Cancer by Sfakianakis Alexandros: 04/12/18

Πέμπτη 12 Απριλίου 2018

Early Steps in the Value of Cancer Care—Many Paths Remain Unexplored

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Fertility‐Sparing Treatment of Endometrial Cancer with Initial Infiltration of Myometrium by Resectoscopic Surgery: A Pilot Study

AbstractThree women with a well‐differentiated grade 1 endometrioid adenocarcinoma of the endometrium with minimal myometrial infiltration were treated with hysteroscopic resection and hormone therapy. The presence of myometrial infiltration has often been mentioned as an exclusion criterion for conservative management in young patients because of worsening cancer prognosis. The subsequent 5‐year follow‐up and the pregnancies achieved may confirm the choice of this temporary treatment and indicate a new option for fertility‐sparing treatment in highly motivated patients.

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Bendamustine plus Rituximab Versus R‐CHOP as First‐Line Treatment for Patients with Follicular Lymphoma Grade 3A: Evidence from a Multicenter, Retrospective Study

AbstractBackground.Rituximab plus bendamustine (R‐B) has been demonstrated to improve outcomes and reduce toxicity compared with rituximab, cyclophosphamide, doxorubicin, and prednisone (R‐CHOP) in follicular lymphoma (FL). Nevertheless, in clinical practice, many centers still prefer R‐CHOP to R‐B in patients with FL grade 3A (FL3A). Therefore, we retrospectively assessed patients with FL3A treated with either R‐CHOP or R‐B in five European cancer centers and compared their outcomes.Materials and Methods.We retrospectively assessed 132 patients affected by FL grade 3A treated with either R‐B or R‐CHOP in the first line and evaluated outcome and toxicity according to the type of treatment. This study included 101 patients who were a subgroup of a previously published cohort.Results.R‐B was less toxic and achieved a similar percentage of complete remissions compared with R‐CHOP (97% vs. 96%, p = .3). During follow‐up, 10 (16%) patients relapsed after R‐B and 29 (41%) after R‐CHOP (p = .001), leading to a median progression‐free survival (PFS) of 15 versus 11.7 years, respectively (p = .03). Furthermore, R‐B overcame the negative prognostic impact of BCL2 expression (15 vs. 4.8 years; p = .001). However, median overall survival was similar between both groups (not reached for both; p = .8).Conclusion.R‐B as a first‐line treatment of FL3A is better tolerated than R‐CHOP and seems to induce more profound responses, leading to a significantly lower relapse rate and prolonged PFS. Therefore, R‐B is a valid treatment option for FL grade 3A.Implications for Practice.Rituximab plus bendamustine (R‐B) has shown to be less toxic and more effective than rituximab, cyclophosphamide, doxorubicin, and prednisone (R‐CHOP) in follicular lymphoma grade 3A. Although both regimens can induce a complete remission in >95% of patients, relapses occur more frequently after R‐CHOP than R‐B, leading to a significantly longer progression‐free survival in the latter. R‐B is also able to overcome the impact of negative prognosticators, such as BCL2 expression. However, because of the indolent course of this disease and efficient salvage treatments, overall survival was similar in both treatment groups. Therefore, R‐B is a valid treatment option in this patient setting.

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The Perils of Single‐Site Genetic Testing for Hereditary Cancer Syndromes in the Era of Next‐Generation Sequencing

AbstractA challenge in counseling patients with a family history suggesting a hereditary cancer syndrome is deciding which genetic tests or panels to order. In this article, we discuss the identification of multiple familial mutations through genetic counseling and panel testing. For patients meeting National Comprehensive Cancer Network criteria for clinical genetic testing, providers should consider expanded panels to provide a more complete assessment of one's genetic risk. The continued use of expanded panel testing in the clinical setting will help inform optimal management of cancer patients, as well as the management of their unaffected family members. The mutation discovered in this case was in the ATM gene. The clinical significance of the mutation, potential therapeutic targets, and proper clinical management are discussed.Key Points. With single‐site genetic testing, there is the potential to miss hereditary genetic syndromes that can be managed clinically.Between 4% and 6% of hereditary breast and ovarian cancer syndromes are caused by genes other than BRCA1 and BRCA2.ATM is a DNA mismatch repair gene associated with double‐stranded DNA break repair and cell cycle checkpoint arrest.The risk of developing female breast cancer by age 50 and by age 80 in ATM heterozygotes is 9% and 17%–52%, respectively.

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Perception of Curability Among Advanced Cancer Patients: An International Collaborative Study

AbstractBackground.There are limited data on illness understanding and perception of cure among advanced cancer patients around the world. The aim of the study was to determine the frequency and factors associated with inaccurate perception of curability among advanced cancer patients receiving palliative care across the globe.Materials and Methods.Secondary analysis of a study to understand the core concepts in end‐of‐life care among advanced cancer patients receiving palliative care from 11 countries across the world. Advanced cancer patients were surveyed using a Patient Illness Understanding survey and Control Preference Scale. Descriptive statistics and multicovariate logistic regression analysis were performed.Results.Fifty‐five percent (763/1,390) of patients receiving palliative care inaccurately reported that their cancer is curable. The median age was 58, 55% were female, 59% were married or had a partner, 48% were Catholic, and 35% were college educated. Sixty‐eight percent perceived that the goal of therapy was "to get rid of their cancer," and 47% perceived themselves as "seriously ill." Multicovariate logistic regression analysis shows that accurate perception of curability was associated with female gender (odds ratio [OR] 0.73, p = .027), higher education (OR 0.37, p < .0001), unemployment status (OR 0.69, p = .02), and being from France (OR 0.26, p < .0001) and South Africa (OR 0.52, p = .034); inaccurate perception of curability was associated with better Karnofsky performance status (OR 1.02 per point, p = .0005), and being from Philippines (OR 15.49, p < .0001), Jordan (OR 8.43, p < .0001), Brazil (OR 2.17, p = .0037), and India (OR 2.47, p = .039).Conclusion.Inaccurate perception of curability in advanced cancer patients is 55% and significantly differs by gender, education, performance status, employment status, and country of origin. Further studies are needed to develop strategies to reduce this misperception of curability in advanced cancer patients.Implications for Practice.The findings of this study indicate that inaccurate perception of curability among advanced cancer patients is 55%. Inaccurate perception of curability significantly differs by gender, education, performance status, employment status, and country of origin. There is great need to facilitate improved patient–physician communication so as to improve health care outcomes and patient satisfaction.

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Therapeutic Anticoagulation in Patients with Primary Brain Tumors or Secondary Brain Metastasis

AbstractPatients with primary or metastatic brain tumors are at increased risk of developing venous thromboses. However, the potential benefit of therapeutic anticoagulation in these patients must be weighed against the deadly complication of intracranial hemorrhage. In this review, we summarize available evidence and recent studies of intracranial bleeding risks in primary and metastatic tumors and the impact of therapeutic anticoagulation. We find that for the majority of primary and treated metastatic brain tumors, the risk of spontaneous bleeding is acceptable and not further increased by careful therapeutic anticoagulation with low molecular weight heparin or direct oral anticoagulants, although thrombocytopenia (platelet count less than 50,000/μL) and other coagulopathies are relative contraindications. Patients with brain metastasis from melanoma, renal cell carcinoma, choriocarcinoma, thyroid carcinoma, and hepatocellular carcinoma have a higher tendency to bleed spontaneously than noted in patients with other malignancies, and thus warrant routine brain imaging and alternative strategies such as inferior vena cava filter placement in the acute setting of venous thromboembolism before consideration of therapeutic anticoagulation.Implications for Practice.Malignant gliomas are associated with increased risks of both venous thromboses and intracranial hemorrhage, but the additional bleeding risk associated with therapeutic anticoagulation appears acceptable, especially after treatment of primary tumors. Most patients with treated brain metastasis have a low risk of intracranial hemorrhage associated with therapeutic anticoagulation, and low molecular weight heparin is currently the preferred agent of choice. Patients with untreated brain metastasis from melanoma, renal cell carcinoma, thyroid cancer, choriocarcinoma, and hepatocellular carcinoma have a higher propensity for spontaneous intracranial bleeding, and systemic anticoagulation may be contraindicated in the acute setting of venous thromboembolism.

