Search

Adjuvant endocrine hormonal therapy (EHT) is highly effective and appropriate for nearly all breast cancer patients with hormone receptor-positive tumors, which represent 75% of all breast cancer diagnoses. Long-term use of EHT reduces recurrence rates and nearly halves the risk of death during the second decade after diagnosis. Despite the proven benefits, about 33% of women receiving EHT do not take their medication as prescribed. This causes an increase in the risk for recurrence and death.To promote adherence to EHT among breast cancer patients, this study will develop and pilot-test an intervention consisting of 1) a bilingual, culturally tailored, personalized, interactive smartphone application (app); and 2) support from a patient navigator. The control group will receive usual care. This 2-group randomized control trial will recruit 120 breast cancer patients receiving EHT at the Mays Cancer Center at UT Health San Antonio. The two-year study will have 3-time assessments (baseline, 3 and 6 months).This theory-based intervention will empower patients' self-monitoring and management. It will facilitate patient education, identification/reporting of side effects, delivery of self-care advice, and simplify communication between the patient and the oncology team. The ultimate goal of this innovative multi-communication intervention is to improve overall survival and life expectancy, enhance quality of life, reduce recurrence, and decrease healthcare cost. The anticipated outcome is a scalable, evidence-based, and easily disseminated intervention with potentially broad use to patients using EHT and other oral anticancer agents. Keywords: Breast cancer, Endocrine hormone therapy, Adherence, Smartphone app, Patient navigation

Purpose: Elacestrant significantly prolonged progression-free survival (PFS) with manageable safety versus standard-of-care (SOC) endocrine therapy (ET) in patients with estrogen receptor-positive (ER+), HER2- metastatic breast cancer and tumors harboring estrogen receptor 1 (ESR1) mutation following ET plus a cyclin-dependent kinase 4/6 inhibitor (ET+CDK4/6i). In patients with ESR1-mutated tumors, we evaluated the efficacy and safety of elacestrant versus SOC based on prior ET+CDK4/6i duration and in clinical subgroups with prior ET+CDK4/6i ≥12 months., Patients and Methods: EMERALD, an open-label phase III trial, randomly assigned patients with ER+, HER2- metastatic breast cancer who had received 1-2 prior lines of ET, mandatory CDK4/6i, and ≤1 chemotherapy to elacestrant (345 mg daily) or SOC (aromatase inhibitor or fulvestrant). PFS was assessed across subgroups in post hoc exploratory analyses without adjustment for multiple testing., Results: In patients with ESR1-mutated tumors and prior ET+CDK4/6i ≥12 months, the median PFS for elacestrant versus SOC was 8.6 versus 1.9 months (HR, 0.41; 95% confidence interval, 0.26-0.63). In this population, the median PFS (in months) for elacestrant versus SOC was 9.1 versus 1.9 (bone metastases), 7.3 versus 1.9 (liver and/or lung metastases), 9.0 versus 1.9 (<3 metastatic sites), 10.8 versus 1.8 (≥3 metastatic sites), 5.5 versus 1.9 (PIK3 catalytic subunit α mutation), 8.6 versus 1.9 (tumor protein p53 gene mutation), 9.0 versus 1.9 (HER2-low), 9.0 versus 1.9 (ESR1D538G-mutated tumors), and 9.0 versus 1.9 (ESR1Y537S/N-mutated tumors). Subgroup safety was consistent with the overall population., Conclusions: The duration of prior ET+CDK4/6i ≥12 months in metastatic breast cancer was associated with a clinically meaningful improvement in PFS for elacestrant compared with SOC and was consistent across all subgroups evaluated in patients with ER+, HER2-, ESR1-mutated tumors., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background: Novel agents have expanded the traditional HER2 definitions to include HER2-Low (HER2L) Breast Cancer (BC). We sought to evaluate the distinct molecular characteristics of HER2L BC to understand potential clinical/biologic factors driving resistance and clinical outcomes., Methods: Retrospective analysis was performed on 13,613 BC samples, tested at Caris Life Sciences via NextGen DNA/RNA Sequencing. BC subtypes were defined by IHC/ISH. CODEai database was used to access clinical outcomes from insurance claims data., Results: Overall, mutational landscape was similar between HER2L and classical subsets of HR+and HRneg cohorts. TP53 mutations were significantly higher in HRneg/HER2L group vs. HR+/HER2L tumors (p<0.001). A higher mutation rate of PIK3CA was observed in HRneg/HER2L tumors compared to TNBC subtype (p=0.016). PD-L1 positivity was elevated in HRneg/HER2L tumors compared to HR+/HER2L tumors, all p<0.01. Patients with HR+/HER2L tumors treated with CDK4/6 inhibitors had similar OS compared to pts with HR+/HER2-0 (HR=0.89, p=0.012). 27.2% of HR+/HER2L pts had activating PIK3CA mutations. Among HR+PIK3CA mutated tumors, HER2L pts treated with alpelisib showed no difference in OS vs. HER2-0 alpelisib-treated pts (HR=1.23, p=0.517). 13.9% of HER2L TNBC pts were PD-L1 + . Interestingly, pts with PD-L1 +  HER2L/HRneg (TNBC) treated with immune checkpoint inhibitors (ICI) showed improved OS than HER2-0 TNBC (HR=0.61, p=0.046)., Conclusion: Our findings expand the understanding of the molecular profile of the HER2L subgroup and comparison to the classically defined breast cancer subgroups. Genomic risk assessments after progression on novel therapeutics can be assessed to better define implications for mechanisms of resistance., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Phosphatidylinositol 3-kinase/AKT-serine threonine kinase/mammalian target of rapamycin (mTOR) pathway abnormalities contribute to endocrine resistance. Everolimus, an mTOR inhibitor, improved progression-free survival in hormone receptor-positive metastatic breast cancer (BC) when combined with endocrine therapy (ET). In this phase III randomized, placebo-controlled trial, we assessed the efficacy of everolimus + ET as adjuvant therapy in high-risk, hormone receptor-positive, human epidermal growth factor receptor 2-negative BC after adjuvant/neoadjuvant chemotherapy., Methods: Patients were randomly assigned 1:1 to physician's choice ET and 1 year of everolimus (10 mg orally once daily) or placebo stratified by risk group. The primary end point was invasive disease-free survival (IDFS) evaluated by a stratified log-rank test with the hazard ratio (HR) estimated by Cox regression. Subset analyses included preplanned evaluation by risk group and exploratory analyses by menopausal status and age. Secondary end points included overall survival (OS) and safety. Everolimus did not improve IDFS/OS when added to ET in patients with early-stage high-risk, hormone receptor-positive BC., Results: One thousand and nine hundred thirty-nine patients were randomly assigned with 1,792 eligible for analysis. Overall, no benefit of everolimus was seen for IDFS (HR, 0.94 [95% CI, 0.77 to 1.14]) or OS (HR, 0.97 [95% CI, 0.75 to 1.26]). The assumption of proportional hazards was not met suggesting significant variability in the HR over time since the start of treatment. In an unplanned subgroup analysis among postmenopausal patients (N = 1,221), no difference in IDFS (HR, 1.08 [95% CI, 0.86 to 1.36]) or OS (HR, 1.19 [95% CI, 0.89 to 1.60]) was seen. In premenopausal patients (N = 571), everolimus improved both IDFS (HR, 0.64 [95% CI, 0.44 to 0.94]) and OS (HR, 0.49 [95% CI, 0.28 to 0.86]). Treatment completion rates were lower in the everolimus arm compared with placebo (48% v 73%) with higher grade 3 and 4 adverse events (35% v 7%)., Conclusion: One year of adjuvant everolimus + ET did not improve overall outcomes. Subset analysis suggests mTOR inhibition as a possible target for patients who remain premenopausal after chemotherapy.

