiemetic use are understudied. Methods: We identified patients treated with an initial dose of HEC (either cisplatin or doxorubicin/cyclophosphamide) from January 2006 to June 2016 using administrative claims data from a US commercial insurance database (OptumLabs). Antiemetic use was determined by identifying intravenous/oral/transdermal administration within ±1 day of the chemotherapy dose and/or prescription fill from 14 days before to 7 days after chemotherapy. We used descriptive statistics to present patient demographics, chemotherapy drugs administered, presence/absence of a central intravenous access device, and antiemetics used. Results: A total of 23,030 patients (67.3%) received doxorubicin/cyclophosphamide and 11,206 (32.7%) received cisplatin. Dexamethasone and 5-hydroxytryptamine 3 receptor antagonists (5-HT3RAs) were consistently used by 85% to 95% of patients, consistent with guideline recommendations. NK1RAs were underused early on, but use increased to approximately 80% in the most recently evaluated year. Fosaprepitant use increased precipitously starting in 2009, preceding a sharp decrease in aprepitant use beginning in 2011. Receipt of olanzapine, rolapitant, and netupitant was minimal throughout the study period. Conclusions: Dexamethasone and 5-HT3RAs were used by most patients receiving HEC, in accordance with guideline recommendations. NK1RA use was less adherent with guidelines.

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NCCN Guidelines Insights: Hodgkin Lymphoma, Version 1.2018

The NCCN Clinical Practice Guidelines in Oncology for Hodgkin Lymphoma (HL) provide recommendations for the management of adult patients with HL. The NCCN Guidelines Panel meets at least annually to review comments from reviewers within the NCCN Member Institutions, examine relevant data, and reevaluate and update the recommendations. These NCCN Guidelines Insights summarize recent updates centered on treatment considerations for relapsed/refractory classic HL.

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Breast Cancer, Version 4.2017, NCCN Clinical Practice Guidelines in Oncology

Ductal carcinoma in situ (DCIS) of the breast represents a heterogeneous group of neoplastic lesions in the breast ducts. The goal for management of DCIS is to prevent the development of invasive breast cancer. This manuscript focuses on the NCCN Guidelines Panel recommendations for the workup, primary treatment, risk reduction strategies, and surveillance specific to DCIS.

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Clinical and Genetic Risk Factors for Adverse Metabolic Outcomes in North American Testicular Cancer Survivors

Background: Testicular cancer survivors (TCS) are at significantly increased risk for cardiovascular disease (CVD), with metabolic syndrome (MetS) an established risk factor. No study has addressed clinical and genetic MetS risk factors in North American TCS. Patients and Methods: TCS were aged <55 years at diagnosis and received first-line chemotherapy. Patients underwent physical examination, and had lipid panels, testosterone, and soluble cell adhesion molecule-1 (sICAM-1) evaluated. A single nucleotide polymorphism in rs523349 (5-α-reductase gene, SRD5A2), recently implicated in MetS risk, was genotyped. Using standard criteria, MetS was defined as ≥3 of the following: hypertension, abdominal obesity, hypertriglyceridemia, decreased high-density lipoprotein (HDL) cholesterol level, and diabetes. Matched controls were derived from the National Health and Nutrition Examination Survey. Results: We evaluated 486 TCS (median age, 38.1 years). TCS had a higher prevalence of hypertension versus controls (43.2% vs 30.7%; P<.001) but were less likely to have decreased HDL levels (23.7% vs 34.8%; P<.001) or abdominal obesity (28.2% vs 40.1%; P<.001). Overall MetS frequency was similar in TCS and controls (21.0% vs 22.4%; P=.59), did not differ by treatment (P=.20), and was not related to rs523349 (P=.61). For other CVD risk factors, TCS were significantly more likely to have elevated low-density lipoprotein (LDL) cholesterol levels (17.7% vs 9.3%; P<.001), total cholesterol levels (26.3% vs 11.1%; P<.001), and body mass index ≥25 kg/m² (75.1% vs 69.1%; P=.04). On multivariate analysis, age at evaluation (P<.001), testosterone level ≤3.0 ng/mL (odds ratio [OR], 2.06; P=.005), and elevated sICAM-1 level (OR_{highest vs lowest quartile}, 3.58; P=.001) were significantly associated with MetS. Conclusions and Recommendations: Metabolic abnormalities in TCS are characterized by hypertension and increased LDL and total cholesterol levels but lower rates of decreased HDL levels and abdominal obesity, signifying possible shifts in fat distribution and fat metabolism. These changes are accompanied by hypogonadism and inflammation. TCS have a high prevalence of CVD risk factors that may not be entirely captured by standard MetS criteria. Cancer treatment–associated MetS requires further characterization.

