PTEN in triple-negative breast carcinoma: protein expression and genomic alteration in pretreatment and posttreatment specimens.

Background: Recent advances have been made in targeting the phosphoinositide 3-kinase pathway in breast cancer. Phosphatase and tensin homolog (PTEN) is a key component of that pathway. Objective: To understand the changes in PTEN expression over the course of the disease in patients with triple-negative breast cancer (TNBC) and whether PTEN copy number variation (CNV) by next-generation sequencing (NGS) can serve as an alternative to immunohistochemistry (IHC) to identify PTEN loss. Methods: We compared PTEN expression by IHC between pretreatment tumors and residual tumors in the breast and lymph nodes after neoadjuvant chemotherapy in 96 patients enrolled in a TNBC clinical trial. A correlative analysis between PTEN protein expression and PTEN CNV by NGS was also performed. Results: With a stringent cutoff for PTEN IHC scoring, PTEN expression was discordant between pretreatment and posttreatment primary tumors in 5% of patients (n = 96) and between posttreatment primary tumors and lymph node metastases in 9% (n = 33). A less stringent cutoff yielded similar discordance rates. Intratumoral heterogeneity for PTEN loss was observed in 7% of the patients. Among pretreatment tumors, PTEN copy numbers by whole exome sequencing (n = 72) were significantly higher in the PTEN-positive tumors by IHC compared with the IHC PTEN-loss tumors (p < 0.0001). However, PTEN-positive and PTEN-loss tumors by IHC overlapped in copy numbers: 14 of 60 PTEN-positive samples showed decreased copy numbers in the range of those of the PTEN-loss tumors. Conclusion: Testing various specimens by IHC may generate different PTEN results in a small proportion of patients with TNBC; therefore, the decision of testing one versus multiple specimens in a clinical trial should be defined in the patient inclusion criteria. Although a distinct cutoff by which CNV differentiated PTEN-positive tumors from those with PTEN loss was not identified, higher copy number of PTEN may confer positive PTEN, whereas lower copy number of PTEN would necessitate additional testing by IHC to assess PTEN loss. Trial registration: NCT02276443.

Predictive Roles of Baseline Stromal Tumor-Infiltrating Lymphocytes and Ki-67 in Pathologic Complete Response in an Early-Stage Triple-Negative Breast Cancer Prospective Trial.

High stromal tumor-infiltrating lymphocytes (sTILs) are associated with improved pathologic complete response (pCR) in triple-negative breast cancer (TNBC). We hypothesize that integrating high sTILs and additional clinicopathologic features associated with pCR could enhance our ability to predict the group of patients on whom treatment de-escalation strategies could be tested. In this prospective early-stage TNBC neoadjuvant chemotherapy study, pretreatment biopsies from 408 patients were evaluated for their clinical and demographic features, as well as biomarkers including sTILs, Ki-67, PD-L1 and androgen receptor. Multivariate logistic regression models were developed to generate a computed response score to predict pCR. The pCR rate for the entire cohort was 41%. Recursive partitioning analysis identified ≥20% as the optimal cutoff for sTILs to denote 35% (143/408) of patients as having high sTILs, with a pCR rate of 59%, and 65% (265/408) of patients as having low sTILs, with a pCR rate of 31%. High Ki-67 (cutoff > 35%) was identified as the only predictor of pCR in addition to sTILs in the training set. This finding was verified in the testing set, where the highest computed response score encompassing both high sTILa and high Ki-67 predicted a pCR rate of 65%. Integrating Ki67 and sTIL may refine the selection of early stage TNBC patients for neoadjuvant clinical trials evaluating de-escalation strategies.

Prognostic Impact of High Baseline Stromal Tumor-Infiltrating Lymphocytes in the Absence of Pathologic Complete Response in Early-Stage Triple-Negative Breast Cancer.

High stromal tumor-infiltrating lymphocytes (sTILs) are associated with an improved pathologic complete response (pCR) and survival in triple-negative breast cancer (TNBC). We hypothesized that high baseline sTILs would have a favorable prognostic impact in TNBC patients without a pCR after neoadjuvant chemotherapy (NACT). In this prospective NACT study, pretreatment biopsies from 318 patients with early-stage TNBC were evaluated for sTILs. Recursive partitioning analysis (RPA) was applied to search for the sTIL cutoff best associated with a pCR. With ≥20% sTILs identified as the optimal cutoff, 33% patients had high sTILs (pCR rate 64%) and 67% had low sTILs (pCR rate 29%). Patients were stratified according to the sTIL cutoff (low vs. high) and response to NACT (pCR vs. residual disease (RD)). The primary endpoint was event-free survival (EFS), with hazard ratios calculated using the Cox proportional hazards regression model and the 3-year restricted mean survival time (RMST) as primary measures. Within the high-sTIL group, EFS was better in patients with a pCR compared with those with RD (HR 0.05; 95% CI 0.01-0.39; p = 0.004). The difference in the 3-year RMST for EFS between the two groups was 5.6 months (95% CI 2.3-8.8; p = 0.001). However, among patients with RD, EFS was not significantly different between those with high sTILs and those with low sTILs (p = 0.7). RNA-seq analysis predicted more CD8+ T cells in the high-sTIL group with favorable EFS compared with the high-sTIL group with unfavorable EFS. This study did not demonstrate that high baseline sTILs confer a benefit in EFS in the absence of a pCR.

A phase II study of Mirvetuximab Soravtansine in triple-negative breast cancer.