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Chemoprevention in Patients with Peutz‐Jeghers Syndrome: Lessons Learned

AbstractLessons Learned. Motivating patients to enroll in chemopreventive studies is challenging.Chemoprevention with toxic drugs is not feasible.Background.LKB1 mutations are the underlying genetic abnormality causing Peutz‐Jeghers syndrome (PJS) and are a potential target for everolimus. In this phase II study, the efficacy of everolimus on polyp and tumor growth in PJS patients was investigated.Methods.Adult patients with a proven LKB1 mutation and who were suitable for everolimus treatment were included in two different PJS cohorts: (a) patients with unresectable malignancies and (b) patients with high‐risk polyps. Treatment in both groups was oral everolimus, 10 mg daily. Response rates were primary endpoints for both cohorts.Results.Between October 2011 and April 2016, only two patients were enrolled, one in each cohort. A 49‐year‐old patient with advanced pancreatic cancer in cohort 1 was progressive after 2 months. A 52‐year‐old male patient in cohort 2 experienced severe toxicity and refused treatment after 4 months, even though endoscopy suggested stabilization of polyps. Adverse events included dental inflammations, mucositis, and rash. In 2016, the trial was aborted for lack of accrual, despite extensive accrual efforts in an area where PJS is highly prevalent and care is highly centralized.Conclusion.Due to accrual problems, no conclusions can be drawn about the value of everolimus in PJS treatment, questioning the feasibility of this agent for chemoprevention.

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Decision‐Making Capacity for Chemotherapy and Associated Factors in Newly Diagnosed Patients with Lung Cancer

AbstractBackground.The objective of this study was to assess decision‐making capacity in patients newly diagnosed with lung cancer, clinical factors associated with impaired capacity, and physicians' perceptions of patients' decision‐making capacity.Materials and Methods.We recruited 122 patients newly diagnosed with lung cancer. One hundred fourteen completed the assessment. All patients were receiving a combination of treatments (e.g., chemotherapy, chemo‐radiotherapy, or targeted therapy). Decision‐making capacity was assessed using the MacArthur Competence Tool for Treatment. Cognitive impairment, depressive symptoms, and frailty were also evaluated. Physicians' perceptions were compared with the ascertainments.Results.Twenty‐seven (24%, 95% confidence interval [CI], 16–31) patients were judged to have incapacity. Clinical teams had difficulty in judging six (22.2%) patients for incapacity. Logistic regression identified frailty (odds ratio, 3.51; 95% CI, 1.13–10.8) and cognitive impairment (odds ratio, 5.45; 95% CI, 1.26–23.6) as the factors associated with decision‐making incapacity. Brain metastasis, emphysema, and depression were not associated with decision‐making incapacity.Conclusion.A substantial proportion of patients diagnosed with lung cancer show impairments in their capacity to make a medical decision. Assessment of cognitive impairment and frailty may provide appropriate decision‐making frameworks to act in the best interest of patients.Implications for Practice.Decision‐making capacity is the cornerstone of clinical practice. A substantial proportion of patients with cancer show impairments in their capacity to make a medical decision. Assessment of cognitive impairment and frailty may provide appropriate decision‐making frameworks to act in the best interest of patients.

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Phase I Trial of a Tablet Formulation of Pilaralisib, a Pan‐Class I PI3K Inhibitor, in Patients with Advanced Solid Tumors

AbstractLessons Learned. A phase I study of the pan‐class I phosphoinositide 3‐kinase inhibitor pilaralisib (in capsule formulation) in advanced solid tumors established the maximum tolerated dose as 600 mg once daily.The current study investigated pilaralisib in tablet formulation.Pilaralisib tablets were associated with a favorable safety profile and preliminary antitumor activity.Based on pharmacokinetic data, the recommended phase II dose of pilaralisib tablets was established as 400 mg once daily.Background.A phase I trial of pilaralisib, an oral pan‐class I phosphoinositide 3‐kinase (PI3K) inhibitor, established the maximum tolerated dose (MTD) of the capsule formulation in patients with advanced solid tumors as 600 mg once daily. This phase I study investigated pilaralisib in tablet formulation.Materials and Methods.Patients with advanced solid tumors received pilaralisib tablets (100–600 mg once daily). Primary endpoints were MTD and safety; secondary and exploratory endpoints included pharmacokinetics (PK), pharmacodynamics, and efficacy.Results.Twenty‐two patients were enrolled. No dose‐limiting toxicities (DLTs) were reported. The most common treatment‐related adverse events were diarrhea (40.9%), fatigue (40.9%), decreased appetite (22.7%), and hyperglycemia (22.7%). Pilaralisib plasma exposure did not appear to increase dose‐proportionally. Steady‐state exposure was higher with pilaralisib tablet formulation at 400 mg than with pilaralisib capsule formulation at 400 or 600 mg (mean area under the curve [AUC0–24] 2,820,000 ng × h/mL vs. 2,653,000 and 1,930,000 ng × h/mL, respectively). Of 18 evaluable patients, 2 (11.1%) had a partial response (PR).Conclusion.Pilaralisib tablets were associated with a favorable safety profile and preliminary antitumor activity. MTD was not determined. The recommended phase II dose for pilaralisib tablets, based on PK data, was 400 mg once daily.

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Safety Profile of Biosimilar Filgrastim (Zarzio/Zarxio): A Combined Analysis of Phase III Studies

AbstractBackground.Evaluation of adverse events (AEs) in pivotal registration trials and ongoing postmarketing surveillance is important for all biologics, including biosimilars. A combined analysis of two pivotal registration studies was performed to strengthen evidence on safety for biosimilar filgrastim EP2006 in patients with breast cancer receiving myelosuppressive chemotherapy, a sensitive clinical setting to confirm biosimilarity of filgrastim.Materials and Methods.Data were combined from two phase III studies of biosimilar filgrastim EP2006. The U.S. registration study was a randomized, double‐blind comparison of biosimilar and reference filgrastim in women aged ≥18 years with breast cancer, receiving (neo)adjuvant treatment with TAC (docetaxel + doxorubicin + cyclophosphamide). The European Union registration study was a single‐arm, open‐label study of biosimilar filgrastim in women aged ≥18 years with breast cancer receiving doxorubicin + docetaxel. Patients received filgrastim as a subcutaneous injection on day 2 of each cycle for <14 days or until the absolute neutrophil count reached 10 × 109/L after the expected nadir. Results were combined for cycles 1–4.Results.A total of 277 patients received biosimilar filgrastim EP2006. Patients had a mean (± standard deviation) age of 51.1 (± 10.8) years, and 78.7% of patients had stage II or III breast cancer. A total of 46 (20.6%) patients receiving biosimilar filgrastim had AEs considered filgrastim‐related. The most frequently reported filgrastim‐related AEs were musculoskeletal or connective tissue disorders (15.2%), including bone pain (7.2%). One death (due to pulmonary embolism) occurred of a patient receiving biosimilar filgrastim (not considered filgrastim‐related). No patient developed antidrug antibodies during the study.Conclusion.Biosimilar filgrastim has a safety profile consistent with previous filgrastim studies and is effective in preventing febrile neutropenia in patients with breast cancer.Implications for Practice.The biosimilar filgrastim EP2006 (Zarzio, Zarxio, biosimilar filgrastim‐sndz) has been approved in Europe since 2009 and in the U.S. since 2015. This combined analysis of two phase III studies provides additional clinical evidence that the biosimilar filgrastim EP2006 has a safety profile consistent with previous studies of reference filgrastim and supports large postmarketing studies of EP2006 in Europe. Strengthening the evidence for biosimilar filgrastim can help improve acceptance of biosimilars and increase patient access to biologics.

