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PURPOSE: Late alopecia, defined as incomplete hair regrowth > 6 months following cytotoxic chemotherapy or > 6 months from initiation of endocrine therapy, negatively impacts quality of life and may affect dose intensity of adjuvant therapy. This study investigates the effect of oral minoxidil in women with chemotherapy and/or endocrine therapy-induced late alopecia. METHODS: The rate of clinical response was assessed by standardized photography and quantitated with trichoscopy. RESULTS: Two hundred and sixteen patients (mean age 57.8 ± 13.7) were included. The most common cancer diagnosis was breast, in 170 patients (79.1%). Alopecia developed after chemotherapy in 31 (14.4%) patients, endocrine monotherapy in 65 (30.1%) patients, and chemotherapy followed by endocrine therapy in 120 (55.6%) patients. In 119 patients, standardized photography assessments were used to determine clinical change in alopecia after a median of 105 (IQR = 70) days on oral minoxidil and revealed improvement in 88 (74%) patients. Forty-two patients received quantitative trichoscopic assessments at baseline and at follow-up after a median of 91 (IQR = 126) days on oral minoxidil. Patients had clinically and statistically significant increases in frontal hair shaft density (from 124.2 hairs/cm2 at initial to 153.2 hairs/cm2 at follow-up assessment, p = 0.008) and occipital shaft density (from 100.3 hairs/cm2 at initial to 123.5 hairs/cm2 at follow-up assessment. p = 0.004). No patients discontinued oral minoxidil due to adverse events. CONCLUSIONS: Overall, oral minoxidil was well tolerated by patients and may benefit both frontal and occipital late alopecia in cancer survivors treated with cytotoxic and/or endocrine therapy by increasing hair shaft and follicle density.
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AIMS: The most appropriate timing of exercise therapy to improve cardiorespiratory fitness (CRF) among patients initiating chemotherapy is not known. The effects of exercise therapy administered during, following, or during and following chemotherapy were examined in patients with breast cancer. METHODS AND RESULTS: Using a parallel-group randomized trial design, 158 inactive women with breast cancer initiating (neo)adjuvant chemotherapy were allocated to receive (1:1 ratio): usual care or one of three exercise regimens-concurrent (during chemotherapy only), sequential (after chemotherapy only), or concurrent and sequential (continuous) (n = 39/40 per group). Exercise consisted of treadmill walking three sessions/week, 20-50 min at 55%-100% of peak oxygen consumption (VO2peak) for ≈16 (concurrent, sequential) or ≈32 (continuous) consecutive weeks. VO2peak was evaluated at baseline (pre-treatment), immediately post-chemotherapy, and ≈16 weeks after chemotherapy. In intention-to-treat analysis, there was no difference in the primary endpoint of VO2peak change between concurrent exercise and usual care during chemotherapy vs. VO2peak change between sequential exercise and usual care after chemotherapy [overall difference, -0.88 mL O2·kg-1·min-1; 95% confidence interval (CI): -3.36, 1.59, P = 0.48]. In secondary analysis, continuous exercise, approximately equal to twice the length of the other regimens, was well-tolerated and the only strategy associated with significant improvements in VO2peak from baseline to post-intervention (1.74 mL O2·kg-1·min-1, P < 0.001). CONCLUSION: There was no statistical difference in CRF improvement between concurrent vs. sequential exercise therapy relative to usual care in women with primary breast cancer. The promising tolerability and CRF benefit of ≈32 weeks of continuous exercise therapy warrant further evaluation in larger trials.
Subject(s)
Breast Neoplasms , Humans , Female , Breast Neoplasms/drug therapy , Quality of Life , Oxygen Consumption , Exercise Therapy/methods , Chemotherapy, AdjuvantABSTRACT
PURPOSE: Chemotherapy with or without immunotherapy remains the mainstay of treatment for triple-negative breast cancer (TNBC). A subset of TNBCs express the androgen receptor (AR), representing a potential new therapeutic target. This study assessed the feasibility of adjuvant enzalutamide, an AR antagonist, in early-stage, AR-positive (AR +) TNBC. METHODS: This study was a single-arm, open-label, multicenter trial in which patients with stage I-III, AR ≥ 1% TNBC who had completed standard-of-care therapy were treated with enzalutamide 160 mg/day orally for 1 year. The primary objective of this study was to evaluate the feasibility of 1 year of adjuvant enzalutamide, defined as the treatment discontinuation rate of enzalutamide due to toxicity, withdrawal of consent, or other events related to tolerability. Secondary endpoints included disease-free survival (DFS), overall survival (OS), safety, and genomic features of recurrent tumors. RESULTS: Fifty patients were enrolled in this study. Thirty-five patients completed 1 year of therapy, thereby meeting the prespecified trial endpoint for feasibility. Thirty-two patients elected to continue with an optional second year of treatment. Grade ≥ 3 treatment-related adverse events were uncommon. The 1-year, 2-year, and 3-year DFS were 94%, 92% , and 80%, respectively. Median OS has not been reached. CONCLUSION: This clinical trial demonstrates that adjuvant enzalutamide is a feasible and well-tolerated regimen in patients with an early-stage AR + TNBC. Randomized trials in the metastatic setting may inform patient selection through biomarker development; longer follow-up is needed to determine the effect of anti-androgens on DFS and OS in this patient population.