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Geriatric Oncology Education for the Oncologist is Overdue

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Genomic Testing in Lung Cancer: Past, Present, and Future

Precision medicine commonly refers to the selection of the most effective cancer treatments based on the presence of specific biomarkers (eg, genomic abnormalities) in a patient's tumor. Therefore, genomic testing is used to identify patients whose tumors harbor the vulnerability that is sensitive to corresponding targeted therapies. This approach allows for the selection of patients who have the greatest chance of deriving benefit from the treatments, reduces toxicity, and significantly improves outcome; precision medicine is recommended for advanced non–small cell lung cancer. This article reviews the evolution of genomic testing in lung cancer, from its development, including first success and failures, to its current use in the care of patients with lung cancer, and addresses future considerations, such as the expected increase of targetable abnormalities, the need to follow the genomic profile over time, and tumor heterogeneity.

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Oncology Research Program

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Trends in Outcomes of Patients With Metastatic Cancer Undergoing Intubation and Mechanical Ventilation: Results of the National Hospital Discharge Survey

Background: There has been an overall decline in intensive care unit mortality over the past 2 decades, including in patients undergoing intubation and mechanical ventilation (MV). Whether this decline extends to patients with metastatic cancer remains unknown. We analyzed the outcomes of patients with metastatic cancer undergoing intubation/MV using the National Hospital Discharge Survey (NHDS) database from 2001 to 2010. Methods: Diagnosis and procedure codes were used to identify patients with metastatic cancer who underwent intubation/MV. Demographics, diagnoses, length of stay (LOS), and discharge information were abstracted. Multivariate linear and logistic regression models with weighted analysis were conducted to study trends in outcomes. Results: During the 10-year study period, 200,350 patients with metastatic cancer and who underwent intubation/MV were identified; the mean age was 65.3 years and 46.2% were men. There was an increase in the total number of patients with metastatic cancer who underwent intubation/MV during the study period, from 36,881 in 2001–2002 to 51,003 in 2009–2010 (P<.001). The overall inpatient mortality rate was 57.3%, discharge to a care facility (DTCF) rate was 40.9% among patients alive at discharge, and mean LOS was 11.1 days. No significant trends were seen in rates of mortality, DTCF, or LOS from 2001 to 2010. Conclusions: In this national database, there was an increase in the number of patients with metastatic cancer who underwent intubation/MV. These patients had high rates of inpatient mortality and DTCF, which did not improve during the study period. Therefore, novel solutions are required to improve outcomes for these patients.

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Molecular Diagnostics: Another Battle Brewing

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Patient-Reported Distress in Myelodysplastic Syndromes and Its Association With Clinical Outcomes: A Retrospective Cohort Study

Background: NCCN defines distress as a multifactorial, unpleasant emotional experience of a psychological nature that may interfere with patients' ability to cope with cancer symptoms and treatment. Patients with myelodysplastic syndromes (MDS) are at risk for distress due to the largely incurable nature of this hematopoietic malignancy and its symptom burden, yet associations with clinical outcomes are unknown. Methods: We retrospectively reviewed patient-reported distress data from adult ambulatory patients with MDS visiting a single, tertiary care medical center from July 2013 to September 2015. Demographic, diagnostic, treatment, and comorbidity information were abstracted from records along with NCCN Distress Thermometer (DT) and Problem List (PL) scores. Survival was analyzed using the Kaplan-Meier method and Cox proportional hazards regression. Results: We abstracted 376 DT scores (median, 1; range, 0–10) from 606 visits and 110 patients (median, 2 DT scores/patient; range, 1–16). NCCN Guidelines suggest that patients with DT scores ≥4 should be evaluated for referral to specialty services to address unmet needs. A total of 54 patients (49%) had at least 1 DT score ≥4 and 20 (18%) had 2 or more DT scores ≥4; 98 patients (89.1%) reported 1,379 problems during 23,613 person-days of follow-up (median, 4 problems/patient/visit; range, 1–23). The 5 most frequently reported problems were fatigue (181 times; 78 patients), pain (95 times; 46 patients), worry (80 times; 45 patients), sleep (78 times; 41 patients), and tingling hands/feet (68 times; 33 patients). After adjustment for risk stratification at diagnosis, a single point increase on the DT was associated with an increased risk of death (hazard ratio, 1.18; 95% CI, 1.01–1.36). Conclusions: Patients with MDS experience a high burden of distress, and patient-reported distress is associated with clinical outcomes. Distress should be further studied as a prognostic variable and a marker of unmet needs in MDS.

