Phase I trial of antigen-targeted autologous dendritic cell-based vaccine with in vivo activation of inducible CD40 for advanced prostate cancer

Abstract

This phase I trial reports the safety and activity of BPX101, a second-generation antigen-targeted autologous antigen presenting cell (APC) vaccine in men with metastatic castration-resistant prostate cancer (mCRPC). To manufacture BPX101, APCs collected in a single leukapheresis were transduced with adenoviral vector Ad5f35 encoding inducible human (ih)-CD40, followed by incubation with protein PA001, which contains the extracellular domain of human prostate-specific membrane antigen. The ih-CD40 represents a modified chimeric version of the dendritic cell (DC) co-stimulatory molecule, CD40, which responds to a bioinert membrane-permeable activating dimerizer drug, rimiducid (AP1903), permitting temporally controlled, lymphoid-localized, DC-specific activation. Eighteen men with progressive mCRPC following ≤1 prior chemotherapy regimen were enrolled to evaluate three doses of BPX101 (4 × 10⁶, 12.5 × 10⁶ and 25 × 10⁶ cells) administered intradermally every 2–4 weeks followed by rimiducid (0.4 mg/kg) intravenous (IV) infusion 24 h after each BPX101 dose. There were no dose-limiting toxicities. Immune upregulation as well as anti-tumor activity was observed with PSA declines, objective tumor regressions and robust efficacy of post-trial therapy. This novel antigen-targeted and in vivo activated immunotherapy platform may warrant further development as monotherapy and as a component of rational combinations.

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Ablative Therapies in Metastatic Breast Cancer: A Systematic Review

Abstract

Purpose

Patients with oligometastatic breast cancer are being increasingly offered ablative therapies, yet it is unclear which subpopulations may derive long-term benefit. This study sought to explore factors that could define a clinically relevant oligometastatic breast cancer population that benefits from ablative therapies.

Methods

A systematic review using MEDLINE for English language articles published between 1985 and April 2014 was undertaken. Criteria for review included studies that reported overall survival (OS) or progression-free survival (PFS) in breast cancer patients with distant metastases which also: quantified the extent of disease, had metachronous presentation of metastases, and reported on at least 5 patients.

Results

Of 59 674 screened studies, 41 studies of 1813 individual patients were identified. All studies were observational cohort studies (level 2B or 4 evidence) and underwent critical review. All outcomes pertaining to OS and PFS were extracted. Extracted data were too heterogeneous to facilitate a meta-analysis. The only factor that suggested worse outcomes was positive margins post-metastasectomy. There was no clear signal for improved outcomes in regards to age, disease extent, disease-free interval, or receptor status.

Conclusion

Existing evidence does not provide meaningful direction on which metastatic breast cancer patients should have ablation of their residual disease due to heterogeneous reporting of disease factors, patient factors, and outcomes. Thorough demonstration of the absence of high- or moderate-level evidence and the absence of clinical data to guide patient selection suggests that metastatic breast cancer patients being treated with ablative modalities should be placed on clinical trial.

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Immediate tissue expander or implant-based breast reconstruction does not compromise the oncologic delivery of post-mastectomy radiotherapy (PMRT)

Abstract

Purpose

Increasingly, women are choosing immediate breast reconstruction (IBR) following mastectomy. Reports have indicated IBR may compromise post-mastectomy radiotherapy (PMRT). We investigated the impact of IBR on timing of PMRT, target coverage, and doses to organs at risk in a modern radiotherapy practice using advanced planning techniques.

Methods

Between 2013 and 2015, PMRT was delivered to 116 patients (66 mastectomy alone, 50 IBR). PMRT was delivered with a median dose of 50 Gy in 25 fractions. Left-sided patients were treated in breath-hold under image guidance. Differences in dosimetric parameters and time to the initiation of PMRT were assessed between patients with and without reconstruction.