Molecular profiling guides precision treatment of breast cancer; however, Asian patients are underrepresented in publicly available large-scale studies. We established a comprehensive multiomics cohort of 773 Chinese patients with breast cancer and systematically analyzed their genomic, transcriptomic, proteomic, metabolomic, radiomic and digital pathology characteristics. Here we show that compared to breast cancers in white individuals, Asian individuals had more targetable AKT1 mutations. Integrated analysis revealed a higher proportion of HER2-enriched subtype and correspondingly more frequent ERBB2 amplification and higher HER2 protein abundance in the Chinese HR + HER2 + cohort, stressing anti-HER2 therapy for these individuals. Furthermore, comprehensive metabolomic and proteomic analyses revealed ferroptosis as a potential therapeutic target for basal-like tumors. The integration of clinical, transcriptomic, metabolomic, radiomic and pathological features allowed for efficient stratification of patients into groups with varying recurrence risks. Our study provides a public resource and new insights into the biology and ancestry specificity of breast cancer in the Asian population, offering potential for further precision treatment approaches., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Use of gonadotropin-releasing hormone (GnRH) agonists has been widely adopted to provide reversible ovarian function suppression for pre-menopausal breast cancer patients who are also receiving aromatase inhibitor or tamoxifen therapy based on results of 25 randomized trials representing almost 15,000 women demonstrating a survival benefit with this approach. Past clinical trials designed to establish the efficacy of GnRH agonists have monitored testosterone in the prostate cancer setting and estradiol in the breast cancer setting. We explore the merits of various biomarkers including estradiol, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) and their utility for informing GnRH agonist treatment decisions in breast cancer. Estradiol remains our biomarker of choice in ensuring adequate ovarian function suppression with GnRH agonist therapy among pre-menopausal women with breast cancer. We recommend future trials to continue to focus on estradiol levels as the primary endpoint, as they have in the past., (© 2024. The Author(s).)

Background: Mammary physiology is distinguished in containing adult stem/progenitor cells that are actively amending the breast tissue throughout the reproductive lifespan of women. Despite their importance in both mammary gland development, physiological maintenance, and reproduction, the exact role of mammary stem/progenitor cells in mammary tumorigenesis has not been fully elucidated in humans or animal models. The implications of modulating adult stem/progenitor cells in women could lead to a better understanding of not only their function, but also toward possible breast cancer prevention led us to evaluate the efficacy of rapamycin in reducing mammary stem/progenitor cell activity and malignant progression markers., Methods: We analyzed a large number of human breast tissues for their basal and luminal cell composition with flow cytometry and their stem and progenitor cell function with sphere formation assay with respect to age and menopausal status in connection with a clinical study (NCT02642094) involving a low-dose (2 mg/day) and short-term (5-7 days) treatment of the mTOR inhibitor sirolimus. The expression of biomarkers in biopsies and surgical breast samples were measured with quantitative analysis of immunohistochemistry., Results: Sirolimus treatment significantly abrogated mammary stem cell activity, particularly in postmenopausal patients. It did not affect the frequency of luminal progenitors but decreased their self-renewal capacity. While sirolimus had no effect on basal cell population, it decreased luminal cell population, particularly in postmenopausal patients. It also significantly diminished prognostic biomarkers associated with breast cancer progression from ductal carcinoma in situ to invasive breast cancer including p16INK4A, COX-2, and Ki67, as well as markers of the senescence-associated secretary phenotype, thereby possibly functioning in preventing early breast cancer progression., Conclusion: Overall, these findings indicate a link from mTOR signaling to mammary stem and progenitor cell activity and cancer progression. Trial registration This study involves a clinical trial registered under the ClinicalTrials.gov identifier NCT02642094 registered December 30, 2015., (© 2023. The Author(s).)

Background: Limited information is available for patients with breast cancer (BC) and coronavirus disease 2019 (COVID-19), especially among underrepresented racial/ethnic populations., Methods: This is a COVID-19 and Cancer Consortium (CCC19) registry-based retrospective cohort study of females with active or history of BC and laboratory-confirmed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection diagnosed between March 2020 and June 2021 in the US. Primary outcome was COVID-19 severity measured on a five-level ordinal scale, including none of the following complications, hospitalization, intensive care unit admission, mechanical ventilation, and all-cause mortality. Multivariable ordinal logistic regression model identified characteristics associated with COVID-19 severity., Results: 1383 female patient records with BC and COVID-19 were included in the analysis, the median age was 61 years, and median follow-up was 90 days. Multivariable analysis revealed higher odds of COVID-19 severity for older age (aOR per decade, 1.48 [95% CI, 1.32-1.67]); Black patients (aOR 1.74; 95 CI 1.24-2.45), Asian Americans and Pacific Islander patients (aOR 3.40; 95 CI 1.70-6.79) and Other (aOR 2.97; 95 CI 1.71-5.17) racial/ethnic groups; worse ECOG performance status (ECOG PS ≥2: aOR, 7.78 [95% CI, 4.83-12.5]); pre-existing cardiovascular (aOR, 2.26 [95% CI, 1.63-3.15])/pulmonary comorbidities (aOR, 1.65 [95% CI, 1.20-2.29]); diabetes mellitus (aOR, 2.25 [95% CI, 1.66-3.04]); and active and progressing cancer (aOR, 12.5 [95% CI, 6.89-22.6]). Hispanic ethnicity, timing, and type of anti-cancer therapy modalities were not significantly associated with worse COVID-19 outcomes. The total all-cause mortality and hospitalization rate for the entire cohort was 9% and 37%, respectively however, it varied according to the BC disease status., Conclusions: Using one of the largest registries on cancer and COVID-19, we identified patient and BC-related factors associated with worse COVID-19 outcomes. After adjusting for baseline characteristics, underrepresented racial/ethnic patients experienced worse outcomes compared to non-Hispanic White patients., Funding: This study was partly supported by National Cancer Institute grant number P30 CA068485 to Tianyi Sun, Sanjay Mishra, Benjamin French, Jeremy L Warner; P30-CA046592 to Christopher R Friese; P30 CA023100 for Rana R McKay; P30-CA054174 for Pankil K Shah and Dimpy P Shah; KL2 TR002646 for Pankil Shah and the American Cancer Society and Hope Foundation for Cancer Research (MRSG-16-152-01-CCE) and P30-CA054174 for Dimpy P Shah. REDCap is developed and supported by Vanderbilt Institute for Clinical and Translational Research grant support (UL1 TR000445 from NCATS/NIH). The funding sources had no role in the writing of the manuscript or the decision to submit it for publication., Clinical Trial Number: CCC19 registry is registered on ClinicalTrials.gov, NCT04354701., Competing Interests: GN, SV, AK, TS, NK, DA, JA, JA, ZB, NB, TB, BB, SB, MB, PB, SB, BB, HB, CC, HC, JD, AD, NE, LF, DF, CF, MG, CG, PG, SG, MH, HH, DH, CH, CJ, SJ, MJ, VK, EK, NK, VK, AK, DK, CL, PL, KL, ML, XL, GL, GL, DM, AM, MM, SM, RM, IM, VM, RN, SN, RN, TN, TO, OP, KP, JP, KP, JP, HP, MP, YR, PR, SR, JR, DR, MR, SR, AR, LS, PS, MS, LS, MS, DS, MS, LT, MT, ST, LW, GW, MW, EW, SM, BF, JW, ML, MA, DS No competing interests declared