Subject(s)
Triple Negative Breast Neoplasms , Benzamides , Feasibility Studies , Humans , Neoplasm Recurrence, Local/drug therapy , Nitriles/therapeutic use , Phenylthiohydantoin/adverse effects , Receptors, Androgen/genetics , Triple Negative Breast Neoplasms/pathologyABSTRACT
Androgen receptor (AR) inhibitor therapy is a developing treatment for AR-positive breast cancer (BC) with ongoing clinical trials. AR splice variant-7 (AR-V7) is a truncated variant of AR that leads to AR inhibitor therapy resistance in prostate cancer; recent studies have identified AR-V7 in BC and theorized that AR-V7 can have a similar impact. This study assessed the prevalence and clinicopathologic features associated with AR-V7 in a large BC cohort. BC samples were evaluated by MSK-Fusion targeted RNAseq for AR-V7 detection and MSK-IMPACT targeted DNAseq, including triple-negative tumors with no driver alteration and estrogen receptor-positive/ESR1 wildtype tumors progressing on therapy. Among 196 primary and metastatic/recurrent cases (196 RNAseq, 194DNAseq), 9.7% (19/196) were AR-V7 positive and 90.3% (177/196) AR-V7 negative. All AR-V7 positive BC were AR-positive by immunohistochemistry (19/19). The prevalence of AR-V7 by receptor subtype (N = 189) was: 18% (12/67) in ER-/PgR-/HER2-negative BC, 3.7% (4/109) in ER-positive/HER2-negative BC, and 15.4% (2/13) in HER2-positive BC; AR-V7 was detected in one ER-positive/HER2-unknown BC. Apocrine morphology was observed in 42.1% (8/19) of AR-V7 positive BC and 3.4% (6/177) AR-V7 negative BC (P < 0.00001). Notably, AR-V7 was detected in 2 primary BC and 7 metastatic/recurrent BC patients with no prior endocrine therapy. We conclude that positive AR IHC and apocrine morphology are pathologic features that may indicate testing for AR-V7 is warranted in both primary and metastatic BC in the appropriate clinical context. The study findings further encourage the assessment of AR-V7 as a predictive biomarker for AR antagonist benefit in ongoing clinical BC trials.
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Breast Neoplasms , Receptors, Androgen , Breast Neoplasms/genetics , Female , Humans , Neoplasm Recurrence, Local , Protein Isoforms/therapeutic use , Receptors, Androgen/geneticsABSTRACT
BACKGROUND: The current study was conducted to evaluate the efficacy and safety of pembrolizumab-mediated programmed cell death protein 1 inhibition plus radiotherapy (RT) in patients with metastatic triple-negative breast cancer who were unselected for programmed death-ligand 1 expression. METHODS: The current study was a single-arm, Simon 2-stage, phase 2 clinical trial that enrolled a total of 17 patients with a median age of 52 years (range, 37-73 years). An RT dose of 3000 centigrays (cGy) was delivered in 5 daily fractions. Pembrolizumab was administered intravenously at a dose of 200 mg within 3 days of the first RT fraction, and then every 3 weeks ± 3 days until disease progression. The median follow-up was 34.5 weeks (range, 2.1-108.3 weeks). The primary endpoint of the current study was the overall response rate (ORR) at week 13 in patients with unirradiated lesions measured using Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1). Secondary endpoints included safety and progression-free survival. Exploratory objectives were to identify biomarkers predictive of ORR and progression-free survival. RESULTS: The ORR for the entire cohort was 17.6% (3 of 17 patients; 95% CI, 4.7%-44.2%), with 3 complete responses (CRs), 1 case of stable disease, and 13 cases of progressive disease. Eight patients died prior to week 13 due to disease progression. Among the 9 women assessed using RECIST version 1.1 at week 13, 3 (33%) achieved a CR, with a 100% reduction in tumor volume outside of the irradiated portal. The CRs were durable for 18 weeks, 20 weeks, and 108 weeks, respectively. The most common grade 1 to 2 toxicity (assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0) was dermatitis (29%). Four grade 3 adverse events were attributed to pembrolizumab: fatigue, lymphopenia, and infection. No were no grade 4 adverse events or treatment-related deaths reported. CONCLUSIONS: The combination of pembrolizumab and RT was found to be safe and demonstrated encouraging activity in patients with poor-prognosis, metastatic, triple-negative breast cancer who were unselected for programmed death-ligand 1 expression. Larger clinical trials of checkpoint blockade plus RT with predictive biomarkers of response are needed.