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Pre‐ and Postoperative Chemotherapy in Localized Extremity Soft Tissue Sarcoma: A European Organization for Research and Treatment of Cancer Expert Survey

AbstractBackground.The management of localized extremity soft tissue sarcomas (STS) is challenging and the role of pre‐ and postoperative chemotherapy is unclear and debated among experts.Materials and Methods.Medical oncology experts of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group were asked to participate in this survey on the use of pre‐ and postoperative chemotherapy in STS. Experts from 12 centers in Belgium, France, Germany, Great Britain, Italy, Switzerland, and The Netherlands agreed to participate and provided their treatment algorithm. Answers were converted into decision trees based on the objective consensus methodology. The decision trees were used as a basis to identify consensus and discrepancies.Results.Several criteria used for decision‐making in extremity STS were identified: chemosensitivity, fitness, grading, location, and size. In addition, resectability and resection status were relevant in the pre‐ and postoperative setting, respectively. Preoperative chemotherapy is considered in most centers for marginally resectable tumors only. Yet, in some centers, neoadjuvant chemotherapy is used routinely and partially combined with hyperthermia. Although most centers do not recommend postoperative chemotherapy, some offer this treatment on a regular basis. Radiotherapy is an undisputed treatment modality in extremity STS.Conclusion.Due to lacking evidence on the utility of pre‐ and postoperative chemotherapy in localized extremity STS, treatment strategies vary considerably among European experts. The majority recommended neoadjuvant chemotherapy for marginally resectable grade 2–3 tumors; the majority did not recommend postoperative chemotherapy in any setting.Implications for Practice.The management of localized extremity soft tissue sarcomas (STS) is challenging and the role of pre‐ and postoperative chemotherapy is unclear and debated among experts. This study analyzed the decision‐making process among 12 European experts on systemic therapy for STS. A wide range of recommendations among experts regarding the use of perioperative chemotherapy was discovered. Discrepancies in the use of decision criteria were also uncovered, including the definition of what constitutes high‐risk cancer, which is a basis for many to recommend chemotherapy. Before any standardization is possible, a common use of decision criteria is necessary.

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Molecular Biomarkers of Primary and Acquired Resistance to T‐Cell‐Mediated Immunotherapy in Cancer: Landscape, Clinical Implications, and Future Directions

AbstractThe emergence of immunotherapy has revolutionized cancer treatment in recent years. Inhibitors of immune checkpoints, including antibodies against cytotoxic T‐lymphocyte‐associated protein 4, programmed cell death protein 1, and programmed death ligand 1, have demonstrated notable efficacy in certain advanced cancers. Unfortunately, many patients do not benefit from these therapies and either exhibit primary resistance to treatment or develop acquired mechanisms of resistance after initially responding to therapy. Here, we review the genomic and immune traits that may promote resistance to T‐cell‐mediated immunotherapy, with a focus on identifying potential biomarkers that could eventually be used in the clinical setting to guide treatment selection. We summarize the clinical evidence for these markers and discuss how current understanding of resistance mechanisms can inform future studies and aid clinical decision‐making in order to derive maximum benefit from immunotherapy.Implications for Practice.Immunotherapy has rapidly progressed as a treatment modality for multiple cancers, but it is still unclear which patients are likely to benefit from these therapies. Studies of resistance mechanisms have only recently started to identify biomarkers that can help predict patient outcomes. This review summarizes the available clinical data in regard to immunotherapy resistance, with a focus on molecular biomarkers that may be useful in guiding clinical decision‐making. It discusses possible applications of these biomarkers and highlights opportunities for further clinical discovery.

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Trastuzumab Plus Pertuzumab Resistance Does Not Preclude Response to Lapatinib Plus Trastuzumab in HER2‐Amplified Colorectal Cancer

AbstractHuman epidermal growth factor 2 (HER2) amplification represents a distinct molecular subgroup of colorectal cancers that is associated with anti‐epidermal growth factor receptor resistance and sensitivity to dual HER2 targeting. Although clinical trials have reported activity for trastuzumab/pertuzumab and trastuzumab/lapatinib combinations, there are no reports on lapatinib plus trastuzumab activity after resistance to trastuzumab plus pertuzumab. Presented are three cases of HER2 amplified colorectal cancer that developed acquired refractoriness to trastuzumab pertuzumab with subsequent clinical benefit to lapatinib plus trastuzumab, highlighting the potential for HER2 tyrosine kinase inhibition plus trastuzumab in overcoming trastuzumab/pertuzumab resistance.

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Neuroendocrine Tumor Heterogeneity Adds Uncertainty to the World Health Organization 2010 Classification: Real‐World Data from the Spanish Tumor Registry (R‐GETNE)

AbstractBackground.Gastroenteropancreatic neuroendocrine neoplasms (GEP‐NENs) are a complex family of tumors of widely variable clinical behavior. The World Health Organization (WHO) 2010 classification provided a valuable tool to stratify neuroendocrine neoplasms (NENs) in three prognostic subgroups based on the proliferation index. However, substantial heterogeneity remains within these subgroups, and simplicity sometimes entails an ambiguous and imprecise prognostic stratification. The purpose of our study was to evaluate the prognostic impact of histological differentiation within the WHO 2010 grade (G) 1/G2/G3 categories, and explore additional Ki‐67 cutoff values in GEP‐NENs.Subjects, Materials, and Methods.A total of 2,813 patients from the Spanish National Tumor Registry (RGETNE) were analyzed. Cases were classified by histological differentiation as NETs (neuroendocrine tumors [well differentiated]) or NECs (neuroendocrine carcinomas [poorly differentiated]), and by Ki‐67 index as G1 (Ki‐67 <2%), G2 (Ki‐67 3%–20%), or G3 (Ki‐67 >20%). Patients were stratified into five cohorts: NET‐G1, NET‐G2, NET‐G3, NEC‐G2, and NEC‐G3.Results.Five‐year survival was 72%. Age, gender, tumor site, grade, differentiation, and stage were all independent prognostic factors for survival. Further subdivision of the WHO 2010 grading improved prognostic stratification, both within G2 (5‐year survival: 81% [Ki‐67 3%–5%], 72% [Ki‐67 6%–10%], 52% [Ki‐67 11%–20%]) and G3 NENs (5‐year survival: 35% [Ki‐67 21%–50%], 22% [Ki‐67 51%–100%]). Five‐year survival was significantly greater for NET‐G2 versus NEC‐G2 (75.5% vs. 58.2%) and NET‐G3 versus NEC‐G3 (43.7% vs. 25.4%).Conclusion.Substantial clinical heterogeneity is observed within G2 and G3 GEP‐NENs. The WHO 2010 classification can be improved by including the additive effect of histological differentiation and the proliferation index.Implications for Practice.Gastroenteropancreatic neuroendocrine neoplasms are tumors of widely variable clinical behavior, roughly stratified by the World Health Organization (WHO) 2010 classification into three subgroups based on proliferation index. Real‐world data from 2,813 patients of the Spanish Registry RGETNE demonstrated substantial clinical heterogeneity within grade (G) 2 and G3 neuroendocrine neoplasms. Tumor morphology and further subdivision of grading substantially improves prognostic stratification of these patients and may help individualize therapy. This combined, additive effect shall be considered in future classifications of neuroendocrine tumors and incorporated for stratification purposes in clinical trials.