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Letter to the Editor: Who's Watching the Kids?

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Community Oncologists' Decision-Making for Treatment of Older Patients With Cancer

Background: This study's objectives were to describe community oncologists' beliefs about and confidence with geriatric care and to determine whether geriatric-relevant information influences cancer treatment decisions. Methods: Community oncologists were recruited to participate in 2 multisite geriatric oncology trials. Participants shared their beliefs about and confidence in caring for older adults. They were also asked to make a first-line chemotherapy recommendation (combination vs single-agent vs no chemotherapy) for a hypothetical vignette of an older patient with advanced pancreatic cancer. Each oncologist received one randomly chosen vignette that varied on 3 variables: age (72/84 years), impaired function (yes/no), and cognitive impairment (yes/no). Other patient characteristics were held constant. Logistic regression models were used to identify associations between oncologist/vignette-patient characteristics and treatment decisions. Results: Oncologist response rate was 61% (n=305/498). Most oncologists agreed that "the care of older adults with cancer needs to be improved" (89%) and that "geriatrics training is essential" (72%). However, <25% were "very confident" in recognizing dementia or conducting a fall risk or functional assessment, and only 23% reported using the geriatric assessment in clinic. Each randomly varied patient characteristic was independently associated with the decision to treat: younger age (adjusted odds ratio [aOR], 5.01; 95% CI, 2.73–9.20), normal cognition (aOR, 5.42; 95% CI, 3.01–9.76), and being functionally intact (aOR, 3.85; 95% CI, 2.12–7.00). Accounting for all vignettes across all scenarios, 161 oncologists (52%) said they would offer chemotherapy. All variables were independently associated with prescribing single-agent over combination chemotherapy (older age: aOR, 3.22; 95% CI 1.43–7.25, impaired cognition: aOR, 3.13; 95% CI, 1.36–7.20, impaired function: aOR, 2.48; 95% CI, 1.12–5.72). Oncologists' characteristics were not associated with decisions about providing chemotherapy. Conclusion: Geriatric-relevant information, when available, strongly influences community oncologists' treatment decisions.

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Letter to the Editor: No Evidence to Promote Interim FDG-PET Adapted Therapy in the NCCN Guidelines for Hodgkin Lymphoma

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NCCN News

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Idelalisib and Rituximab in 17p Deletion-Positive Splenic Marginal Zone Lymphoma

Splenic marginal zone lymphoma (SMZL) is a rare indolent B-cell malignancy involving the spleen and bone marrow. Various cytogenetic abnormalities with prognostic value have been identified in SMZL. Complexity of karyotype, 14q aberrations, and TP53 deletions have been found to be poor prognostic indicators. We report an unusual case of SMZL with a complex karyotype including 17p deletion, primarily refractory to 2 chemoimmunotherapy regimens, that responded well to treatment with phosphatidylinositol-3-kinase delta (PI3K) inhibitors idelalisib and rituximab.

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Adherence to the World Cancer Research Fund/American Institute for Cancer Research Guideline Is Associated With Better Health-Related Quality of Life Among Chinese Patients With Breast Cancer

Background: The 2007 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) guideline provides recommendations for cancer prevention among cancer survivors. Limited data have examined whether guideline adherence is related to health-related quality of life (HRQoL) among Chinese patients with breast cancer. Methods: An ongoing prospective cohort study involving 1,462 Chinese women with early-stage breast cancer assessed exercise, diet, and body mass index (BMI) at baseline and at 18-months follow-up after diagnosis. Each assessment recorded patient habits within the previous 12 months. HRQoL was evaluated by the EORTC Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30). We first compared the level of adherence to WCRF/AICR recommendations before and after cancer diagnosis. We then examined whether adherence to these recommendations after diagnosis was associated with HRQoL at 18 months. Results: The mean adherence score significantly increased from baseline (3.2; SD, 1.1) to 18-month follow-up (3.9; SD, 1.1; P<.001). Overall, increasing adherence to the WCRF/AICR guideline was associated with higher scores of global health status/quality of life (QoL; P_trend=.011), physical (P_trend<.001) and role functioning (P_trend=.024), and lower scores for fatigue (P_trend=.016), nausea and vomiting (P_trend<.001), pain (P_trend=.004), dyspnea (P_trend=.030), loss of appetite (P_trend=.007), and diarrhea (P_trend=.020). Patients with cancer who met the BMI recommendation had higher scores for physical functioning (P=.001) and lower scores for fatigue (P=.024), pain (P<.001), and dyspnea (P=.045). Adherence to physical activity recommendation was associated with better scores of global health status/QoL (P<.001), physical functioning (P=.003), fatigue (P=.002), pain (P=.018), and dyspnea (P=.021). Higher adherence to diet recommendation was associated with lower scores of nausea and vomiting (P_trend=.005), loss of appetite (P_trend=.026), constipation (P_trend=.040), and diarrhea (P_trend=.031). Conclusions: Chinese patients with breast cancer made positive lifestyle changes early after cancer diagnosis. Increased adherence to WCRF/AICR recommendations after cancer diagnosis may improve HRQoL. Our data suggest that Chinese patients with breast cancer should follow the WCRF/AICR guideline to improve overall well-being.