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Radiotherapy/methods , Triple Negative Breast Neoplasms/therapy , Adult , Aged , Antibodies, Monoclonal, Humanized/adverse effects , Antineoplastic Agents, Immunological/adverse effects , Antineoplastic Agents, Immunological/therapeutic use , Chemoradiotherapy/adverse effects , Chemoradiotherapy/methods , Cohort Studies , Dermatitis/etiology , Fatigue/etiology , Female , Humans , Kaplan-Meier Estimate , Lymphopenia/etiology , Middle Aged , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/metabolism , Radiotherapy/adverse effects , Treatment Outcome , Triple Negative Breast Neoplasms/metabolism , Triple Negative Breast Neoplasms/pathologyABSTRACT
PURPOSE: Male breast cancer (BC) is rare, representing approximately 1% of cancers that occur in men and approximately 1% of all BCs worldwide. Because male BC is rare, not much is known about the disease, and treatment recommendations are typically extrapolated from data available from clinical trials enrolling female BC patients. METHODS: We review the epidemiology, risk factors, prognosis, and the varied molecular and clinicopathologic features that characterize male BC. In addition, we summarize the available data for the use of systemic therapy in the treatment of male BC and explore the ongoing development of targeted therapeutic agents for the treatment of this subgroup of BCs. RESULTS: There are important biological differences between male and female BC. Male BC is almost exclusively hormone receptor positive (+), including the androgen receptor (AR), and is associated with an increased prevalence of BRCA2 germline mutations, especially in men with increased risk for developing high-risk BC. Additional research is warranted to better characterize male BC. To accomplish this, a multi-national consortium approach, such as the International Male Breast Cancer Program, is needed in response to the scarcity of patients. This approach allows the pooling of information from a large number of men with BC and the creation of registries for future therapeutic-focused clinical trials. CONCLUSIONS: Given the unique biology of BC in men, promising new therapeutic targets are currently under investigation, including the use of poly-ADP-ribose polymerase inhibitors or AR-targeted agents either as monotherapy or in combination with other agents.
Subject(s)
Breast Neoplasms, Male/epidemiology , Breast Neoplasms, Male/therapy , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Breast Neoplasms, Male/etiology , Clinical Trials as Topic , Epigenesis, Genetic , Female , Gene Expression Regulation, Neoplastic , Humans , Male , SEER ProgramABSTRACT
PURPOSE: To investigate the utility of mammography for breast cancer screening in a population of males at increased risk for breast cancer. METHODS: In this HIPAA-compliant institutional review board-approved single-institution study, mammography records and clinical data of 827 male patients who underwent digital mammography from September 2011-July 2018 were analyzed via the electronic medical record. 664 of these men presented with masses, pain, or nipple discharge and were excluded from this study. The remaining 163 asymptomatic men with familial and/or personal history of breast cancer, or with a known germline mutation in BRCA, underwent screening mammography and were included in this analysis. RESULTS: 163 asymptomatic men (age: mean 63 years, range 24-87 years) underwent 806 screening mammograms. 125/163 (77%) had a personal history of breast cancer and 72/163 (44%) had a family history of breast cancer. 24/163 (15%) were known mutation carriers: 4/24 (17%) BRCA1 and 20/24 (83%) BRCA2. 792/806 (98%) of the screening mammograms were negative (BI-RADS 1 or 2); 10/806 (1.2%) were classified as BI-RADS 3, all of which were eventually downgraded to BI-RADS 2 on follow-up. 4/806 (0.4%) mammograms were abnormal (BI-RADS 4/5): all were malignant. The cancer detection rate in this cohort was 4.9 cancers/1000 examinations. CONCLUSIONS: In our cohort, screening mammography yielded a cancer detection rate of 4.9 cancers/1000 examinations which is like the detection rate of screening mammography in a population of women at average risk, indicating that screening mammography is of value in male patients at high risk for breast cancer.