Purpose: To evaluate the performance of a biopsy decision support algorithmic model, the intelligent-augmented breast cancer risk calculator (iBRISK), on a multicenter patient dataset., Materials and Methods: iBRISK was previously developed by applying deep learning to clinical risk factors and mammographic descriptors from 9700 patient records at the primary institution and validated using another 1078 patients. All patients were seen from March 2006 to December 2016. In this multicenter study, iBRISK was further assessed on an independent, retrospective dataset (January 2015-June 2019) from three major health care institutions in Texas, with Breast Imaging Reporting and Data System (BI-RADS) category 4 lesions. Data were dichotomized and trichotomized to measure precision in risk stratification and probability of malignancy (POM) estimation. iBRISK score was also evaluated as a continuous predictor of malignancy, and cost savings analysis was performed., Results: The iBRISK model's accuracy was 89.5%, area under the receiver operating characteristic curve (AUC) was 0.93 (95% CI: 0.92, 0.95), sensitivity was 100%, and specificity was 81%. A total of 4209 women (median age, 56 years [IQR, 45-65 years]) were included in the multicenter dataset. Only two of 1228 patients (0.16%) in the "low" POM group had malignant lesions, while in the "high" POM group, the malignancy rate was 85.9%. iBRISK score as a continuous predictor of malignancy yielded an AUC of 0.97 (95% CI: 0.97, 0.98). Estimated potential cost savings were more than $420 million., Conclusion: iBRISK demonstrated high sensitivity in the malignancy prediction of BI-RADS 4 lesions. iBRISK may safely obviate biopsies in up to 50% of patients in low or moderate POM groups and reduce biopsy-associated costs. Keywords: Mammography, Breast, Oncology, Biopsy/Needle Aspiration, Radiomics, Precision Mammography, AI-augmented Biopsy Decision Support Tool, Breast Cancer Risk Calculator, BI-RADS 4 Mammography Risk Stratification, Overbiopsy Reduction, Probability of Malignancy (POM) Assessment, Biopsy-based Positive Predictive Value (PPV3) Supplemental material is available for this article. Published under a CC BY 4.0 license.See also the commentary by McDonald and Conant in this issue., Competing Interests: Disclosures of conflicts of interest: C.F.E. No relevant relationships. T.H. No relevant relationships. T.A.P. No relevant relationships. V.K. Consultant fees from AstraZeneca, Daiichi, Seagen, Gilead, Novartis, Lilly, Pfizer, Genentech, and TerSera; payment or honoraria from AstraZeneca, Daiichi, Seagen, Gilead, Novartis, Lilly, and Genentech. M.E. No relevant relationships. E.B. No relevant relationships. P.M.O. No relevant relationships. K.A.K. No relevant relationships. H.S. No relevant relationships. L.W. No relevant relationships. J.E. No relevant relationships. Y.C.T.S. Research grants from the National Cancer Institute on topics unrelated to this manuscript. B.K. No relevant relationships. I.W.P. No relevant relationships. A.L.C. Grants or contracts from Novartis and Acrotech. K.K. No relevant relationships. D.S. No relevant relationships. W.T.Y. Research grant with Clarity sponsorship for “Evaluation of individual level breast cancer risk prediction in a cohort of patients with a personal history of breast cancer using a novel software as a medical device;” royalties or licenses from Elsevier. J.C.C. Support from the Breast Cancer Research Foundation (BCRF); philanthropic support from M. Neal and R. Neal; National Cancer Institute/National Institutes of Health grant number U01 CA268813; grants or contracts from the Cancer Prevention and Research Institute of Texas (grant no. RP220650); payment or honoraria from Duke and NUS Singapore (August 7, 2022); sole inventor on patent application number 10420838 entitled “Methods for treating cancer using iNOS-inhibitory compositions” held by Houston Methodist Hospital; participation on Merck Triple Negative Breast Cancer Advisory Board (December 13, 2022), Lilly Loxo Advisory Board (December 8, 2022), and BCRF Annual Meeting (October 26, 2022). S.T.C.W. No relevant relationships., (© 2023 by the Radiological Society of North America, Inc.)

Breast cancer has replaced lung cancer as the most common malignancy worldwide. The 5-year survival rate of breast cancer has reached 90%. Systemic treatment of breast cancer has developed into a mature system including chemotherapy, targeted therapy, endocrine therapy and immunotherapy. This article summarizes the annual progress of breast cancer chemotherapy, targeted therapy, endocrine therapy and immunotherapy in 2022, providing valuable information for future research to better guide individualized treatment of breast cancer, thereby improving the prognosis and quality of life of breast cancer patients., Competing Interests: Professor Binghe Xu and Fei Ma are members of the Cancer Innovation Editorial Board. To minimize bias, they were excluded from all editorial decision‐making related to the acceptance of this article for publication. The remaining authors declare no conflicts of interest., (© 2023 The Authors. Cancer Innovation published by John Wiley & Sons Ltd on behalf of Tsinghua University Press.)