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A Novel PRKAR1B-BRAF Fusion in Gastrointestinal Stromal Tumor Guides Adjuvant Treatment Decision-Making During Pregnancy

Gastrointestinal stromal tumors (GISTs) are rare in pregnancy, with only 11 reported cases. Adjuvant imatinib therapy, which targets the most common driver mutations in GIST (KIT and PDGFRA), is recommended for patients with high-risk GIST, but it has known teratogenicity in the first trimester. A 34-year-old G3P2 woman underwent exploratory laparotomy at 16 weeks' gestation for a presumed adnexal mass. Surgical findings included normal adnexa and a 14-cm solid small bowel mass. The mass was resected en bloc with a segment of jejunum followed by a primary anastomosis. Histopathology and genomic analyses demonstrated a GIST with high-risk features but lack of KIT/PDGFRA mutations and identified the presence of a previously unreported, pathogenic PRKAR1B-BRAF gene fusion. Given her tumor profile, adjuvant therapy with imatinib was not recommended. GIST is rare in pregnancy, but can masquerade as an adnexal mass in women of childbearing age. Because neoadjuvant/adjuvant imatinib has risks of teratogenicity, tumor molecular profiling is critical as we identified a previously unreported gene fusion of PRKAR1B with BRAF that is predicted to be imatinib-resistant. In this case, testing provided the rationale for not offering adjuvant imatinib to avoid unnecessary toxicity to the patient and fetus.

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Ten-Year Trends in Antiemetic Prescribing in Patients Receiving Highly Emetogenic Chemotherapy

Purpose: Prevention of chemotherapy-induced nausea and vomiting is essential to preserve quality of life in patients with cancer receiving highly emetogenic chemotherapy (HEC). Recently, new drugs (eg, fosaprepitant, and the newer neurokinin-1 receptor antagonists [NK1RAs] rolapitant and netupitant) and updated antiemetic guidelines have emerged. However, trends in real-world antiemetic use are understudied. Methods: We identified patients treated with an initial dose of HEC (either cisplatin or doxorubicin/cyclophosphamide) from January 2006 to June 2016 using administrative claims data from a US commercial insurance database (OptumLabs). Antiemetic use was determined by identifying intravenous/oral/transdermal administration within ±1 day of the chemotherapy dose and/or prescription fill from 14 days before to 7 days after chemotherapy. We used descriptive statistics to present patient demographics, chemotherapy drugs administered, presence/absence of a central intravenous access device, and antiemetics used. Results: A total of 23,030 patients (67.3%) received doxorubicin/cyclophosphamide and 11,206 (32.7%) received cisplatin. Dexamethasone and 5-hydroxytryptamine 3 receptor antagonists (5-HT3RAs) were consistently used by 85% to 95% of patients, consistent with guideline recommendations. NK1RAs were underused early on, but use increased to approximately 80% in the most recently evaluated year. Fosaprepitant use increased precipitously starting in 2009, preceding a sharp decrease in aprepitant use beginning in 2011. Receipt of olanzapine, rolapitant, and netupitant was minimal throughout the study period. Conclusions: Dexamethasone and 5-HT3RAs were used by most patients receiving HEC, in accordance with guideline recommendations. NK1RA use was less adherent with guidelines.

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NCCN Guidelines Insights: Hodgkin Lymphoma, Version 1.2018

The NCCN Clinical Practice Guidelines in Oncology for Hodgkin Lymphoma (HL) provide recommendations for the management of adult patients with HL. The NCCN Guidelines Panel meets at least annually to review comments from reviewers within the NCCN Member Institutions, examine relevant data, and reevaluate and update the recommendations. These NCCN Guidelines Insights summarize recent updates centered on treatment considerations for relapsed/refractory classic HL.

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Breast Cancer, Version 4.2017, NCCN Clinical Practice Guidelines in Oncology

Ductal carcinoma in situ (DCIS) of the breast represents a heterogeneous group of neoplastic lesions in the breast ducts. The goal for management of DCIS is to prevent the development of invasive breast cancer. This manuscript focuses on the NCCN Guidelines Panel recommendations for the workup, primary treatment, risk reduction strategies, and surveillance specific to DCIS.