Subject(s)
Breast Neoplasms, Male/diagnostic imaging , Breast Neoplasms, Male/epidemiology , Early Detection of Cancer , Mammography , Adult , Aged , Aged, 80 and over , Early Detection of Cancer/methods , Ethnicity , Humans , Male , Mammography/methods , Mass Screening , Middle Aged , Population Surveillance , United States/epidemiology , United States/ethnology , Young AdultABSTRACT
PURPOSE: Seviteronel (INO-464) is an oral, selective cytochrome P450c17a (CYP17) 17,20-lyase (lyase) and androgen receptor inhibitor with in vitro and in vivo anti-tumor activity. This open-label phase 1 clinical study evaluated safety, tolerability, pharmacokinetics (PK), and activity of once-daily (QD) seviteronel in women with locally advanced or metastatic TNBC or ER+ breast cancer. METHODS: Seviteronel was administered in de-escalating 750, 600, and 450 mg QD 6-subject cohorts. The 750 mg QD start dose was a phase 2 dose determined for men with castration-resistant prostate cancer in (Shore et al. J Clin Oncol 34, 2016). Enrollment at lower doses was initiated in the presence of dose-limiting toxicities (DLTs). The primary objective of this study was to determine seviteronel safety, tolerability, and MTD. The secondary objectives included description of its PK in women and its initial activity, including clinical benefit rate at 4 (CBR16) and 6 months (CBR24). RESULTS: Nineteen women were enrolled. A majority of adverse events (AEs) were Grade (Gr) 1/2, independent of relationship; the most common were tremor (42%), nausea (42%), vomiting (37%), and fatigue (37%). Four Gr 3/4 AEs (anemia, delirium, mental status change, and confusional state) deemed possibly related to seviteronel occurred in four subjects. DLTs were observed at 750 mg (Gr 3 confusional state with paranoia) and 600 mg (Gr 3 mental status change and Gr 3 delirium) QD, with none at 450 mg QD. The recommended phase 2 dose (RP2D) was 450 mg QD, and at the RP2D, 4 of 7 subjects reached at least CBR16 (2 TNBC subjects and 2 ER+ subjects achieved CBR16 and CBR24, respectively); no objective tumor responses were reported. CONCLUSIONS: Once-daily seviteronel was generally well tolerated in women with and 450 mg QD was chosen as the RP2D.
Subject(s)
Androgen Receptor Antagonists/therapeutic use , Antineoplastic Agents/therapeutic use , Breast Neoplasms/drug therapy , Steroid 17-alpha-Hydroxylase/antagonists & inhibitors , Triple Negative Breast Neoplasms/drug therapy , Aged , Aged, 80 and over , Androgen Receptor Antagonists/administration & dosage , Androgen Receptor Antagonists/adverse effects , Androgen Receptor Antagonists/pharmacokinetics , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Biomarkers, Tumor , Breast Neoplasms/metabolism , Female , Humans , Middle Aged , Receptors, Androgen/metabolism , Treatment Outcome , Triple Negative Breast Neoplasms/metabolismABSTRACT
A growing body of literature supports the conclusion that the androgen receptor (AR) plays an important role in breast cancer pathogenesis and may prove to be a relevant therapeutic target for patients with AR-driven breast cancer. This has been most apparent in the subset of patients with triple-negative breast cancer (TNBC), in whom approximately 50% of tumors may have androgen dependence. Recent phase 2 clinical trials of agents that antagonize AR or reduce androgen production have shown clinical benefit and efficacy to varying degrees. This review highlights three of these recent trials of AR+ TNBC and acknowledge ongoing research in this exciting area.