Background: The COVID-19 pandemic has disrupted medical care, increased isolation, and exacerbated anxiety in breast cancer patients. Since March 2020, Breastcancer.org experienced a sustained surge in requested pandemic-related information and support. To characterize the pandemic-related experiences of breast cancer patients, we surveyed the Breastcancer.org Community early in the COVID-19 era., Methods: Breastcancer.org Community members were invited to complete an online questionnaire regarding their experience during the pandemic. Self-reported data on demographics, comorbidities, care disruptions, anxiety, coping ability, telemedicine use, and satisfaction with care were collected. Results were analyzed using Stata 16.0 (Stata Corp., Inc)., Results: Included were 568 current and previous breast cancer patients, primarily with U.S. residence. Overall, 43.8% reported at least one comorbidity associated with severe COVID-19 illness and 61.9% experienced care delays. Moderate to extreme anxiety about contracting COVID-19 was reported by 36.5%, increasing with number of comorbidities (33.0% vs. 55.4%, p = 0.021), current breast cancer diagnosis (30.4% vs. 42.5%, p = 0.011), and poorer coping ability (15.5% vs. 53.9%, p < 0.0001). Moderate to extreme anxiety about cancer care disruptions was reported by 29.1%, increasing with current breast cancer diagnosis (19.1% vs. 38.9%, p < 0.0001), actual delayed care (18.9% vs. 35.3%, p < 0.0001), and poorer coping ability (13.1% vs. 57.7%, p < 0.0001). Most utilized telehealth and found it helpful, but also expressed increased anxiety and subjectively expressed that these were less preferable., Conclusion: Early in the COVID-19 pandemic, anxiety was reported by a large proportion of breast cancer patients, with increased prevalence in those with risk factors. Attention to mental health is critical, as emotional distress not only harms quality of life but may also compromise outcomes., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Aberrant activities of various cell cycle and DNA repair proteins promote cancer growth and progression and render them resistant to therapies. Here, we demonstrate that the anti-depressant imipramine blocks growth of triple-negative (TNBC) and estrogen receptor-positive (ER+) breast cancers by inducing cell cycle arrest and by blocking heightened homologous recombination (HR) and non-homologous end joining-mediated (NHEJ) DNA repair activities. Our results reveal that imipramine inhibits the expression of several cell cycle- and DNA repair-associated proteins including E2F1, CDK1, Cyclin D1, and RAD51. In addition, we show that imipramine inhibits the growth of ER + breast cancers by inhibiting the estrogen receptor- α (ER-α) signaling. Our studies in preclinical mouse models and ex vivo explants from breast cancer patients show that imipramine sensitizes TNBC to the PARP inhibitor olaparib and endocrine resistant ER + breast cancer to anti-estrogens. Our studies suggest that repurposing imipramine could enhance routine care for breast cancer patients. Based on these results, we designed an ongoing clinical trial, where we are testing the efficacy of imipramine for treating patients with triple-negative and estrogen receptor-positive breast cancer. Since aberrant DNA repair activity is used by many cancers to survive and become resistant to therapy, imipramine could be used alone and/or with currently used drugs for treating many aggressive cancers., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

The major limitations of DNA-targeting chemotherapy drugs include life-threatening toxicity, acquired resistance and occurrence of secondary cancers. Here, we report a small molecule, Carbazole Blue (CB), that binds to DNA and inhibits cancer growth and metastasis by targeting DNA-related processes that tumor cells use but not the normal cells. We show that CB inhibits the expression of pro-tumorigenic genes that promote unchecked replication and aberrant DNA repair that cancer cells get addicted to survive. In contrast to chemotherapy drugs, systemic delivery of CB suppressed breast cancer growth and metastasis with no toxicity in pre-clinical mouse models. Using PDX and ex vivo explants from estrogen receptor (ER) positive, ER mutant and TNBC patients, we further demonstrated that CB effectively blocks therapy-sensitive and therapy-resistant breast cancer growth without affecting normal breast tissue. Our data provide a strong rationale to develop CB as a viable therapeutic for treating breast cancers., (© 2022. The Author(s).)