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Early and Locally Advanced Metaplastic Breast Cancer: Presentation and Survival by Receptor Status in Surveillance, Epidemiology, and End Results (SEER) 2010–2014

AbstractBackground.Metaplastic breast cancer (MBC) is a rare disease subtype characterized by an aggressive clinical course. MBC is commonly triple negative (TN), although hormone receptor (HR) positive and human epidermal growth receptor 2 (HER2) positive cases do occur. Previous studies have reported similar outcomes for MBC with regard to HR status. Less is known about outcomes for HER2 positive MBC.Materials and Methods.Surveillance, Epidemiology, and End Results Program data were used to identify women diagnosed 2010–2014 with MBC or invasive ductal carcinoma (IDC). Kaplan‐Meier curves estimated overall survival (OS) and multivariate Cox models were fitted. For survival analyses, only first cancers were included, and 2014 diagnoses were excluded to allow for sufficient follow‐up.Results.Our MBC sample included 1,516 women. Relative to women with IDC, women with MBC were more likely to be older (63 vs. 61 years), black (16.0% vs. 11.1%), and present with stage III disease (15.6% vs. 10.8%). HER2 positive and HER2 negative/HR positive MBC tumors represented 5.2% and 23.0% of cases. For MBC overall, 3‐year OS was greatest for women with HER2 positive MBC (91.8%), relative to women with TN (75.4%) and HER2 negative/HR positive MBC (77.1%). This difference was more pronounced for stage III MBC, for which 3‐year OS was 92.9%, 47.1%, and 42.2% for women with HER2 positive, TN, and HER2 negative/HR positive MBC, respectively. A multivariate Cox model of MBC demonstrated that HER2 positive tumors (relative to TN) were associated with improved survival (hazard ratio = 0.32, 95% confidence interval [CI] 0.13–0.79). In a second Cox model of exclusively HER2 positive tumors, OS did not differ between MBC and IDC disease subtypes (hazard ratio = 1.16, 95% CI 0.48–2.81).Conclusion.In this contemporary, population‐based study of women with MBC, HER2 but not HR status was associated with improved survival. Survival was similar between HER2 positive MBC and HER2 positive IDC. This suggests HER2 positive MBC is responsive to HER2‐directed therapy, a finding that may offer insights for additional therapeutic approaches to MBC.Implications for Practice.This population‐based study reports recent outcomes, by receptor status, for women with metaplastic breast cancer. Survival in metaplastic breast cancer is not impacted by hormone receptor status. To the authors' knowledge, this is the first report indicating that women with human epidermal growth receptor 2 (HER2) positive metaplastic breast cancer have survival superior to women with HER2 negative metaplastic breast cancer and survival similar to women with HER2 positive invasive ductal carcinoma. This information can be used for counseling patients diagnosed with metaplastic breast cancer. Further understanding of HER2 positive metaplastic breast cancer could offer insights for the development of therapeutic approaches to metaplastic breast cancer more broadly.

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Patient‐Reported Comorbidity and Survival in Older Adults with Cancer

AbstractBackground.Our ability to optimize the care of older adults with cancer and comorbid illnesses is insufficient because most clinical trials lack systematic measurement. The primary purpose of this study was to evaluate the association between patient‐reported comorbidity and all‐cause mortality using various comorbidity scoring algorithms.Materials and Methods.The Carolina Senior Registry was linked with the North Carolina Central Cancer Registry to obtain mortality data. Comorbidity was assessed using the patient‐reported Older Americans Resources and Services Questionnaire subscale that assesses 13 specific conditions and the degree to which each impairs activities. Multivariable Cox proportional hazard regression models were used to evaluate the association between comorbidities and all‐cause mortality.Results.The study sample included 539 patients; the median age was 72 years, 72% were female, and 47% had breast cancer. Overall, 92% reported ≥1 comorbid condition, with a mean of 2.7 conditions (range 0–10), with arthritis and hypertension the most common (52% and 50%, respectively). Approximately 60% reported a functional limitation related to comorbidity. After adjusting for time from diagnosis to geriatric assessment, age, cancer type, and stage, the risk of death increased by 5% for each unit increase in comorbidity burden score (adjusted hazard ratio [HR] = 1.05, 95% confidence interval [CI]: 1.01–1.10) and 12% for each comorbid condition impacting function (HR = 1.12, 95% CI: 1.02–1.23).Conclusion.Comorbid conditions in older adults with cancer are highly prevalent and associated with all‐cause mortality, particularly those conditions that impair function. Routine comorbidity assessment should be included in clinical trials and can be measured via a simple one‐page patient‐reported questionnaire.Implications for Practice.In order to optimize and personalize the care of older adults with cancer, systematic measurement of comorbidities is necessary in both clinical trials and routine practice. Patient‐reported comorbid conditions in older adults with cancer are highly prevalent and are associated with increased risk of all‐cause mortality, particularly for those conditions that impair function. Comorbidity can be systematically measured via a one‐page patient‐reported questionnaire and should be incorporated into future clinical trials and considered for use in oncology clinics to aid in assessing older adults with cancer.

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Benefit‐Risk Summary of Regorafenib for the Treatment of Patients with Advanced Hepatocellular Carcinoma That Has Progressed on Sorafenib

AbstractOn April 27, 2017, the U.S. Food and Drug Administration approved regorafenib for the treatment of patients with advanced hepatocellular carcinoma (HCC) who had previously been treated with sorafenib. Approval was based on the results of a single, randomized, placebo‐controlled trial (RESORCE) that demonstrated an improvement in overall survival (OS). Patients were randomly allocated to receive regorafenib160 mg orally once daily or matching placebo for the first 21 days of each 28‐day cycle. The trial demonstrated a significant improvement in OS (hazard ratio [HR] = 0.63; 95% confidence interval [CI], 0.50–0.79, p < .0001) with an estimated median OS of 10.6 months in the regorafenib arm and 7.8 months in the placebo arm. A statistically significant improvement in progression‐free survival (PFS) based on modified RECIST for HCC [Semin Liver Dis 2010;30:52–60] (HR = 0.46; 95% CI, 0.37–0.56, p < .0001) was also demonstrated; the estimated median PFS was 3.1 and 1.5 months in the regorafenib and placebo arms, respectively. The overall response rate, based on modified RECIST for HCC, was 11% in the regorafenib arm and 4% in the placebo arm. The toxicity profile was consistent with that observed in other indications; the most clinically significant adverse reactions were palmar‐plantar erythrodysesthesia, diarrhea, and hypertension. Based on the improvement in survival and acceptable toxicity, a favorable benefit‐to‐risk evaluation led to approval for treatment of patients with advanced HCC.Implications for Practice.Regorafenib is the first drug approved by the U.S. Food and Drug Administration for the treatment of hepatocellular carcinoma that has progressed on sorafenib and is expected to become a standard of care for these patients.