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Clinical and Genetic Risk Factors for Adverse Metabolic Outcomes in North American Testicular Cancer Survivors

Background: Testicular cancer survivors (TCS) are at significantly increased risk for cardiovascular disease (CVD), with metabolic syndrome (MetS) an established risk factor. No study has addressed clinical and genetic MetS risk factors in North American TCS. Patients and Methods: TCS were aged <55 years at diagnosis and received first-line chemotherapy. Patients underwent physical examination, and had lipid panels, testosterone, and soluble cell adhesion molecule-1 (sICAM-1) evaluated. A single nucleotide polymorphism in rs523349 (5-α-reductase gene, SRD5A2), recently implicated in MetS risk, was genotyped. Using standard criteria, MetS was defined as ≥3 of the following: hypertension, abdominal obesity, hypertriglyceridemia, decreased high-density lipoprotein (HDL) cholesterol level, and diabetes. Matched controls were derived from the National Health and Nutrition Examination Survey. Results: We evaluated 486 TCS (median age, 38.1 years). TCS had a higher prevalence of hypertension versus controls (43.2% vs 30.7%; P<.001) but were less likely to have decreased HDL levels (23.7% vs 34.8%; P<.001) or abdominal obesity (28.2% vs 40.1%; P<.001). Overall MetS frequency was similar in TCS and controls (21.0% vs 22.4%; P=.59), did not differ by treatment (P=.20), and was not related to rs523349 (P=.61). For other CVD risk factors, TCS were significantly more likely to have elevated low-density lipoprotein (LDL) cholesterol levels (17.7% vs 9.3%; P<.001), total cholesterol levels (26.3% vs 11.1%; P<.001), and body mass index ≥25 kg/m² (75.1% vs 69.1%; P=.04). On multivariate analysis, age at evaluation (P<.001), testosterone level ≤3.0 ng/mL (odds ratio [OR], 2.06; P=.005), and elevated sICAM-1 level (OR_{highest vs lowest quartile}, 3.58; P=.001) were significantly associated with MetS. Conclusions and Recommendations: Metabolic abnormalities in TCS are characterized by hypertension and increased LDL and total cholesterol levels but lower rates of decreased HDL levels and abdominal obesity, signifying possible shifts in fat distribution and fat metabolism. These changes are accompanied by hypogonadism and inflammation. TCS have a high prevalence of CVD risk factors that may not be entirely captured by standard MetS criteria. Cancer treatment–associated MetS requires further characterization.

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Geriatric Oncology Education for the Oncologist is Overdue

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The Effect of Message Content and Clinical Outcome on Patients' Perception of Physician Compassion: A Randomized Controlled Trial

AbstractBackground.In a previous randomized crossover study, patients perceived a physician delivering a more optimistic message (MO) as more compassionate and professional. However, the impact of the clinical outcome of the patient on patient's perception of physician's level of compassion and professionalism has not been previously studied. Our aim was to determine if the reported clinical outcome modified the patient's perception of physician compassion, professionalism, impression, and preference for physician.Materials and Methods.One hundred twenty‐eight advanced cancer patients in an outpatient Supportive Care Center were randomized to complete validated questionnaires about patients' perception of physician's level of compassion, professionalism, impression, and preference of physician for themselves and their family after watching scripted videos depicting a physician delivering an MO versus a less optimistic (LO) message followed by a clinical vignette depicting a worse outcome.Results.Median age was 61 years and 55% were female. There was no difference in compassion score after the vignette in the MO and LO groups. However, there were significantly worse overall impression and professionalism scores in both the MO and LO groups after the vignette. In the MO group, preference for the physician for themselves and their family significantly decreased after the vignette.Conclusion.Seeing a worse clinical outcome did not change the patients' appraisal of an inappropriately optimistic physician. However, it reduced the overall impression of both physicians that conveyed an MO or an LO message and it also resulted in less likelihood of choosing the MO physician for themselves and their family.Implications for Practice.The study found that a patient's perception of a physician's compassion did not change after reading a vignette describing a negative clinical outcome, regardless of whether the physician had given a more or a less optimistic message to the patient. However, the results suggested that patients perceived worse professionalism and overall physician impression scores for both more and less optimistic physicians and lower likelihood to choose the more optimistic physician for themselves and their family.