Background: Despite advances, there continues to be unmet need in breast cancer. Combining anti-programmed death-ligand 1 (PD-L1) cancer immunotherapy atezolizumab with other targeted therapies may enhance T-cell-dependent cytolytic antitumor activity., Methods: This open-label, phase Ib study evaluated the safety of atezolizumab-based combinations with antibody-dependent cellular cytotoxicity or antibody-drug conjugate (ADC) agents. Patients with unresectable human epidermal growth factor receptor 2-positive (HER2 + ) locally advanced or metastatic breast cancer (mBC) received atezolizumab with trastuzumab/pertuzumab, atezolizumab with the ADC ado-trastuzumab emtansine (T-DM1), or atezolizumab with trastuzumab/pertuzumab and docetaxel. In an early-breast cancer (eBC) "window of opportunity" study, patients with operable HER2 + locally advanced or inflammatory eBC received neoadjuvant atezolizumab with trastuzumab/pertuzumab or atezolizumab/T-DM1, followed by docetaxel, carboplatin, and trastuzumab/pertuzumab. Exploratory outcomes included tumor response and biomarkers., Results: By March 15, 2019, 73 patients were enrolled. Safety findings were consistent with the treatment components' individual profiles. Objective responses were observed in 2 of 6 and 5 of 14 patients in 2 mBC cohorts receiving atezolizumab/T-DM1 and in 6 of 6 patients with mBC receiving atezolizumab, trastuzumab/pertuzumab, and docetaxel. PD-L1 in immune cells was the only biomarker that increased with atezolizumab/T-DM1. In the window of opportunity cohorts, PD-L1 levels and CD8 + T-cell infiltration increased from baseline in HER2 + eBC tumors receiving atezolizumab with trastuzumab/pertuzumab or T-DM1, irrespective of response. Despite increases in T-cell and B-cell gene signatures with trastuzumab/pertuzumab, but not T-DM1, neither combination promoted T-cell receptor clonal expansion., Conclusion: Atezolizumab with antibody-dependent cellular cytotoxicity or ADC agents appears safe and may activate the adaptive immune system of patients with HER2 + eBC tumors more than those with mBC tumors., Competing Interests: Disclosure All authors have received grants and nonfinancial support from F. Hoffmann-La Roche during the conduct of the study. E.P.H. reports research funding to her institution from AbbVie, Acerta Pharma, Amgen, Aravive, ArQule, Arvinas, AstraZeneca, Black Diamond Therapeutics, Boehringer Ingelheim, Clovis Oncology, Compugen, Curis, CytomX, Daiichi Sankyo, Dana-Farber Cancer Hospital, Deciphera Pharmaceuticals, eFFECTOR Therapeutics, EMD Serono, Fochon Pharmaceuticals, Fujifilm, G1 Therapeutics, Genentech/Roche, H3 Biomedicine, Harpoon Therapeutics, Hutchison MediPharma, ImmunoGen, Immunomedics, Infinity Pharmaceuticals, InventisBio, Karyopharm, Leap Therapeutics, Lilly, Lycera, MacroGenics, MedImmune, Medivation, Merck, Mersana Therapeutics, Merus, Millennium Pharmaceuticals, Molecular Templates, Novartis, NuCana, Olema Oncology, OncoMed Pharmaceuticals, Onconova Therapeutics, Oncothyreon, Fosun Orinove PharmaTech, Pfizer, PharmaMar, Plexxikon, Polyphor, Puma Biotechnology, Radius Health, Regeneron Pharmaceuticals, Rgenix, Seattle Genetics, Sermonix Pharmaceuticals, Silverback Therapeutics, Stemcentrx, Sutro Biopharma, Syndax, Syros Pharmaceuticals, Taiho, Takeda, TapImmune, Tesaro, Torque Pharma, Verastem Oncology, Zenith Epigenetics, and Zymeworks; has acted in an advisory or consultancy role with fees paid to her institution from AstraZeneca, Black Diamond Therapeutics, Boehringer Ingelheim, CytomX, Daiichi Sankyo, Dantari, Genentech/Roche, H3 Biomedicine, Lilly, Merck, Mersana Therapeutics, Novartis, Pfizer, Puma Biotechnology, and Silverback Therapeutics; and has received travel support from AstraZeneca, Daiichi Sankyo, Lilly, Pfizer, and Puma Biotechnology. V.K. reports research funding from Eisai; has acted in an advisory or consultancy role for Amgen, AstraZeneca, Athenex Oncology, Celldex Therapeutics, Daiichi Sankyo, Eisai, Puma Biotechnology, and Seattle Genomics; and has served on speakers bureaus for Celgene, Eisai, Genentech, Genomic Health, Novartis, Pfizer, and Puma Biotechnology. C.F. has acted in an advisory or consultancy role for Cardinal Health, EMD Serono, Lilly, Novartis, Pfizer, Genentech/Roche, and Seattle Genetics/Astellas. G.A.V. reports research funding from AstraZeneca, Bristol Myers Squibb, Celcuity, GTx Inc, Halozyme, Immunomedics, Lilly, Merck, Pfizer, Puma Biotechnology, Genentech/Roche, and Tesaro; has acted in an advisory or consultancy role for Immunomedics, Lilly, Pfizer, Puma Biotechnology, and Genentech/Roche; and has served on speakers bureaus for AstraZeneca, Lilly, Novartis, Pfizer, and Puma Biotechnology. P.J.W. has acted in an advisory or consultancy role with fees paid to her institution from Genentech/Roche. M.P. is an employee of and reports stock ownership in Roche. S.Y.C. is an employee of Genentech/Roche and reports stock ownership in Roche. J.R. is an employee of Genentech and reports stock ownership in Roche. K.G. is a contracted biostatistician for Genentech/Roche. L.M. is an employee of Genentech/Roche and reports stock ownership in Roche. Y.L. is an employee of Genentech/Roche and reports stock ownership in Roche. L.A.E. reports research funding from Aduro Biotech, AstraZeneca, Bristol Myers Squibb, Bolt Biotherapeutics, Breast Cancer Research Foundation, Corvus Pharmaceuticals, US Department of Defense, EMD Serono, Genentech, HeritX, MacroGenics, MaxCyte, Merck, NSABP Foundation, National Cancer Institute, Novartis, Roche, Silverback Therapeutics, and Tempest Therapeutics; has acted in an advisory or consultancy role for AbbVie, Amgen, AstraZeneca, Bayer, Celgene, Chugai, CytomX, Genentech, Gritstone Oncology, Lilly, MacroGenics, MedImmune, Peregrine Pharmaceuticals, Replimune, Roche, Shionogi, Syndax, and Vaccinex; has received travel support from Bristol Myers Squibb, Genentech/Roche, and Novartis; has received nonfinancial compensation from eTheRNA; and has received royalties or milestone payments from Aduro Biotech and MolecuVax., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Opinion Statement: Since the 2013 Supreme Court declaration, panel testing for hereditary cancer syndromes has evolved into the gold standard for oncology germline genetic testing. With the advent of next-generation sequencing, competitive pricing, and developing therapeutic options, panel testing is now well integrated into breast cancer management and surveillance. Although many established syndromes have well-defined cancer risks and management strategies, several breast cancer genes are currently classified as limited-evidence genes by the National Comprehensive Cancer Network (NCCN). Follow-up for individuals with mutations in these genes is a point of contention due to conflicting information in the literature. The most recent NCCN guidelines have stratified management based on gene-specific cancer risks indicating that expanding data will allow for better recommendations as research progresses. The evolving management for these genes emphasizes the clinicians' need for evidence-based understanding of low penetrance breast cancer genes and their implications for patient care. This article reviews current literature for limited evidence genes, detailing cancer risks, association with triple-negative breast cancer, and recommendations for surveillance. A brief review of the challenges and future directions is outlined to discuss the evolving nature of cancer genetics and the exciting opportunities that can impact management., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Patients with cancer experience a higher burden of SARS-CoV-2 infection, disease severity, complications, and mortality, than the general population. SARS-CoV-2 mRNA vaccines are highly effective in the general population; however, few data are available on their efficacy in patients with cancer. Using a prospective cohort, we assessed the seroconversion rates and anti-SARS-CoV-2 spike protein antibody titers following the first and second dose of BNT162b2 and mRNA-1273 SARS-CoV-2 vaccines in patients with cancer in US and Europe from January to April 2021. Among 131 patients, most (94%) achieved seroconversion after receipt of two vaccine doses. Seroconversion rates and antibody titers in patients with hematological malignancy were significantly lower than those with solid tumors. None of the patients with history of anti-CD-20 antibody in the 6 months before vaccination developed antibody response. Antibody titers were highest for clinical surveillance or endocrine therapy groups and lowest for cytotoxic chemotherapy or monoclonal antibody groups., Competing Interests: Declaration of interests A.A. reported receiving personal fees for attending advisory from Bristol-Myers Squibb, AstraZeneca, Roche, Pfizer, Merck Sharp and Dohme, Astella, Eli Lilly, and Boehringer Ingelheim and receiving fees for speaking bureau for Eli Lilly, AstraZeneca, Merck Sharp and Dohme for work performed outside of this study. P.S. reported receiving a grant from the Biomedical Advanced Research and Development Authority outside of this work. I.L.-G. reported receiving personal fees for attending advisory from AstraZeneca. N.M. is a founder and minority shareholder of MaxiVAX SA, a private biotech company based in Geneva, Switzerland, working on personalized cancer immunotherapy and infectious disease vaccines, with no impact on the current manuscript. R.M. reported receiving research support from Celgene, Incyte, Abbvie, Samus, Genotech, Promedior, and CTI; and consulting fees from Novartis, Sierra Onc, LaJolla, and Pharma. D.S. reported receiving a grant from the Biomedical Advanced Research and Development Authority outside of this work. All other co-authors reported no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: This phase I study (RAD1901-005; NCT02338349) evaluated elacestrant, an investigational oral selective estrogen receptor degrader (SERD), in heavily pretreated women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer, including those with estrogen receptor gene alpha ( ESR1 ) mutation. The primary objective was to determine the maximum tolerated dose and/or recommended phase II dose (RP2D)., Methods: The study consisted of a 3 + 3 design (elacestrant capsules) followed by expansion at RP2D (400-mg capsules, then 400-mg tablets) for the evaluation of safety and antitumor activity. Elacestrant was taken once daily until progression or intolerability., Results: Of 57 postmenopausal women enrolled, 50 received RP2D (400 mg once daily): median age, 63 years; median three prior anticancer therapies, including cyclin-dependent kinase 4,6 inhibitors (CDK4/6i; 52%), SERD (52%), and ESR1 mutation (circulating tumor DNA; 50%). No dose-limiting toxicities occurred; the most common adverse events at RP2D (400-mg tablet; n = 24) were nausea (33.3%) and increased blood triglycerides and decreased blood phosphorus (25.0% each). Most adverse events were grade 1-2 in severity. The objective response rate was 19.4% (n = 31 evaluable patients receiving RP2D), 15.0% in patients with prior SERD, 16.7% in patients with prior CDK4/6i, and 33.3% in patients with ESR1 mutation (n = 5/15). The clinical benefit rate (24-week) was 42.6% overall (n = 47 patients receiving RP2D), 56.5% (n = 23, ESR1 mutation), and 30.4% (n = 23, prior CDK4/6i). Elacestrant clinical benefit was associated with decline in ESR1 mutant allele fraction., Conclusion: Elacestrant 400 mg orally once daily has an acceptable safety profile and demonstrated single-agent activity with confirmed partial responses in heavily pretreated patients with estrogen receptor-positive metastatic breast cancer. Notably, responses were observed in patients with ESR1 mutation as well as those with prior CDK4/6i and prior SERD. A phase III trial investigating elacestrant versus standard endocrine therapy is ongoing., Competing Interests: Aditya BardiaConsulting or Advisory Role: Novartis, Genentech, Pfizer, Spectrum Pharmaceuticals, BioTheranostics, Merck, Radius Health, Inc., Immunomedics, Genentech/Roche, Innocrin Pharma, Sanofi, Puma Biotechnology, Daiichi Sankyo/AstraZenecaResearch Funding: BioTheranostics Virginia KaklamaniHonoraria: Celgene, Eisai, Genentech, Novartis, Pfizer, Genomic Health, Puma Biotechnology, AstraZeneca, Seattle Genetics, Daiichi SankyoConsulting or Advisory Role: Amgen, Eisai, Puma Biotechnology, Celldex, AstraZeneca, AthenexSpeakers' Bureau: Eisai, Genentech, Celgene, Novartis, Genomic Health, Puma Biotechnology, PfizerResearch Funding: Eisai Sharon WilksHonoraria: Seattle GeneticsConsulting or Advisory Role: Seattle GeneticsResearch Funding: Seattle Genetics Donald RichardsConsulting or Advisory Role: Ipsen, Taiho Pharmaceutical, Seattle Genetics/Astellas, Mirati Therapeutics Wael HarbResearch Funding: AI Therapeutics Cynthia OsborneHonoraria: Agendia, Guardant Health, Breast Cancer Index, Seattle Genetics, ImmunomedicsSpeakers' Bureau: Novartis, LillyTravel, Accommodations, Expenses: Novartis, Lilly Robert WesolowskiConsulting or Advisory Role: Puma Biotechnology, Pfizer, Roche DiagnosticsResearch Funding: Acerta PharmaTravel, Accommodations, Expenses: Puma Biotechnology, Pfizer, Roche Diagnostics Meghan KaruturiConsulting or Advisory Role: Pfizer, MD Anderson Physician's Network Paul ConklingEmployment: Virginia Oncology AssociatesResearch Funding: Bristol-Myers Squibb, EMD Serono, Arcus Biosciences, Aptose Biosciences, Janssen, Pfizer, Bayer, Astex Pharmaceuticals Rebecca G. BagleyEmployment: Radius Health, Inc. Yamei WangEmployment: Radius Health, Inc.Stock and Other Ownership Interests: RDUS Maureen G. ConlanEmployment: Radius Health, Inc.Stock and Other Ownership Interests: Radius Health, Inc. Peter KabosConsulting or Advisory Role: LillyResearch Funding: Radius Health, Inc., Lilly, Pfizer, AstraZeneca, Sanofi, Genentech, AngiochemNo other potential conflicts of interest were reported.