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Bendamustine plus Rituximab Versus R‐CHOP as First‐Line Treatment for Patients with Follicular Lymphoma Grade 3A: Evidence from a Multicenter, Retrospective Study

The Perils of Single‐Site Genetic Testing for Hereditary Cancer Syndromes in the Era of Next‐Generation Sequencing

A Phase I Dose‐Escalation Study of Clofarabine in Patients with Relapsed or Refractory Low‐Grade or Intermediate‐Grade B‐Cell or T‐Cell Lymphoma

AbstractLessons Learned. Clofarabine can be active in relapsed and refractory lymphoid malignancies on a weekly dosing schedule.Responses were seen in patients with T‐cell lymphomas, including cutaneous T‐cell lymphoma, but not in patients with aggressive B‐cell lymphomas.Background.Clofarabine is a second‐generation purine nucleoside analog currently approved for the treatment of pediatric relapsed or refractory acute lymphoblastic leukemia. In adults, clofarabine has been investigated in several phase I and II trials as a single agent and in combination for relapsed or refractory acute leukemia. These studies have shown that clofarabine has activity and an acceptable safety profile in patients with hematological malignancies. In this phase I dose escalation trial, clofarabine was evaluated in patients with relapsed or refractory, low‐grade or intermediate‐grade, B‐cell or T‐cell lymphoma.Methods.The starting dose of 10 mg/m2 per week was administered intravenously (IV) for 3 consecutive weeks every 28 days, and doses were escalated in cohorts of three. The study objectives were to determine the maximum tolerated dose (MTD), characterize and quantify the toxicity profile, and determine the overall response rate of clofarabine administered once a week for 3 weeks and repeated every 4 weeks. Eligible patients were over the age of 18, had a histologically confirmed low‐grade or intermediate‐grade B‐cell or T‐cell lymphoma, and must have previously been treated with one standard chemotherapy regimen, excluding single‐agent rituximab. The primary objectives included in statistical analyses were MTD, toxicity, and overall response rate (ORR). Four patients were enrolled in cohort 1 (clofarabine 10 mg/m2), four in cohort 2 (clofarabine 15 mg/m2), three in cohort 3 (clofarabine 20 mg/m2), two in cohort 4 (clofarabine 30 mg/m2), and one in cohort 5 (clofarabine 40 mg/m2) (Table 2).Results.MTD was not reached in the study. The most common toxicity observed was myelosuppression. A total of four (29%) patients experienced grade 3 leukopenia, with three (21%) patients experiencing grade 4 neutropenia. The myelosuppression was not considered to be a dose‐limiting toxicity, as it resolved within 7 days.Fourteen patients were enrolled: 10 patients with T‐cell non‐Hodgkin lymphoma (NHL) and 4 patients with B‐cell NHL (see Table 1). All 14 patients received at least one dose of clofarabine and were evaluable for response. One patient with cutaneous T‐cell lymphoma (CTCL) had a partial response; five (36%) had stable disease, and eight patients (57%) had no response. The one patient with a response had stage III erythroderma and was treated in the 10 mg/m2 cohort; a nodal complete response by positron emission tomography scan was observed with a partial response of the skin.Conclusion.In this study, weekly administration of clofarabine was demonstrated to be safe and associated with minimal hematologic toxicity at doses ranging from 10–40 mg/m2. In prior studies when dosed daily for 5 consecutive days, the MTD was shown to be 4 mg/m2. Weekly dosing within this dose range did not result in dose modifications, and the MTD was not reached. Clinical efficacy was observed in one patient with CTCL who was treated in the lowest‐dose cohort.

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Chemoprevention in Patients with Peutz‐Jeghers Syndrome: Lessons Learned

Decision‐Making Capacity for Chemotherapy and Associated Factors in Newly Diagnosed Patients with Lung Cancer

Phase I Trial of a Tablet Formulation of Pilaralisib, a Pan‐Class I PI3K Inhibitor, in Patients with Advanced Solid Tumors

Early Steps in the Value of Cancer Care—Many Paths Remain Unexplored

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Safety Profile of Biosimilar Filgrastim (Zarzio/Zarxio): A Combined Analysis of Phase III Studies

Pre‐ and Postoperative Chemotherapy in Localized Extremity Soft Tissue Sarcoma: A European Organization for Research and Treatment of Cancer Expert Survey

Molecular Biomarkers of Primary and Acquired Resistance to T‐Cell‐Mediated Immunotherapy in Cancer: Landscape, Clinical Implications, and Future Directions

Trastuzumab Plus Pertuzumab Resistance Does Not Preclude Response to Lapatinib Plus Trastuzumab in HER2‐Amplified Colorectal Cancer

Neuroendocrine Tumor Heterogeneity Adds Uncertainty to the World Health Organization 2010 Classification: Real‐World Data from the Spanish Tumor Registry (R‐GETNE)

Early and Locally Advanced Metaplastic Breast Cancer: Presentation and Survival by Receptor Status in Surveillance, Epidemiology, and End Results (SEER) 2010–2014

Patient‐Reported Comorbidity and Survival in Older Adults with Cancer

Benefit‐Risk Summary of Regorafenib for the Treatment of Patients with Advanced Hepatocellular Carcinoma That Has Progressed on Sorafenib

Barriers and Explanatory Mechanisms of Delays in the Patient and Diagnosis Intervals of Care for Breast Cancer in Mexico

AbstractBackground.Most breast cancer patients in low‐ and middle‐income settings are diagnosed at advanced stages due to lengthy intervals of care. This study aimed to understand the mechanisms through which delays occur in the patient interval and diagnosis interval of care.Materials and Methods.We conducted a cross‐sectional survey including 886 patients referred to four major public cancer hospitals in Mexico City. Based in a conceptual model of help‐seeking behavior, a path analysis strategy was used to identify the relationships between explanatory factors of patient delay and diagnosis delay.Results.The patient and the diagnosis intervals were greater than 3 months in 20% and 65% of participants, respectively. We present explanatory models for each interval and the interrelationship between the associated factors. The patient interval was longer among women who were single, interpreted their symptoms as not worrisome, concealed symptoms, and perceived a lack of financial resources and the difficulty of missing a day of work as barriers to seek care. These barriers were more commonly perceived among patients who were younger, had lower socioeconomic status, and lived outside of Mexico City. The diagnosis interval was longer among those who used several different health services prior to the cancer hospital and perceived medical errors in these services. More health services were used among those who perceived errors and long waiting times for appointments, and who first consulted private services.Conclusion.Our findings support the relevance of strengthening early cancer diagnosis strategies, especially the improvement of quality of primary care and expedited referral routes to cancer services.Implications for Practice.This study's findings suggest that policy in low‐ and middle‐income countries (LMICs) should be directed toward reducing delays in diagnosis, before the implementation of mammography screening programs. The results suggest several factors susceptible to early diagnosis interventions. To reduce patient delays, the usually proposed intervention of awareness promotion could better work in LMIC contexts if the message goes beyond the advertising of screening mammography to encourage the recognition of potential cancer symptoms and sharing of symptoms with significant others. To reduce diagnosis delay, efforts should focus on strengthening the quality of public primary care services and improving referral routes to cancer care centers.