Subject(s)
Androgen Receptor Antagonists/therapeutic use , Breast Neoplasms/drug therapy , Gene Expression Regulation, Neoplastic/drug effects , Receptors, Androgen/chemistry , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Female , Humans , Prognosis , Receptors, Androgen/genetics , Receptors, Androgen/metabolismSubject(s)
Bacteria/isolation & purification , Breast Neoplasms/drug therapy , Fungi/isolation & purification , Paronychia/chemically induced , Paronychia/microbiology , Skin Diseases, Bacterial/microbiology , Antineoplastic Agents, Phytogenic/adverse effects , Dermatomycoses/drug therapy , Dermatomycoses/microbiology , Docetaxel , Female , Humans , Paclitaxel/adverse effects , Skin Diseases, Bacterial/drug therapy , Taxoids/adverse effectsABSTRACT
PURPOSE OF REVIEW: HIV-infected individuals remain at an increased risk for developing malignancies despite the use of combined antiretroviral therapy. Lymphomas comprise a large proportion of the malignancies that affect the HIV-infected population in developed countries. This review summarizes the recent progress made in HIV lymphoma research published in 2009 through January 2010. RECENT FINDINGS: The majority of investigation in this field has been in diffuse large B-cell lymphoma, with infusional therapy remaining promising. Rituximab likely improves complete response and possibly overall survival, but may be associated with increased infections in a subset of patients with very low CD4 cell counts. Risk factors associated with the development of lymphoma include low CD4 cell count and likely cumulative HIV viremia. Biologic insights have been realized regarding pathogenesis. SUMMARY: Overall, the outcome for HIV lymphoma continues to improve as insights into the pathophysiology and treatment advance.
Subject(s)
Antiretroviral Therapy, Highly Active/methods , HIV Infections/therapy , Lymphoma, AIDS-Related/therapy , Stem Cell Transplantation/methods , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal, Murine-Derived , CD4 Lymphocyte Count , Combined Modality Therapy , HIV/drug effects , HIV Infections/complications , Humans , Lymphoma, AIDS-Related/complications , Lymphoma, Large B-Cell, Diffuse/complications , Lymphoma, Large B-Cell, Diffuse/therapy , RituximabABSTRACT
PURPOSE: To determine whether the androgen receptor (AR) inhibitor, enzalutamide, improves effectiveness of endocrine therapy (ET) in hormone receptor-positive (HR+) breast cancer. PATIENTS AND METHODS: In this phase II trial, patients with HR+/HER2 normal advanced/metastatic breast cancer were randomized 1:1 to exemestane 25 mg with placebo or exemestane 50 mg with enzalutamide 160 mg daily (NCT02007512). Two parallel cohorts enrolled patients with 0 (cohort 1) or 1 (cohort 2) prior ET for advanced disease. Progression-free survival (PFS) was the primary endpoint in the intent-to-treat (ITT) population of each cohort. Biomarkers were evaluated in an exploratory analysis. RESULTS: Overall, 247 patients were randomized (cohort 1, n = 127 and cohort 2, n = 120). PFS was not improved in either cohort of the ITT population [HR, 0.82 (95% confidence interval (CI), 0.54-1.26); P = 0.3631 for cohort 1 and HR, 1.02 (95% CI, 0.66-1.59); P = 0.9212 for cohort 2]. In cohort 1, high levels of AR mRNA were associated with greater benefit of enzalutamide (P interaction = 0.0048). This effect was particularly apparent in patients with both high levels of AR mRNA and low levels of ESR1 mRNA [HR, 0.24 (95% CI, 0.10-0.60); P = 0.0011]. The most common any grade adverse events in the enzalutamide arms were nausea (39%) in cohort 1 and fatigue (37%) in cohort 2. CONCLUSIONS: Enzalutamide with exemestane was well tolerated. While PFS was not improved by the addition of enzalutamide to exemestane in an unselected population, ET-naïve patients with high AR mRNA levels, particularly in combination with low ESR1 mRNA levels, may benefit from enzalutamide with exemestane.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Receptor, ErbB-2/metabolism , Receptors, Estrogen/metabolism , Receptors, Progesterone/metabolism , Adult , Aged , Aged, 80 and over , Androstadienes/administration & dosage , Benzamides/administration & dosage , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Double-Blind Method , Female , Follow-Up Studies , Humans , Middle Aged , Nitriles/administration & dosage , Phenylthiohydantoin/administration & dosage , Prognosis , Survival RateABSTRACT
PURPOSE: IBM Watson for Oncology trained by Memorial Sloan Kettering (WFO) is a clinical decision support tool designed to assist physicians in choosing therapies for patients with cancer. Although substantial technical and clinical expertise has guided the development of WFO, patients' perspectives of this technology have not been examined. To facilitate the optimal delivery and implementation of this tool, we solicited patients' perceptions and preferences about WFO. METHODS: We conducted nine focus groups with 46 patients with breast, lung, or colorectal cancer with various treatment experiences: neoadjuvant/adjuvant chemotherapy, chemotherapy for metastatic disease, or systemic therapy through a clinical trial. In-depth qualitative and quantitative data were collected and analyzed to describe patients' attitudes and perspectives concerning WFO and how it may be used in clinical care. RESULTS: Analysis of the qualitative data identified three main themes: patient acceptance of WFO, physician competence and the physician-patient relationship, and practical and logistic aspects of WFO. Overall, participant feedback suggested high levels of patient interest, perceived value, and acceptance of WFO, as long as it was used as a supplementary tool to inform their physicians' decision making. Participants also described important concerns, including the need for strict processes to guarantee the integrity and completeness of the data presented and the possibility of physician overreliance on WFO. CONCLUSION: Participants generally reacted favorably to the prospect of WFO being integrated into the cancer treatment decision-making process, but with caveats regarding the comprehensiveness and accuracy of the data powering the system and the potential for giving WFO excessive emphasis in the decision-making process. Addressing patients' perspectives will be critical to ensuring the smooth integration of WFO into cancer care.