Triple-negative breast cancer (TNBC) is a highly heterogeneous disease, and molecular subtyping may result in improved diagnostic precision and targeted therapies. Our previous study classified TNBCs into four subtypes with putative therapeutic targets. Here, we conducted the FUTURE trial (ClinicalTrials.gov identifier: NCT03805399), a phase Ib/II subtyping-based and genomic biomarker-guided umbrella trial, to evaluate the efficacy of these targets. Patients with refractory metastatic TNBC were enrolled and stratified by TNBC subtypes and genomic biomarkers, and assigned to one of these seven arms: (A) pyrotinib with capecitabine, (B) androgen receptor inhibitor with CDK4/6 inhibitor, (C) anti PD-1 with nab-paclitaxel, (D) PARP inhibitor included, (E) and (F) anti-VEGFR included, or (G) mTOR inhibitor with nab-paclitaxel. The primary end point was the objective response rate (ORR). We enrolled 69 refractory metastatic TNBC patients with a median of three previous lines of therapy (range, 1-8). Objective response was achieved in 20 (29.0%, 95% confidence interval (CI): 18.7%-41.2%) of the 69 intention-to-treat (ITT) patients. Our results showed that immunotherapy (arm C), in particular, achieved the highest ORR (52.6%, 95% CI: 28.9%-75.6%) in the ITT population. Arm E demonstrated favorable ORR (26.1%, 95% CI: 10.2%-48.4% in the ITT population) but with more high grade (≥ 3) adverse events. Somatic mutations of TOP2A and CD8 immunohistochemical score may have the potential to predict immunotherapy response in the immunomodulatory subtype of TNBC. In conclusion, the phase Ib/II FUTURE trial suggested a new concept for TNBC treatment, demonstrating the clinical benefit of subtyping-based targeted therapy for refractory metastatic TNBC.