Folate receptor alpha (FRα) has been reported to be expressed in up to 80% of triple-negative breast cancers (TNBC) with limited expression in normal tissues, making it a promising therapeutic target. Mirvetuximab soravtansine (mirvetuximab-s) is an antibody drug conjugate which has shown promise in the treatment of FRα-positive solid tumors in early phase clinical trials. Herein, are the results of the first prospective phase II trial evaluating mirvetuximab-s in metastatic TNBC. Patients with advanced, FRα-positive TNBC were enrolled on this study. Mirvetuximab-s was administered at a dose of 6.0 mg/kg every 3 weeks. 96 patients with advanced TNBC consented for screening. FRα staining was performed on tumor tissue obtained from 80 patients. The rate of FRα positivity by immunohistochemistry was 10.0% (8/80). Two patients were treated on study, with best overall responses of stable disease in one and progressive disease in the other. Adverse events were consistent with earlier studies. The study was terminated early due to the low rate of FRα positivity in the screened patient population and lack of disease response in the two patients treated. The observed rate of FRα positivity was considerably lower than previously reported and none of the patients had a partial or complete response. Treatment with mirvetuximab-s should only be further explored in TNBC if an alternate biomarker strategy is developed for patient selection on the basis of additional preclinical data.

Rapid Breast Cancer Disease Progression Following Cyclin Dependent Kinase 4 and 6 Inhibitor Discontinuation.

Background: CDK 4 and 6 inhibitors (CDK4/6i), which arrest unregulated cancer cell proliferation, show clinical efficacy in breast cancer. Unexpectedly, a patient treated on a CDK4/6i-based trial, as first-line therapy in metastatic breast cancer, developed rapid disease progression following discontinuation of study drug while receiving standard second-line therapy off trial. We thus sought to expand this observation within a population of patients treated similarly at The University of Texas MD Anderson Cancer Center. Methods: Using an IRB-approved protocol, 4 patients previously enrolled on CDK4/6i trials were analyzed for outcomes after discontinuing study drug. These patients were treated on a randomized trial of first-line endocrine therapy +/- a CDK4/6i. Rapid disease progression was defined as progression occurring within 4 months of CDK4/6i discontinuation. Results: In total, 4 patients developed rapid disease progression and died; 2 of whom died within 6 months of CDK4/6i discontinuation. Conclusion: This case series suggests a potential for rapid disease progression following CDK4/6i discontinuation. However, the clinical course following progression must be validated in large CDK4/6i clinical trials and standard-of-care cohorts. If confirmed, such observations may alter the algorithm for subsequent therapy in patients with disease progression on CDK4/6i. Nevertheless, the need remains to define a mechanistic basis for this rapid progression and formulate alternative therapeutic strategies.

Metaplastic breast cancer: clinical overview and molecular aberrations for potential targeted therapy.

Metaplastic breast cancer is a rare subtype of invasive mammary carcinoma, with an aggressive behavior and usually poor outcome. Responses to systemic chemotherapy are suboptimal compared to patients with standard invasive ductal carcinoma. Limited data are available in regards to best treatment modalities, including chemotherapy. This review gives an overview of metaplastic breast cancer and its clinical and pathologic characteristics, in addition to treatment strategies, clinical trials, and future directions.

Leptomeningeal disease and breast cancer: the importance of tumor subtype.

Breast cancer (BC) is one of the most common tumors to involve the leptomeninges. We aimed to characterize clinical features and outcomes of patients with LMD based on BC subtypes. We retrospectively reviewed records of 233 patients diagnosed with LMD from BC between 1997 and 2012. Survival was estimated by the Kaplan-Meier method and significant differences in survival were determined by Cox proportional hazards or log-rank tests. Of 190 patients with BC subtype available, 67 (35 %) had hormone receptor positive (HR+)/human epidermal growth factor receptor 2 (HER2)-negative BC, 56 (29 %) had HER2+BC, and 67 (35 %) had triple-negative BC (TNBC). Median age at LMD diagnosis was 50 years. Median overall survival (OS) from LMD diagnosis was 4.4 months for HER2+BC (95 % CI 2.8, 6.9), 3.7 months (95 % CI 2.4, 6.0) for HR+/HER2-BC, and 2.2 months (95 % CI 1.5, 3.0) for TNBC (p = 0.0002). Older age was associated with worse outcome (p < 0.0001). Patients with HER2+BC and LMD were more likely to receive systemic therapy (ST) (p = 0.001). Use of intrathecal therapy (IT) (52 %) was similar (p = 0.35). Both IT (p < 0.0001) and ST (p < 0.0001) administration were associated with improved OS. After adjusting for age, IT, extracranial disease, and ST, patients with HER2+BC had better OS compared with HR+/HER2-BC (HR 1.72; 95 %CI 1.07-2.76) and TNBC (HR 3.30; 95 %CI 1.98-5.52). LMD carries a dismal prognosis. Modest survival differences by tumor subtype were seen. Patients with HER2+BC had the best outcome. There is an urgent need to develop effective treatment strategies.

Optimal therapy sequencing in metastatic castration-resistant prostate cancer.

Prostate cancer is the most common cancer in men worldwide, accounting for approximately 242,000 new cases and 28,000 deaths annually in the USA. Although localized disease is often curable, advanced disease is generally not, especially when the cancer becomes castration-resistant and metastasizes to bone. Fortunately, advances in research have led to the recent approval of several novel therapies for the treatment of metastatic disease, and many other promising agents are in development. With this success arises the distinct challenge of optimizing both sequencing and the design of rational combinations with these agents. This review focuses on practical and experimental approaches to this challenge.