Subject(s)
Medical Oncology/education , Adult , Aged , Aged, 80 and over , Female , Focus Groups , Humans , Male , Middle Aged , United States , Young AdultABSTRACT
Importance: Taxanes with trastuzumab and pertuzumab for initial treatment of human epidermal growth factor receptor 2 (ERBB2, formerly HER2)-positive metastatic breast cancer is associated with improved progression-free survival (PFS) and overall survival. While continued use of trastuzumab in therapeutic combinations after disease progression is standard, the efficacy of continuing pertuzumab is unknown. Objective: To evaluate the efficacy and safety of pertuzumab in combination with gemcitabine and trastuzumab after prior treatment with pertuzumab for ERBB2-positive metastatic breast cancer. Design, Setting, and Participants: This is a phase 2 single-arm clinical trial of dual anti-ERBB2 therapy after prior treatment with pertuzumab. The study took place at a single academic center from March 2015 to April 2017 among women with ERBB2-positive metastatic breast cancer, prior pertuzumab-based treatment, and 3 or fewer prior chemotherapy regimens. Data were analyzed between January 2019 and March 2019. Intervention: Treatment consisted of gemcitabine, 1200 mg/m2 (later amended to 1000 mg/m2) on days 1 and 8 every 3 weeks, plus trastuzumab (8-mg/kg loading dose, then 6 mg/kg) and pertuzumab (840-mg loading dose, then 420 mg) once every 3 weeks. Main Outcomes and Measures: The primary end point was 3-month PFS. Based on prior trials, a target rate of 70% or higher was selected as the promising progression-free rate at 3 months. Secondary outcomes included safety, tolerability, and overall survival. Results: A total of 45 patients (median [range] age, 57.1 [31.7-77.2] years) were enrolled; 22 (49%) were treated in the second-line setting, and 23 (51%) were treated in the third-line setting or beyond. Of these, 22 (49%) received prior trastuzumab emtansine (T-DM1). At a median (range) follow-up of 27.6 (8.3-36.0) months, 3-month PFS was 73.3% (95% CI, 61.5%-87.5%). Overall, median PFS was 5.5 months (95% CI, 5.4-8.2 months). Treatment was well tolerated, with no occurrences of febrile neutropenia or symptomatic left ventricular systolic dysfunction. Conclusions and Relevance: In this phase 2 trial, treatment with gemcitabine, trastuzumab, and pertuzumab after prior pertuzumab-based therapy for ERBB2-positive metastatic breast cancer was associated with a 3-month PFS rate of 73.3% and was well tolerated. Continuation of pertuzumab beyond progression was associated with apparent clinical benefit. Trial Registration: ClinicalTrials.gov identifier: NCT02252887.