Purpose: Patients with triple-negative breast cancer (TNBC) with homologous recombination deficient tumors achieve significantly higher pathologic complete response (pCR) rates when treated with neoadjuvant platinum-based therapy. Tumor-infiltrating lymphocytes (TIL) are prognostic and predictive of chemotherapy benefit in early stage TNBC. The relationship between TILs, BRCA1/2 mutation status, and homologous recombination deficiency (HRD) status in TNBC remains unclear., Experimental Design: We performed a pooled analysis of five phase II studies that included patients with TNBC treated with neoadjuvant platinum-based chemotherapy to evaluate the association of TILs with HRD status (Myriad Genetics) and tumor BRCA1/2 mutation status. Furthermore, the relationship between pathologic response assessed using the residual cancer burden (RCB) index and HRD status with adjustment for TILs was evaluated., Results: Among 161 patients, stromal TIL (sTIL) density was not significantly associated with HRD status ( P = 0.107) or tumor BRCA1/2 mutation status ( P = 0.391). In multivariate analyses, sTIL density [OR, 1.23; 95% confidence interval (CI), 0.94-1.61; P = 0.139] was not associated with pCR, but was associated with RCB 0/I status (OR 1.62; 95% CI, 1.20-2.28; P = 0.001). HRD was significantly associated with both pCR (OR 12.09; 95% CI, 4.11-44.29; P = 7.82 × 10 -7 ) and RCB 0/I (OR 10.22; 95% CI, 4.11-28.75; P = 1.09 × 10 -7 ) in these models., Conclusions: In patients with TNBC treated with neoadjuvant platinum-based therapy, TIL density was not significantly associated with either tumor BRCA1/2 mutation status or HRD status. In this pooled analysis, HRD and sTIL density were independently associated with treatment response, with HRD status being the strongest predictor., (©2019 American Association for Cancer Research.)

Background: The purpose of this study was to investigate the value of 18 [F]-fluorodeoxyglucose ( 18 F-FDG) positron emission tomography/computed tomography (PET/CT) in tailoring axillary surgery by predicting nodal response among patients with node-positive breast cancer after neoadjuvant chemotherapy (NAC)., Methods: One hundred thirty-three patients with breast cancer with biopsy-confirmed nodal metastasis were prospectively enrolled. 18 F-FDG PET/CT scan was performed before NAC (a second one after two cycles with baseline maximum standardized uptake value [SUV max ] ≥2.5), and a subset of patients underwent targeted axillary dissection (TAD). All the patients underwent axillary lymph node dissection (ALND). The accuracy was calculated by a comparison with the final pathologic results., Results: With the cutoff value of 2.5 for baseline SUV max and 78.4% for change in SUV max , sequential 18 F-FDG PET/CT scans demonstrated a sensitivity of 79.0% and specificity of 71.4% in predicting axillary pathologic complete response with an area under curve (AUC) of 0.75 (95% confidence interval, 0.65-0.84). Explorative subgroup analyses indicated little value for estrogen receptor (ER)-negative, human epidermal growth factor receptor 2 (HER2)-positive patients (AUC, 0.55; sensitivity, 56.5%; specificity, 50.0%). Application of 18 F-FDG PET/CT could spare 19 patients from supplementary ALNDs and reduce one of three false-negative cases in TAD among the remaining patients without ER-negative/HER2-positive subtype., Conclusion: Application of the subtype-guided 18 F-FDG PET/CT could accurately predict nodal response and aid in tailoring axillary surgery among patients with node-positive breast cancer after NAC, which includes identifying candidates appropriate for TAD or directly proceeding to ALND. This approach might help to avoid false-negative events in TAD., Implications for Practice: This feasibility study showed that 18 [F]-fluorodeoxyglucose ( 18 F-FDG) positron emission tomography/computed tomography (PET/CT) could accurately predict nodal response after neoadjuvant chemotherapy (NAC) among patients with breast cancer with initial nodal metastasis except in estrogen receptor-negative, human epidermal growth factor receptor 2-positive subtype. Furthermore, the incorporation of 18 F-FDG PET/CT can tailor subsequent axillary surgery by identifying patients with residual nodal disease, thus sparing those patients supplementary axillary lymph node dissection. Finally, we have proposed a possibly feasible flowchart involving 18 F-FDG PET/CT that might be applied in post-NAC axillary evaluation., (© AlphaMed Press 2019.)

Purpose: We evaluated the role of everolimus in the prevention of ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) progression., Experimental Design: The effects of everolimus on breast cancer cell invasion, DCIS formation, and DCIS progression to IDC were investigated in a 3D cell culturing model, intraductal DCIS xenograft model, and spontaneous MMTV-Her2/neu mouse model. The effect of everolimus on matrix metalloproteinase 9 (MMP9) expression was determined with Western blotting and IHC in these models and in patients with DCIS before and after a window trial with rapamycin. Whether MMP9 mediates the inhibition of DCIS progression to IDC by everolimus was investigated with knockdown or overexpression of MMP9 in breast cancer cells., Results: Everolimus significantly inhibited the invasion of human breast cancer cells in vitro . Daily intragastric treatment with everolimus for 7 days significantly reduced the number of invasive lesions from intraductal DCIS foci and inhibited DCIS progression to IDC in the MMTV-Her2/neu mouse mammary tumor model. Mechanistically, everolimus treatment decreased the expression of MMP9 in the in vitro and in vivo models, and in breast tissues from patients with DCIS treated with rapamycin for 1 week. Moreover, overexpression of MMP9 stimulated the invasion, whereas knockdown of MMP9 inhibited the invasion of breast cancer cell-formed spheroids in vitro and DCIS in vivo . Knockdown of MMP9 also nullified the invasion inhibition by everolimus in vitro and in vivo ., Conclusions: Targeting mTORC1 can inhibit DCIS progression to IDC via MMP9 and may be a potential strategy for DCIS or early-stage IDC therapy., (©2019 American Association for Cancer Research.)

Newly diagnosed breast cancer patients seek information through a variety of sources. In this small pilot study, we evaluated the feasibility of providing personalizable breast cancer video education prior to the first oncology consultation and compared outcomes to patients receiving standard of care educational materials. Personalized videos included detailed information on a patient's specific grade, stage, and tumor subtype (e.g., grade 2, stage 3, triple negative breast cancer) in addition to general videos that defined the terms of grade, stage, and cancer subtype. Newly diagnosed breast cancer patients who were scheduled for an initial oncology appointment at two sites were enrolled in this prospective, randomized control trial. Twenty-eight patients were assigned to receive either video education (experimental group) with the possibility of personalization or a video explaining how to view cancer education materials at the cancer center website (control group). Sixteen oncologists at the two centers also participated in evaluating patient outcomes. Pre- and post-education surveys queried patient-perceived understanding of breast cancer and treatment, perceived ability for decision-making, confidence in providers, and anxiety and depression symptoms. We observed that patients given video education had greater improvements in some of these areas, with the biggest improvement seen in patients who received a personalized video on their specific tumor subtype (based on tumor receptor status). Overall, however, there were no statistically significant differences between the study groups. We conclude that providing personalized video education during the time prior to first oncologic consultation is feasible and may provide benefit for patients, especially for explaining complex components of a diagnosis, such as a cancer subtype. Further research is needed to determine how to optimally provide education tailored to a given patient and tumor type, and how to leverage patients' electronic devices as an education delivery vehicle.