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Two Doctors, One Patient, and a Common Goal

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Two Doctors, One Patient, and a Common Goal

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ER{alpha}-Mediated Nuclear Sequestration of RSK2 Is Required for ER+ Breast Cancer Tumorigenesis

Although ribosomal protein S6 kinase A3 (RSK2) activation status positively correlates with patient responses to antiestrogen hormonal therapies, the mechanistic basis for these observations is unknown. Using multiple in vitro and in vivo models of estrogen receptor–positive (ER+) breast cancer, we report that ERα sequesters active RSK2 into the nucleus to promote neoplastic transformation and facilitate metastatic tumor growth. RSK2 physically interacted with ERα through its N terminus to activate a proneoplastic transcriptional network critical to the ER+ lineage in the mammary gland, thereby providing a gene signature that effectively stratified patient tumors according to ERα status. ER+ tumor growth was strongly dependent on nuclear RSK2, and transgenic mice engineered to stably express nuclear RSK2 in the mammary gland developed high-grade ductal carcinoma in situ. Mammary cells isolated from the transgenic model and introduced systemically successfully disseminated and established metastatic lesions. Antiestrogens disrupted the interaction between RSK2 and ERα, driving RSK2 into the cytoplasm and impairing tumor formation. These findings establish RSK2 as an obligate participant of ERα-mediated transcriptional programs, tumorigenesis, and divergent patient responses to antiestrogen therapies.Significance: Nuclear accumulation of active RSK drives a protumorigenic transcriptional program and renders ER+ breast cancer susceptible to endocrine-based therapies. Cancer Res; 78(8); 2014–25. ©2018 AACR.

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Lessons from the Crypt: HMGA1—Amping up Wnt for Stem Cells and Tumor Progression

High mobility group A1 (HMGA1) chromatin remodeling proteins are enriched in aggressive cancers and stem cells, although their common function in these settings has remained elusive until now. Recent work in murine intestinal stem cells (ISC) revealed a novel role for Hmga1 in enhancing self-renewal by amplifying Wnt signaling, both by inducing genes expressing Wnt agonist receptors and Wnt effectors. Surprisingly, Hmga1 also "builds" a stem cell niche by upregulating Sox9, a factor required for differentiation to Paneth cells; these cells constitute an epithelial niche by secreting Wnt and other factors to support ISCs. HMGA1 is also highly upregulated in colon cancer compared with nonmalignant epithelium and SOX9 becomes overexpressed during colon carcinogenesis. Intriguingly, HMGA1 is overexpressed in diverse cancers with poor outcomes, where it regulates developmental genes. Similarly, HMGA1 induces genes responsible for pluripotency and self-renewal in embryonic stem cells. These findings demonstrate that HMGA1 maintains Wnt and other developmental transcriptional networks and suggest that HMGA1 overexpression fosters carcinogenesis and tumor progression through dysregulation of these pathways. Studies are now needed to determine more precisely how HMGA1 modulates chromatin structure to amplify developmental genes and how to disrupt this process in cancer therapy. Cancer Res; 78(8); 1890–7. ©2018 AACR.

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Small-Molecule Activators of Protein Phosphatase 2A for the Treatment of Castration-Resistant Prostate Cancer

Primary prostate cancer is generally treatable by androgen deprivation therapy, however, later recurrences of castrate-resistant prostate cancer (CRPC) that are more difficult to treat nearly always occur due to aberrant reactivation of the androgen receptor (AR). In this study, we report that CRPC cells are particularly sensitive to the growth-inhibitory effects of reengineered tricyclic sulfonamides, a class of molecules that activate the protein phosphatase PP2A, which inhibits multiple oncogenic signaling pathways. Treatment of CRPC cells with small-molecule activators of PP2A (SMAP) in vitro decreased cellular viability and clonogenicity and induced apoptosis. SMAP treatment also induced an array of significant changes in the phosphoproteome, including most notably dephosphorylation of full-length and truncated isoforms of the AR and downregulation of its regulatory kinases in a dose-dependent and time-dependent manner. In murine xenograft models of human CRPC, the potent compound SMAP-2 exhibited efficacy comparable with enzalutamide in inhibiting tumor formation. Overall, our results provide a preclinical proof of concept for the efficacy of SMAP in AR degradation and CRPC treatment.Significance: A novel class of small-molecule activators of the tumor suppressor PP2A, a serine/threonine phosphatase that inhibits many oncogenic signaling pathways, is shown to deregulate the phosphoproteome and to destabilize the androgen receptor in advanced prostate cancer. Cancer Res; 78(8); 2065–80. ©2018 AACR.

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Silencing the Snail-Dependent RNA Splice Regulator ESRP1 Drives Malignant Transformation of Human Pulmonary Epithelial Cells

Epithelial-to-mesenchymal transition (EMT) is organized in cancer cells by a set of key transcription factors, but the significance of this process is still debated, including in non–small cell lung cancer (NSCLC). Here, we report increased expression of the EMT-inducing transcription factor Snail in premalignant pulmonary lesions, relative to histologically normal pulmonary epithelium. In immortalized human pulmonary epithelial cells and isogenic derivatives, we documented Snail-dependent anchorage-independent growth in vitro and primary tumor growth and metastatic behavior in vivo. Snail-mediated transformation relied upon silencing of the tumor-suppressive RNA splicing regulatory protein ESRP1. In clinical specimens of NSCLC, ESRP1 loss was documented in Snail-expressing premalignant pulmonary lesions. Mechanistic investigations showed that Snail drives malignant progression in an ALDH+CD44+CD24− pulmonary stem cell subset in which ESRP1 and stemness-repressing microRNAs are inhibited. Collectively, our results show how ESRP1 loss is a critical event in lung carcinogenesis, and they identify new candidate directions for targeted therapy of NSCLC.Significance: This study defines a Snail-ESRP1 cancer axis that is crucial for human lung carcinogenesis, with implications for new intervention strategies and translational opportunities. Cancer Res; 78(8); 1986–99. ©2018 AACR.

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HER2 Overexpression Triggers an IL1{alpha} Proinflammatory Circuit to Drive Tumorigenesis and Promote Chemotherapy Resistance

Systemic inflammation in breast cancer correlates with poor prognosis, but the molecular underpinnings of this connection are not well understood. In this study, we explored the relationship between HER2 overexpression, inflammation, and expansion of the mammary stem/progenitor and cancer stem–like cell (CSC) population in breast cancer. HER2-positive epithelial cells initiated and sustained an inflammatory milieu needed to promote tumorigenesis. HER2 induced a feedforward activation loop of IL1α and IL6 that stimulated NFκB and STAT3 pathways for generation and maintenance of breast CSC. In mice, Il1a genetic deficiency delayed MMTV-Her2–induced tumorigenesis and reduced inflammatory cytokine expression as well as CSC in primary tumors. In clinical specimens of human breast tumor tissues, tissue microarray analysis revealed a strong positive correlation between IL1α/IL6 expression and CSC-positive phenotype. Pharmacologic blockade of IL1α signaling reduced the CSC population and improved chemotherapeutic efficacy. Our findings suggest new therapeutic or prevention strategies for HER2-positive breast cancers.Significance: IL1α signaling driven by HER2 promotes chronic inflammation needed to support cancer stem-like cell maintenance in HER2-positive breast cancers. Cancer Res; 78(8); 2040–51. ©2018 AACR.