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Deoxycytidine/analogs & derivatives , Receptor, ErbB-2/genetics , Trastuzumab/therapeutic use , Adult , Aged , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Deoxycytidine/administration & dosage , Deoxycytidine/adverse effects , Deoxycytidine/therapeutic use , Female , Humans , Middle Aged , Progression-Free Survival , Trastuzumab/administration & dosage , Trastuzumab/adverse effects , Treatment Outcome , GemcitabineSubject(s)
Anticoagulants/adverse effects , Drugs, Generic/adverse effects , Enoxaparin/adverse effects , Skin/drug effects , Aged , Anticoagulants/pharmacokinetics , Drugs, Generic/pharmacokinetics , Enoxaparin/pharmacokinetics , Female , Humans , Male , Middle Aged , Necrosis/chemically induced , Necrosis/pathology , Skin/pathology , Therapeutic EquivalencyABSTRACT
Purpose Studies suggest that a subset of patients with triple-negative breast cancer (TNBC) have tumors that express the androgen receptor (AR) and may benefit from an AR inhibitor. This phase II study evaluated the antitumor activity and safety of enzalutamide in patients with locally advanced or metastatic AR-positive TNBC. Patients and Methods Tumors were tested for AR with an immunohistochemistry assay optimized for breast cancer; nuclear AR staining > 0% was considered positive. Patients received enzalutamide 160 mg once per day until disease progression. The primary end point was clinical benefit rate (CBR) at 16 weeks. Secondary end points included CBR at 24 weeks, progression-free survival, and safety. End points were analyzed in all enrolled patients (the intent-to-treat [ITT] population) and in patients with one or more postbaseline assessment whose tumor expressed ≥ 10% nuclear AR (the evaluable subgroup). Results Of 118 patients enrolled, 78 were evaluable. CBR at 16 weeks was 25% (95% CI, 17% to 33%) in the ITT population and 33% (95% CI, 23% to 45%) in the evaluable subgroup. Median progression-free survival was 2.9 months (95% CI, 1.9 to 3.7 months) in the ITT population and 3.3 months (95% CI, 1.9 to 4.1 months) in the evaluable subgroup. Median overall survival was 12.7 months (95% CI, 8.5 months to not yet reached) in the ITT population and 17.6 months (95% CI, 11.6 months to not yet reached) in the evaluable subgroup. Fatigue was the only treatment-related grade 3 or higher adverse event with an incidence of > 2%. Conclusion Enzalutamide demonstrated clinical activity and was well tolerated in patients with advanced AR-positive TNBC. Adverse events related to enzalutamide were consistent with its known safety profile. This study supports additional development of enzalutamide in advanced TNBC.
Subject(s)
Phenylthiohydantoin/analogs & derivatives , Receptors, Androgen/biosynthesis , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/metabolism , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Benzamides , Female , Humans , Immunohistochemistry , Kaplan-Meier Estimate , Middle Aged , Neoplasm Metastasis , Nitriles , Phenylthiohydantoin/administration & dosage , Phenylthiohydantoin/adverse effects , Progression-Free Survival , Triple Negative Breast Neoplasms/pathologyABSTRACT
Obesity, a cause of subclinical inflammation, is a risk factor for the development of postmenopausal breast cancer and is associated with poorer cancer outcomes. Docosahexaenoic acid (DHA), an omega-3 fatty acid, possesses anti-inflammatory properties. We hypothesized that treatment with DHA would reduce the expression of proinflammatory genes and aromatase, the rate-limiting enzyme for estrogen biosynthesis, in benign breast tissue of overweight/obese women. A randomized, placebo-controlled, double-blind phase II study of DHA given for 12 weeks to overweight/obese women with a history of stage I-III breast cancer, DCIS/LCIS, Paget's disease, or proliferative benign breast disease was carried out. In this placebo controlled trial, the primary objective was to determine whether DHA (1,000 mg by mouth twice daily) reduced breast tissue levels of TNFα. Secondary objectives included evaluation of the effect of DHA on breast tissue levels of COX-2, IL1ß, aromatase, white adipose tissue inflammation, and gene expression by RNA-seq. Red blood cell fatty acid levels were measured to assess compliance. From July 2013 to November 2015, 64 participants were randomized and treated on trial (32 women per arm). Increased levels of omega-3 fatty acids in red blood cells were detected following treatment with DHA (P < 0.001) but not placebo. Treatment with DHA did not alter levels of TNFα (P = 0.71), or other biomarkers including the transcriptome in breast samples. Treatment with DHA was overall well-tolerated. Although compliance was confirmed, we did not observe changes in the levels of prespecified biomarkers in the breast after treatment with DHA when compared with placebo. Cancer Prev Res; 11(4); 203-14. ©2018 AACRSee related editorial by Fabian and Kimler, p. 187.