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Anti‐EGFR Therapy in Small Bowel Adenocarcinoma

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The Concept of Biosimilars: From Characterization to Evolution—A Narrative Review

AbstractBiologic agents are currently the fastest emerging segment of drug expenditure. Unlike chemically synthesized small‐molecule drugs, biologics are more complex, medicinal products produced by a living organism. They have become part of the standard of care in the treatment of a large variety of diseases, such as growth disorders, autoimmune diseases, cancer, cardiovascular illnesses, hemophilia, and rare genetic conditions, to name a few. Biosimilars, which are copies of biologics that are highly similar, were introduced in the market with an aim to offer efficacy that is not clinically different from the originator or reference product, at lower prices. We aim to clarify the concept of biosimilar, from definitions, history, market entry, challenges faced, and future evolution. For that purpose, we performed a literature search on the sites of the medicines regulatory agencies and PubMed from 1990 to 2014 with the keywords "biosimilars," "market," and "regulatory." In 2006, the first biosimilar, somatropin [rDNA origin], was marketed and led the way for biosimilar drug manufacturing. As a result, manufacturers have entered a diversified competition, facing challenges in manufacturing these complex agents, such as immunogenicity and efficiency. Biosimilars are set to evolve differently in various markets, namely the U.S., Japan, the European Union, and the "pharmerging" economies.Implications for Practice.This article highlights the importance of biosimilars, as a cost‐cutting strategy, in the delivery of state‐of‐the‐art health care in developing countries, at a fraction of what a reference biological agent would cost.

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Phase II Study of Panitumumab in RAS Wild‐Type Metastatic Adenocarcinoma of Small Bowel or Ampulla of Vater

AbstractLessons Learned. Panitumumab has no clinical activity in metastatic RAS wild‐type small bowel adenocarcinoma (SBA) and ampullary adenocarcinoma (AAC), possibly due to the foregut and midgut derivation of small bowel and ampulla.These results, along with findings from genomic characterization of SBA, suggest that SBA represents a unique intestinal malignancy and treatments should not be habitually extrapolated from colorectal cancer.Further studies evaluating the benefit of targeted therapies exclusively in SBA and AAC are warranted.Background.Given the benefit of epidermal growth factor receptor (EGFR) monoclonal antibodies in colorectal cancer (CRC), we sought to evaluate the efficacy of panitumumab in metastatic RAS wild‐type small bowel adenocarcinoma (SBA) and ampullary adenocarcinoma (AAC).Methods.We conducted a single‐center, open‐label, single‐arm, Bayesian phase II trial. The primary objective was response rate (RR). Panitumumab was administered at a dose of 6 mg/kg intravenously (IV) every 14 days.Results.Nine patients (male/female 7:2, median age: 61 years [range: 40–74], Eastern Cooperative Oncology Group [ECOG] performance status 0/1: 2/7) were enrolled from September 2013 to October 2015. One patient had AAC (pancreaticobiliary subtype) and eight patients had SBA (three duodenal, five jejunal/ileal). Acneiform rash was the most common toxicity. The study was stopped early due to futility with no responses, stable disease (SD) in two patients, and progression of disease (PD) in seven patients. Median progression‐free survival (PFS) and overall survival (OS) were 2.4 and 5.7 months, respectively. No patients had extended RAS mutations (exons 2/3/4), but two patients had BRAF G469A and one patient had PIK3CA H1074R mutations.Conclusion.Panitumumab had no clinically meaningful activity in patients with metastatic RAS wild‐type SBA and AAC. Our findings may relate to the primarily midgut and foregut derivation of the small bowel and ampulla.

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Does Chemotherapy Induce Metastases?

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Comparative Efficacy of Daratumumab Monotherapy and Pomalidomide Plus Low‐Dose Dexamethasone in the Treatment of Multiple Myeloma: A Matching Adjusted Indirect Comparison