Results

Reconstructed patients were younger and had lower clinical stage disease. Reconstruction did not significantly increase the mean time to PMRT initiation (51 days reconstructed vs. 45 days non-reconstructed, p = 0.14) or the number of patients who initiated PMRT within 12 weeks of the last therapeutic intervention (48/50 [96.0] vs. 61/66 [92.4%], p = 0.41). There was no significant difference in the percentage of patients in whom the internal mammary lymph nodes (IMNs) were targeted (72 vs. 80%, p = 0.29) or in IMN target coverage (mean IMN V40.5 Gy 92.6 vs. 94.1%, p = 0.62). Reconstruction did not significantly affect the mean ipsilateral lung V20 (25.4 vs. 26.4%, p = 0.37) or the mean heart dose (2.2 vs. 2.1 Gy, p = 0.63).

Conclusions

In a specialized breast multidisciplinary practice, immediate breast reconstruction did not significantly delay PMRT, compromise target coverage, or increase dose to organs at risk.

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Squamous cell carcinoma of the breast in the United States: incidence, demographics, tumor characteristics, and survival

Abstract

Purpose

Squamous cell carcinoma of breast accounts for less than 0.1% of all breast cancers. The purpose of this study is to describe the epidemiology and survival of this rare malignancy.

Methods

Data were extracted from the National Cancer Institute's Surveillance, Epidemiology and End Results Registry to identify women diagnosed with squamous cell carcinoma of breast between 1998 and 2013. SEER*Stat 8.3.1 was used to calculate age-adjusted incidence, age-wise distribution, and annual percentage change in incidence. Kaplan–Meier curves were plotted for survival analysis. Univariate and multivariate Cox proportional hazard regression model was used to determine predictors of survival.

Results

A total of 445 cases of squamous cell carcinoma of breast were diagnosed during the study period. The median age of diagnosis was 67 years. The overall age-adjusted incidence between 1998 and 2013 was 0.62 per 1,000,000 per year, and the incidence has been on a decline. Approximately half of the tumors were poorly differentiated. Stage II was the most common stage at presentation. Majority of the cases were negative for expression of estrogen and progesterone receptor. One-third of the cases underwent breast conservation surgery while more than half of the cases underwent mastectomy (unilateral or bilateral). Approximately one-third of cases received radiation treatment. The 1-year and 5-year cause-specific survival was 81.6 and 63.5%, respectively. Excluding patient with metastasis or unknown stage at presentation, in multivariate Cox proportional hazard model, older age at diagnosis and higher tumor stage (T3 or T4) or nodal stage at presentation were significant predictors of poor survival.

Conclusions

Our study describes the unique characteristics of squamous cell carcinoma of breast and demonstrates that it is an aggressive tumor with a poor survival. Older age and higher tumor or nodal stages at presentation were independent predictors of poor survival for loco-regional stages.

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Sleep quality, duration, and breast cancer aggressiveness

Abstract

Purpose

Epidemiological studies suggest that short sleep duration and poor sleep quality may increase breast cancer risk. However, whether sleep is associated with breast tumor aggressiveness characteristics has largely been unexplored.

Methods

The study included 4171 non-Hispanic whites (NHW) and 235 African Americans (AA) diagnosed with incident, primary, invasive breast cancer in the Women's Health Initiative (WHI) Observational Study (1994–2013). We used logistic regression to examine the association of baseline sleep (sleep duration, sleep quality, WHI Insomnia Rating Scale) with tumor grade, stage, hormone receptor status, HER2 status.

Results

In NHW, women who reported 6 h of sleep/night were more likely to have tumors classified as regional/distant stage at diagnosis compared to women who slept 7–8 h/night (adjusted odds ratio (OR): 1.25, 95% confidence interval (CI): 1.05–1.48). AA women who reported their typical night's sleep as 'average quality' or 'restless or very restless sleep' were more likely to be diagnosed with triple-negative tumors than those who reported 'sound or restful' sleep (adjusted ORs: 2.91 (1.11, 7.63) and 3.74 (1.10, 12.77), respectively).