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Highlights from Recent Cancer Literature

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Germline Mutations in the Mitochondrial 2-Oxoglutarate/Malate Carrier SLC25A11 Gene Confer a Predisposition to Metastatic Paragangliomas

Comprehensive genetic analyses have identified germline SDHB and FH gene mutations as predominant causes of metastatic paraganglioma and pheochromocytoma. However, some suspicious cases remain unexplained. In this study, we performed whole-exome sequencing of a paraganglioma exhibiting an SDHx-like molecular profile in the absence of SDHx or FH mutations and identified a germline mutation in the SLC25A11 gene, which encodes the mitochondrial 2-oxoglutarate/malate carrier. Germline SLC25A11 mutations were identified in six other patients, five of whom had metastatic disease. These mutations were associated with loss of heterozygosity, suggesting that SLC25A11 acts as a tumor-suppressor gene. Pseudohypoxic and hypermethylator phenotypes comparable with those described in SDHx- and FH-related tumors were observed both in tumors with mutated SLC25A11 and in Slc25a11Δ/Δ immortalized mouse chromaffin knockout cells generated by CRISPR-Cas9 technology. These data show that SLC25A11 is a novel paraganglioma susceptibility gene for which loss of function correlates with metastatic presentation.Significance: A gene encoding a mitochondrial carrier is implicated in a hereditary cancer predisposition syndrome, expanding the role of mitochondrial dysfunction in paraganglioma. Cancer Res; 78(8); 1914–22. ©2018 AACR.

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NRAS-Mutated Rhabdomyosarcoma Cells Are Vulnerable to Mitochondrial Apoptosis Induced by Coinhibition of MEK and PI3K{alpha}

Sequencing studies have revealed recurrent mutations in the RAS pathway in rhabdomyosarcoma (RMS). However, RAS effector pathways in RMS are poorly defined. Here, we report that coinhibition of NRAS or MEK plus PI3Kα triggers widespread apoptosis in NRAS-mutated RMS cells. Subtoxic concentrations of the MEK inhibitor MEK162 and the PI3Kα-specific inhibitor BYL719 synergized to trigger apoptosis in NRAS-mutated RMS cells in vitro and in vivo. NRAS- or HRAS-mutated cell lines were more vulnerable to MEK162/BYL719 cotreatment than RAS wild-type cell lines, and MEK162/BYL719 cotreatment was more effective to trigger apoptosis in NRAS-mutated than RAS wild-type RMS tumors in vivo. We identified BCL-2–modifying factor (BMF) as an inhibitory target of oncogenic NRAS, with either NRAS silencing or MEK inhibition upregulating BMF mRNA and protein levels, which BYL719 further increased. BMF silencing ablated MEK162/BYL719-induced apoptosis. Mechanistic investigations implicated a proapoptotic rebalancing of BCL-2 family members and suppression of cap-dependent translation in apoptotic sensitivity upon MEK162/BYL719 cotreatment. Our results offer a rationale for combining MEK- and PI3Kα-specific inhibitors in clinical treatment of RAS-mutated RMS.Significance: These findings offer a mechanistic rationale for combining MEK- and PI3Kα-specific inhibitors in the clinical treatment of RAS-mutated forms of often untreatable rhabdomyosarcomas. Cancer Res; 78(8); 2000–13. ©2018 AACR.

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LPA Induces Metabolic Reprogramming in Ovarian Cancer via a Pseudohypoxic Response

Although hypoxia has been shown to reprogram cancer cells toward glycolytic shift, the identity of extrinsic stimuli that induce metabolic reprogramming independent of hypoxia, especially in ovarian cancer, is largely unknown. In this study, we use patient-derived ovarian cancer cells and high-grade serous ovarian cancer cell lines to demonstrate that lysophosphatidic acid (LPA), a lipid growth factor and GPCR ligand whose levels are substantially increased in ovarian cancer patients, triggers glycolytic shift in ovarian cancer cells. Inhibition of the G protein α-subunit Gαi2 disrupted LPA-stimulated aerobic glycolysis. LPA stimulated a pseudohypoxic response via Rac-mediated activation of NADPH oxidase and generation of reactive oxygen species, resulting in activation of HIF1α. HIF1α in turn induced expression of glucose transporter-1 and the glycolytic enzyme hexokinase-2 (HKII). Treatment of mice bearing ovarian cancer xenografts with an HKII inhibitor, 3-bromopyruvate, attenuated tumor growth and conferred a concomitant survival advantage. These studies reveal a critical role for LPA in metabolic reprogramming of ovarian cancer cells and identify this node as a promising therapeutic target in ovarian cancer.Significance: These findings establish LPA as a potential therapeutic target in ovarian cancer, revealing its role in the activation of HIF1α-mediated metabolic reprogramming in this disease. Cancer Res; 78(8); 1923–34. ©2018 AACR.

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ER{alpha}-Mediated Nuclear Sequestration of RSK2 Is Required for ER+ Breast Cancer Tumorigenesis

Cancer Research: Embracing the Complexity of Cancer and Emergence of Truth

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Spatial Heterogeneity and Evolutionary Dynamics Modulate Time to Recurrence in Continuous and Adaptive Cancer Therapies

Treatment of advanced cancers has benefited from new agents that supplement or bypass conventional therapies. However, even effective therapies fail as cancer cells deploy a wide range of resistance strategies. We propose that evolutionary dynamics ultimately determine survival and proliferation of resistant cells. Therefore, evolutionary strategies should be used with conventional therapies to delay or prevent resistance. Using an agent-based framework to model spatial competition among sensitive and resistant populations, we applied antiproliferative drug treatments to varying ratios of sensitive and resistant cells. We compared a continuous maximum-tolerated dose schedule with an adaptive schedule aimed at tumor control via competition between sensitive and resistant cells. Continuous treatment cured mostly sensitive tumors, but with any resistant cells, recurrence was inevitable. We identified two adaptive strategies that control heterogeneous tumors: dose modulation controls most tumors with less drug, while a more vacation-oriented schedule can control more invasive tumors. These findings offer potential modifications to treatment regimens that may improve outcomes and reduce resistance and recurrence.Significance: By using drug dose modulation or treatment vacations, adaptive therapy strategies control the emergence of tumor drug resistance by spatially suppressing less fit resistant populations in favor of treatment sensitive ones. Cancer Res; 78(8); 2127–39. ©2018 AACR.

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Lessons from the Crypt: HMGA1—Amping up Wnt for Stem Cells and Tumor Progression

The Plausibility of Obesity Paradox in Cancer—Point

In contrast to the convincing evidence that obesity (measured by body mass index, BMI) increases the risk of many different types of cancer, there is an ambiguity in the role of obesity in survival among cancer patients. Some studies suggested that higher BMI decreased mortality risk in cancer patients, a phenomenon called the obesity paradox. The spurious positive association between BMI and cancer survival is likely to be explained by several methodologic limitations including confounding, reverse causation, and collider stratification bias. Also, the inadequacy of BMI as a measure of body fatness in cancer patients commonly experiencing changes in body weight and body composition may have resulted in the paradox. Other factors contributing to the divergent results in literature are significant heterogeneity in study design and method (e.g., study population, follow-up length); time of BMI assessment (pre-, peri-, or post-diagnosis); and lack of consideration for variability in the strength and directions of associations by age, sex, race/ethnicity, and cancer subtype. Robust but practical methods to accurately assess body fatness and body compositions and weight trajectories in cancer survivors are needed to advance this emerging field and to develop weight guidelines to improve both the length and the quality of cancer survival. Cancer Res; 78(8); 1898–903. ©2018 AACR.