AbstractBackground.Daratumumab (a human CD38‐directed monoclonal antibody) and pomalidomide (an immunomodulatory drug) plus dexamethasone are both relatively new treatment options for patients with heavily pretreated multiple myeloma. A matching adjusted indirect comparison (MAIC) was used to compare absolute treatment effects of daratumumab versus pomalidomide + low‐dose dexamethasone (LoDex; 40 mg) on overall survival (OS), while adjusting for differences between the trial populations.Materials and Methods.The MAIC method reduces the risk of bias associated with naïve indirect comparisons. Data from 148 patients receiving daratumumab (16 mg/kg), pooled from the GEN501 and SIRIUS studies, were compared separately with data from patients receiving pomalidomide + LoDex in the MM‐003 and STRATUS studies.Results.The MAIC‐adjusted hazard ratio (HR) for OS of daratumumab versus pomalidomide + LoDex was 0.56 (95% confidence interval [CI], 0.38–0.83; p = .0041) for MM‐003 and 0.51 (95% CI, 0.37–0.69; p < .0001) for STRATUS. The treatment benefit was even more pronounced when the daratumumab population was restricted to pomalidomide‐naïve patients (MM‐003: HR, 0.33; 95% CI, 0.17–0.66; p = .0017; STRATUS: HR, 0.41; 95% CI, 0.21–0.79; p = .0082). An additional analysis indicated a consistent trend of the OS benefit across subgroups based on M‐protein level reduction (≥50%, ≥25%, and <25%).Conclusion.The MAIC results suggest that daratumumab improves OS compared with pomalidomide + LoDex in patients with heavily pretreated multiple myeloma.Implications for Practice.This matching adjusted indirect comparison of clinical trial data from four studies analyzes the survival outcomes of patients with heavily pretreated, relapsed/refractory multiple myeloma who received either daratumumab monotherapy or pomalidomide plus low‐dose dexamethasone. Using this method, daratumumab conferred a significant overall survival benefit compared with pomalidomide plus low‐dose dexamethasone. In the absence of head‐to‐head trials, these indirect comparisons provide useful insights to clinicians and reimbursement authorities around the relative efficacy of treatments.

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Clinical Activity of Pazopanib in Patients with Advanced Desmoplastic Small Round Cell Tumor

AbstractBackground.Desmoplastic small round cell tumor (DSRCT) is an aggressive, often fatal soft tissue sarcoma that lacks an optimal salvage regimen. We retrospectively reviewed data from 29 pretreated DSRCT patients who received pazopanib at MD Anderson Cancer Center after failure of standard chemotherapies.Subjects, Materials, and Methods.Medical records of patients treated from January 2012 to December 2016 were reviewed and regression analyses were performed. Median progression‐free survival (PFS) and overall survival (OS) were estimated using the Kaplan‐Meier method and differences in survival were assessed by a log‐rank test. A landmark statistical analysis was used to assess OS at a predefined 12‐week time point following pazopanib initiation.Results.The mean age at pazopanib treatment was 27.5 years (range, 6.3–50.1 years). According to RECIST 1.1 criteria, 16 patients (55%) had stable disease, 1 patient (3%) had partial response, 1 patient (3%) had complete response, and 11 patients (38%) had progressive disease. Estimated median PFS was 5.63 months (95% confidence interval [CI]: 3.23–7.47). Median OS was 15.7 months (95% CI: 10.3–32.4). As of December 2016, 11 patients (38%) were still alive, with a median follow‐up time of 16.8 (range 3.8–30.1) months. Doses between 400 and 800 mg were included. Pazopanib was well tolerated and 23 (79%) of the patients continued it until progression or death, 4 discontinued because of side effects, and 2 were still on pazopanib at the time of data analysis.Conclusion.In the largest study conducted to date in DSRCT, pazopanib was well tolerated and clinically active in heavily pretreated patients who otherwise lack good treatment options.Implications for Practice.Desmoplastic small round cell tumor (DSRCT) is a rare, extremely aggressive soft tissue sarcoma subtype that most commonly occurs in adolescent and young adult males. No DSRCT‐specific therapies exist, and for lack of a better treatment approach, current therapies have relied upon U.S. Food and Drug Administration‐approved drugs like pazopanib that exhibit clinical activity in other sarcoma subtypes. This article describes the largest experience to date using pazopanib as salvage treatment in heavily pretreated DSRCT patients. Pazopanib was well tolerated and clinically active, surpassing predefined metrics proposed by the European Organization for Research and Treatment of Cancer indicative of "active" sarcoma drugs (5.63 months progression‐free survival [PSF], with 62% of the study population achieving progression‐free survival at 12 weeks).

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The Role of Rituximab in Chronic Lymphocytic Leukemia Treatment and the Potential Utility of Biosimilars