Subject(s)
Biomarkers, Tumor/genetics , Breast Neoplasms/drug therapy , Carcinoma, Intraductal, Noninfiltrating/drug therapy , Docosahexaenoic Acids/therapeutic use , Fibrocystic Breast Disease/drug therapy , Precancerous Conditions/drug therapy , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Carcinoma, Intraductal, Noninfiltrating/genetics , Carcinoma, Intraductal, Noninfiltrating/pathology , Double-Blind Method , Female , Fibrocystic Breast Disease/genetics , Fibrocystic Breast Disease/pathology , Follow-Up Studies , Gene Expression Profiling , Humans , Middle Aged , Neoplasm Invasiveness , Precancerous Conditions/genetics , Precancerous Conditions/pathology , PrognosisABSTRACT
Purpose: Several lines of evidence support targeting the androgen signaling pathway in breast cancer. Enzalutamide is a potent inhibitor of androgen receptor signaling. Preclinical data in estrogen-expressing breast cancer models demonstrated activity of enzalutamide monotherapy and enhanced activity when combined with various endocrine therapies (ET). Enzalutamide is a strong cytochrome P450 3A4 (CYP3A4) inducer, and ETs are commonly metabolized by CYP3A4. The pharmacokinetic (PK) interactions, safety, and tolerability of enzalutamide monotherapy and in combination with ETs were assessed in this phase I/Ib study.Experimental Design: Enzalutamide monotherapy was assessed in dose-escalation and dose-expansion cohorts of patients with advanced breast cancer. Additional cohorts examined effects of enzalutamide on anastrozole, exemestane, and fulvestrant PK in patients with estrogen receptor-positive/progesterone receptor-positive (ER+/PgR+) breast cancer.Results: Enzalutamide monotherapy (n = 29) or in combination with ETs (n = 70) was generally well tolerated. Enzalutamide PK in women was similar to prior data on PK in men with prostate cancer. Enzalutamide decreased plasma exposure to anastrozole by approximately 90% and exemestane by approximately 50%. Enzalutamide did not significantly affect fulvestrant PK. Exposure of exemestane 50 mg/day given with enzalutamide was similar to exemestane 25 mg/day alone.Conclusions: These results support a 160 mg/day enzalutamide dose in women with breast cancer. Enzalutamide can be given in combination with fulvestrant without dose modifications. Exemestane should be doubled from 25 mg/day to 50 mg/day when given in combination with enzalutamide; this combination is being investigated in a randomized phase II study in patients with ER+/PgR+ breast cancer. Clin Cancer Res; 23(15); 4046-54. ©2017 AACR.
Subject(s)
Antineoplastic Agents, Hormonal/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Breast Neoplasms/drug therapy , Phenylthiohydantoin/analogs & derivatives , Adult , Aged , Anastrozole , Antineoplastic Agents, Hormonal/adverse effects , Antineoplastic Agents, Hormonal/pharmacokinetics , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Aromatase Inhibitors/administration & dosage , Aromatase Inhibitors/adverse effects , Benzamides , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Cytochrome P-450 CYP3A/genetics , Dose-Response Relationship, Drug , Drug-Related Side Effects and Adverse Reactions/classification , Drug-Related Side Effects and Adverse Reactions/pathology , Female , Humans , Middle Aged , Neoplasm Staging , Nitriles/administration & dosage , Phenylthiohydantoin/administration & dosage , Phenylthiohydantoin/adverse effects , Phenylthiohydantoin/pharmacokinetics , Postmenopause , Receptors, Estrogen/genetics , Receptors, Progesterone/genetics , Triazoles/administration & dosageABSTRACT
Obesity is associated with breast white adipose tissue (WAT) inflammation, elevated levels of the estrogen biosynthetic enzyme, aromatase, and systemic changes that have been linked to the pathogenesis of breast cancer. Here, we determined whether metabolic obesity, including changes in breast biology and systemic effects, occurs in a subset of women with normal body mass index (BMI). Breast WAT and fasting blood were collected from 72 women with normal BMI (<25 kg/m2) undergoing mastectomy for breast cancer risk reduction or treatment. WAT inflammation was defined by the presence of crown-like structures of the breast (CLS-B) which are composed of dead or dying adipocytes surrounded by macrophages. Severity of inflammation was measured as CLS-B/cm2 The primary objective was to determine whether breast WAT inflammation is associated with aromatase expression and activity. Secondary objectives included assessment of circulating factors and breast adipocyte size. Breast WAT inflammation was present in 39% of women. Median BMI was 23.0 kg/m2 (range, 18.4-24.9 kg/m2) in women with breast WAT inflammation versus 21.8 kg/m2 (range, 17.3-24.6 kg/m2) in those without inflammation (P = 0.04). Breast WAT inflammation was associated with elevated aromatase expression and activity, which increased with severity of inflammation (P < 0.05). Breast WAT inflammation correlated with larger adipocytes (P = 0.01) and higher circulating levels of C-reactive protein, leptin, insulin, and triglycerides (P ≤ 0.05). A subclinical inflammatory state associated with elevated aromatase in the breast, adipocyte hypertrophy, and systemic metabolic dysfunction occurs in some normal BMI women and may contribute to the pathogenesis of breast cancer. Cancer Prev Res; 10(4); 235-43. ©2017 AACRSee related article by Berger, p. 223-25.