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Silencing the Snail-Dependent RNA Splice Regulator ESRP1 Drives Malignant Transformation of Human Pulmonary Epithelial Cells

The Plausibility of the Obesity Paradox in Cancer—Response—Reply to Point

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HER2 Overexpression Triggers an IL1{alpha} Proinflammatory Circuit to Drive Tumorigenesis and Promote Chemotherapy Resistance

The Importance of Body Composition in Explaining the Overweight Paradox in Cancer—Counterpoint

Despite a greater risk of cancer associated with higher BMI, overweight (BMI 25–<30 kg/m2) and class I obese (BMI 30–<35 kg/m2) patients often have a paradoxically lower risk of overall mortality after a cancer diagnosis, a phenomenon called the "obesity paradox." Only when patients exceed a BMI ≥35 kg/m2 are elevations in mortality risk consistently noted. This paradox has been dismissed as the result of methodologic bias, which we will describe and debate here. However, even if such bias influences associations, there is growing evidence that body composition may in part explain the paradox. This phenomenon may more accurately be described as a BMI paradox. That is, BMI is a poor proxy for adiposity and does not distinguish muscle from adipose tissue, nor describe adipose tissue distribution. Low muscle mass is associated with higher risk of recurrence, overall and cancer-specific mortality, surgical complications, and treatment-related toxicities. Patients with who are overweight or obese have on average higher levels of muscle than their normal-weight counterparts. Also, there is some evidence that patients with moderate levels of subcutaneous adipose tissue may have lower mortality. More research utilizing body composition is needed to clarify the effects of adiposity on cancer mortality. Cancer Res; 78(8); 1906–12. ©2018 AACR.

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Evidence for an Overweight Paradox in Cancer: Insights from Body Composition—Reply to Counterpoint

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NRAS-Mutated Rhabdomyosarcoma Cells Are Vulnerable to Mitochondrial Apoptosis Induced by Coinhibition of MEK and PI3K{alpha}

LPA Induces Metabolic Reprogramming in Ovarian Cancer via a Pseudohypoxic Response

CXCL12{gamma} Promotes Metastatic Castration-Resistant Prostate Cancer by Inducing Cancer Stem Cell and Neuroendocrine Phenotypes

There is evidence that cancer stem-like cells (CSC) and neuroendocrine behavior play critical roles in the pathogenesis and clinical course of metastatic castration-resistant prostate cancer (m-CRPC). However, there is limited mechanistic understanding of how CSC and neuroendocrine phenotypes impact the development of m-CRPC. In this study, we explored the role of the intracellular chemokine CXCL12γ in CSC induction and neuroendocrine differentiation and its impact on m-CRPC. CXCL12γ expression was detected in small-cell carcinoma of metastatic tissues and circulating tumor cells from m-CRPC patients and in prostate cancer cells displaying an neuroendocrine phenotype. Mechanistic investigations demonstrated that overexpression of CXCL12γ induced CSC and neuroendocrine phenotypes in prostate cancer cells through CXCR4-mediated PKCα/NFκB signaling, which promoted prostate tumor outgrowth, metastasis, and chemoresistance in vivo. Together, our results establish a significant function for CXCL12γ in m-CRPC development and suggest it as a candidate therapeutic target to control aggressive disease.Significance: Expression of CXCL12γ induces the expression of a cancer stem cell and neuroendocrine phenotypes, resulting in the development of aggressive m-CRPC. Cancer Res; 78(8); 2026–39. ©2018 AACR.

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Tumorigenic and Antiproliferative Properties of the TALE-Transcription Factors MEIS2D and MEIS2A in Neuroblastoma

Neuroblastoma is one of only a few human cancers that can spontaneously regress even after extensive dissemination, a poorly understood phenomenon that occurs in as many as 10% of patients. In this study, we identify the TALE-homeodomain transcription factor MEIS2 as a key contributor to this phenomenon. We identified MEIS2 as a MYCN-independent factor in neuroblastoma and showed that in this setting the alternatively spliced isoforms MEIS2A and MEIS2D exert antagonistic functions. Specifically, expression of MEIS2A was low in aggressive stage 4 neuroblastoma but high in spontaneously regressing stage 4S neuroblastoma. Moderate elevation of MEIS2A expression reduced proliferation of MYCN-amplified human neuroblastoma cells, induced neuronal differentiation and impaired the ability of these cells to form tumors in mice. In contrast, MEIS2A silencing or MEIS2D upregulation enhanced the aggressiveness of the tumor phenotype. Mechanistically, MEIS2A uncoupled a negative feedback loop that restricts accumulation of cellular retinoic acid, an effective agent in neuroblastoma treatment. Overall, our results illuminate the basis for spontaneous regression in neuroblastoma and identify an MEIS2A-specific signaling network as a potential therapeutic target in this common pediatric malignancy.Significance: This study illuminates the basis for spontaneous regressions that can occur in a common pediatric tumor, with implications for the development of new treatment strategies. Cancer Res; 78(8); 1935–47. ©2018 AACR.

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S-Nitrosylation of cIAP1 Switches Cancer Cell Fate from TNF{alpha}/TNFR1-Mediated Cell Survival to Cell Death

TNFα is a prominent proinflammatory cytokine and a critical mediator for the development of many types of cancer such as breast, colon, prostate, cervical, skin, liver, and chronic lymphocytic leukemia. Binding of TNFα to TNFR1 can lead to divergent signaling pathways promoting predominantly NF-κB activation but also cell death. We report here that the nitric oxide (NO) donor glyceryl trinitrate (GTN) converts TNFα, generated from immune cells or cancer cells stimulated by chemotherapy, into a prodeath mediator in colon and mammary cancer cells. GTN-mediated S-nitrosylation of cIAP1 on cysteines 571 and 574 inhibited its E3 ubiquitin ligase activity, which in turn reduced Lys63-linked ubiquitination of RIP1 and initiated assembly of a death complex. These findings provide insights into how NO can harness advantageous aspects of inflammation in cancer and provide new therapeutic strategies.Significance: Combination of an NO donor with chemotherapeutic drug–induced TNFα represents a potentially valuable anticancer strategy. Cancer Res; 78(8); 1948–57. ©2018 AACR.

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Tumorigenic and Antiproliferative Properties of the TALE-Transcription Factors MEIS2D and MEIS2A in Neuroblastoma

Targeting Brain-Adaptive Cancer Stem Cells Prohibits Brain Metastatic Colonization of Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) exhibits more traits possessed by cancer stem cells (CSC) than other breast cancer subtypes and is more likely to develop brain metastases. TNBC patients usually have shorter survival time after diagnosis of brain metastasis, suggesting an innate ability of TNBC tumor cells in adapting to the brain. In this study, we establish novel animal models to investigate early tumor adaptation in brain metastases by introducing both patient-derived and cell line–derived CSC-enriched brain metastasis tumorsphere cells into mice. We discovered astrocyte-involved tumor activation of protocadherin 7 (PCDH7)-PLCβ-Ca2+-CaMKII/S100A4 signaling as a mediator of brain metastatic tumor outgrowth. We further identified and evaluated the efficacy of a known drug, the selective PLC inhibitor edelfosine, in suppressing the PCDH7 signaling pathway to prohibit brain metastases in the animal models. The results of this study reveal a novel signaling pathway for brain metastases in TNBC and indicate a promising strategy of metastatic breast cancer prevention and treatment by targeting organ-adaptive cancer stem cells.Significance: These findings identify a compound to block adaptive signaling between cancer stem cells and brain astrocytes. Cancer Res; 78(8); 2052–64. ©2018 AACR.

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