AbstractChronic lymphocytic leukemia (CLL) is managed with observation for asymptomatic or clinically silent disease; pharmacologic intervention is generally required for symptomatic patients with clinically significant adenopathy or cytopenia. In the front‐line treatment of CLL, the current standard‐of‐care includes chemotherapy in combination with an anti‐CD20 monoclonal antibody (e.g., rituximab, ofatumumab, or obinutuzumab) or ibrutinib as single agent. Despite the evolving treatment paradigm toward targeted therapy, it is likely that rituximab (plus chemotherapy), with or without targeted agents, will retain a significant role in CLL treatment. However, patents for many biologics, including rituximab, have expired or will expire in the near future. Furthermore, access to rituximab has remained challenging, particularly in countries with restricted resources. Together, these concerns have prompted the development of safe and effective rituximab biosimilars. The term "biosimilar" refers to a biologic that is highly similar to an approved reference (originator) product, notwithstanding minor differences in clinically inactive components, and for which there are no clinically meaningful differences in purity, potency, or safety. Biosimilars are developed to treat the same condition(s) using the same treatment regimens as an approved reference biologic and have the potential to increase access to more affordable treatments. We review the importance of rituximab in the current treatment of CLL, the scientific basis of its future role in combination with chemotherapy, and the role of new and emerging agents in the treatment of CLL, which could potentially be used in combination with rituximab biosimilars. We also discuss rituximab biosimilars currently in development.Implications for Practice.Front‐line treatments for chronic lymphocytic leukemia (CLL) include chemotherapy in combination with an anti‐CD20 monoclonal antibody (e.g., rituximab, ofatumumab, or obinutuzumab) or ibrutinib as single agent. Despite the evolving treatment paradigm, it is likely rituximab (plus chemotherapy) and targeted agents undergoing clinical evaluation will retain a significant role in CLL treatment. However, patents for many biologics, including rituximab, have expired or will expire in the near future and, in many regions, access to rituximab remains challenging. Together, these concerns have prompted the development of safe and effective rituximab biosimilars, with the potential to increase access to more affordable treatments.

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Revisiting Expectations in an Era of Precision Oncology

AbstractAs we enter an era of precision medicine and targeted therapies in the treatment of metastatic cancer, we face new challenges for patients and providers alike as we establish clear guidelines, regulations, and strategies for implementation. At the crux of this challenge is the fact that patients with advanced cancer may have disproportionate expectations of personal benefit when participating in clinical trials designed to generate generalizable knowledge. Patient and physician goals of treatment may not align, and reconciliation of their disparate perceptions must be addressed. However, it is particularly challenging to manage a patient's expectations when the goal of precision medicine—personalized response—exacerbates our inability to predict outcomes for any individual patient. The precision medicine informed consent process must therefore directly address this issue. We are challenged to honestly, clearly, and compassionately engage a patient population in an informed consent process that is responsive to their vulnerability, as well as ever‐evolving indications and evidence. This era requires a continual reassessment of expectations and goals from both sides of the bed.

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First Prospective Multicenter Italian Study on the Impact of the 21‐Gene Recurrence Score in Adjuvant Clinical Decisions for Patients with ER Positive/HER2 Negative Breast Cancer

AbstractBackground.The Breast DX Italy prospective study evaluated the impact of the 21‐gene recurrence score (RS) result on adjuvant treatment decisions for patients with early breast cancer.Materials and Methods.Nine centers (two Hub and seven Spoke centers of the Veneto Oncology Network) participated. Consecutive patients with estrogen receptor positive, human epidermal growth receptor negative, T1–T3, N0–N1 early breast cancer were prospectively registered; only those meeting protocol‐defined clinicopathological "intermediate risk" criteria were eligible for the RS test. Pre‐RS and post‐RS physicians' treatment recommendations and treatment actually received were collected.Results.A total of n = 124 N0 and n = 126 N1 patients underwent the RS assay. The majority had Grade 2 tumors (71%); median age was 55 years, median tumor size was 16 mm, and median Ki67 expression was 20%. Patients enrolled at Hub centers presented higher‐risk features. The distribution of RS results was <18 (60.8%), 18–30 (32.4%), and >30 (6.8%). The indication before RS was hormonal therapy (HT) alone in 52% of cases. An indication before RS of chemotherapy (CT)+HT was more frequent for patients with N1 versus N0 tumors (57% vs. 39%, p = .0035) and for patients enrolled at Hub versus Spoke centers (54% vs. 36%, p = .007).The overall rate of change in treatment decision was 16% (n = 40), mostly from CT+HT to HT (n = 30). According to nodal status, rate of change in treatment decision was 12% for the N0 cohort and 20% for the N1 cohort. The proportion of patients recommended to CT+HT was significantly reduced from before to after RS (48% to 40%, p < .0016), especially in the N1 cohort (57% to 45%, p = .0027) and at Hub centers (54% to 44%, p = .001).Conclusion.Despite frequent indication of HT before RS, the use of the RS assay further contributed to sparing CT, especially for patients with N1 tumors and at Hub centers.Implications for Practice.This study shows that, although a high proportion of patients were recommended to receive endocrine treatment alone before knowing the recurrence score (RS) assay, the RS test further contributed in sparing chemotherapy for some of these patients, especially in case of the N1 stage or for patients enrolled at referral centers. These data highlight the need for further work in collaboration with health authorities and companies in order to define strategies for the implementation of the use of RS testing in clinical practice in the Italian setting.

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