Conclusions

Our findings provide indications that aspects of sleep (sleep duration and quality), partially modifiable health behaviors, may be associated with development of aggressive tumor characteristics in postmenopausal women. The role of these sleep attributes may differ for NHW and AA women; however, further study in robust, racial diverse samples is needed. This study provides evidence that facets of sleep behavior are associated with the development of aggressive tumor features and these associations differ by race.

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Assessment of the prognostic and discriminating value of the novel bioscore system for breast cancer; a SEER database analysis

Abstract

Background

An updated bioscore has been proposed within the context of the 8th edition American Joint Committee on Cancer (AJCC) staging system for breast cancer. This study seeks to validate the discriminating value of this bioscore among non-metastatic breast cancer patients registered within the surveillance, epidemiology, and end results (SEER) database.

Methods

Through SEER*Stat program, SEER database (2010–2013) was accessed and bioscore was formulated for each patient. Overall and cancer-specific survival analyses according to both bioscore and AJCC pathological stages were conducted through Kaplan–Meier analysis/log-rank testing, and multivariate analysis was conducted through a Cox proportional model.

Results

A total of 181030 patients with non-metastatic, surgically treated breast cancer were identified in the period from 2010 to 2013. For overall and cancer-specific survival assessment according to the bioscore system, P values for pairwise comparisons among different score points were significant (P < 0.0001) except for the comparison between score 0 and score 1. For cancer-specific survival assessment according to the AJCC stages, P values for pairwise comparisons among different stages were significant (P < 0.0001) except for the comparison between stages IIIB and IIIC. For overall survival assessment according to the AJCC stages, P values for pairwise comparisons among different stages were significant (P < 0.001) except for the comparison between stages IA and IB. In a multivariate analysis, the following factors were associated with better cancer-specific survival (earlier stage disease, ER positivity, PR positivity, Her2 neu positivity, and nuclear grade) (P < 0.0001).

Conclusion

The current analysis confirms the prognostic utility of the bioscore system and suggests it may be incorporated into decision-making algorithms for non-metastatic breast cancer.

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MRI predicts pathologic complete response in HER2-positive breast cancer after neoadjuvant chemotherapy

Abstract

Background

Neoadjuvant treatment of HER2-positive breast cancer frequently leads to a pathologic complete response (pCR), which is associated with favourable long-term outcome. Treatment regimens typically consist of 6–9 cycles of trastuzumab-based chemotherapy, although many patients achieve early radiologic complete response (rCR). If rCR accurately predicts pCR, the number of chemotherapy cycles can possibly be reduced.

Methods

We performed a diagnostic accuracy study to determine the association between rCR and pCR in patients with stage II–III HER2-positive breast cancer treated with neoadjuvant trastuzumab-based chemotherapy at the Netherlands Cancer Institute. RCR was defined as the disappearance of pathologic contrast enhancement in the original tumour region on repeated magnetic resonance imaging (MRI). PCR was defined as the absence of invasive tumour cells in the resected breast specimen (ypT0/is). Diagnostic accuracy was estimated in the overall population and in subgroups based on hormone receptor (HR) status. The prognostic value of rCR for recurrence-free interval was evaluated as an exploratory analysis.

Results

We identified 296 eligible patients with 297 HER2-positive tumours (154 HR-negative and 143 HR-positive) treated with neoadjuvant trastuzumab-based chemotherapy between 2004 and 2016. Overall, the rCR rate was 69% (206/297) and the pCR rate was 61% (181/297). Among 206 patients with rCR, 150 also had pCR (negative predictive value [NPV] = 150/206 = 73%). Among 91 patients without rCR, 60 had residual tumour at pathology (positive predictive value [PPV] = 60/91 = 66%). The NPV was better in HR-negative compared to HR-positive tumours (88 vs. 57%), while the PPV was better in HR-positive tumours (50 vs. 78%). Achieving rCR was associated with a 5-year recurrence-free interval of 88% compared to 68% without rCR (hazard ratio 0.34, 95% confidence interval 0.17–0.65, P = 0.001).

Conclusion

Achieving rCR corresponds well with pCR in HER2-positive breast cancer, particularly in the HR-negative subgroup. RCR is also associated with improved long-term outcome.

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