Background: Increased signaling through growth factor receptor pathways, including HER2, plays a role in resistance to endocrine therapy (ET) in patients with hormone receptor (HR)-positive metastatic breast cancer (MBC). Inhibition of mechanistic target of rapamycin improves outcomes when used in addition to ET in patients with HR-positive MBC, who previously received ET. We hypothesized that the additional use of trastuzumab (T) or everolimus (E) could restore sensitivity to ET in patients with endocrine-resistant, HR-positive, HER2-negative MBC., Patients and Methods: Patients with endocrine-resistant HR-positive, HER2-negative MBC continued the ET during which they had experienced disease progression, and were randomized to receive T or E. At disease progression, patients could continue the therapy they were receiving and have E or T used in addition., Results: Fifty-four patients were randomized to the additional use of E (n = 30) or T (n = 24) with existing ET. Progression-free survival (PFS) was 5.7 months, and 2.2 months, respectively, and clinical benefit rate at 24 weeks was 48% and 11% for patients receiving E or T, respectively. PFS was 4.5 months and 3.1 months for patients in whom E (n = 16) or T (n = 12) was used post progression, respectively. There were no new safety signals apart from 2 patients who had a decreased ejection fraction while receiving E with ET., Conclusion: These results suggest that E, but not T, can potentially reverse resistance to ET in patients with endocrine-resistant HR-positive, HER2-negative MBC. Further, the additional use of E with an ET to which the cancer has already been exposed might offer the possibility of delaying time to use of chemotherapy., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Eribulin is a novel microtubule inhibitor with mitotic and nonmitotic mechanisms of action. Both pooled and subgroup analyses from large-scale Phase III clinical trials demonstrated that eribulin has substantial activity in patients with pretreated (anthracycline and a taxane) advanced or metastatic breast cancer. We review recent pharmacological and clinical findings pertaining to eribulin use in metastatic breast cancer - particularly highlighting eribulin in difficult-to-treat and aggressive disease, and safety data in specific patient populations. Additionally, recent advancements in our understanding of the mechanism of action of eribulin and potential future directions for its clinical development are discussed. Ongoing studies of eribulin in combination with immunotherapies and established cytotoxic agents may help shape the future landscape of breast cancer treatment.

The PI3K pathway is mutated and aberrantly activated in many cancers and plays a central role in tumor cell proliferation and survival, making it a rational therapeutic target. Until recently, however, results from clinical trials with PI3K inhibitors in solid tumors have been largely disappointing. Here, we describe several factors that have limited the success of these agents, including the weak driver oncogenic activity of mutant PI3K, suboptimal patient selection in trials, drug-related toxicities, feedback upregulation of compensatory mechanisms when PI3K is blocked, increased insulin production upon PI3Kα inhibition, lack of mutant-specific inhibitors, and a relative scarcity of studies using combinations with PI3K antagonists. We also suggest strategies to improve the impact of these agents in solid tumors. Despite these challenges, we are optimistic that isoform-specific PI3K inhibitors, particularly in combination with other agents, may be valuable in treating appropriately selected patients with PI3K-dependent tumors. SIGNIFICANCE: Despite the modest clinical activity of PI3K inhibitors in solid tumors, there is an increasing understanding of the factors that may have limited their success. Strategies to ameliorate drug-related toxicities, use of rational combinations with PI3K antagonists, development of mutant-selective PI3K inhibitors, and better patient selection should improve the success of these targeted agents against solid tumors., (©2019 American Association for Cancer Research.)

We comprehensively analyzed clinical, genomic, and transcriptomic data of a cohort of 465 primary triple-negative breast cancer (TNBC). PIK3CA mutations and copy-number gains of chromosome 22q11 were more frequent in our Chinese cohort than in The Cancer Genome Atlas. We classified TNBCs into four transcriptome-based subtypes: (1) luminal androgen receptor (LAR), (2) immunomodulatory, (3) basal-like immune-suppressed, and (4) mesenchymal-like. Putative therapeutic targets or biomarkers were identified among each subtype. Importantly, the LAR subtype showed more ERBB2 somatic mutations, infrequent mutational signature 3 and frequent CDKN2A loss. The comprehensive profile of TNBCs provided here will serve as a reference to further advance the understanding and precision treatment of TNBC., (Copyright © 2019 Elsevier Inc. All rights reserved.)

[This corrects the article DOI: 10.1016/j.conctc.2018.10.001.].

Minority representation in clinical trials is vital for researchers to assess differential effects in outcomes of therapies on biological and genetic characteristics among groups. This study assessed the effect of Choices, a bilingual multi-component intervention, on perceived understanding of clinical trials, agreement with stages of decision readiness and consideration of clinical trials as a treatment option, among Latina breast cancer patients. This randomized controlled pilot study compared Choices with a control condition providing general clinical trial information to eligible patients. Seventy-seven Latina breast cancer patients were randomly assigned to either Choices (n = 38) or the control (n = 39). Choices included three components: an educational interactive video, a low-literacy booklet, and care coordination by patient navigation (i.e., educational and psychosocial support, coordinating appointments, translating, interacting with the medical team). Choices was more effective than the control in improving perceived understanding of clinical trials (p = .033) and increasing consideration of clinical trials as a treatment option (p = .008). Additionally, intervention participants showed significant changes between baseline and post-intervention on agreement with stages of decision readiness statements (p < .002) than control participants (p > .05); the percentage of intervention women in agreement with preparation to action statements increased from 52.8% at baseline to 86.1% at post-intervention, and those in agreement with ready to action stages rose from 50.0% to 88.9%. Computer-based videos and care coordination provided by patient navigation-specifically tailored to Latinos-are effective strategies to successfully address awareness, and improved decision-making skills to make informed decisions about clinical trial participation.

Background: Homologous recombination defects in BRCA1/2-mutated tumors result in sensitivity to poly(ADP-ribose) polymerase inhibitors, which interfere with DNA damage repair. Veliparib, a potent poly(ADP-ribose) polymerase inhibitor, enhanced the antitumor activity of platinum agents and temozolomide in early phase clinical trials. This phase II study examined the safety and efficacy of intermittent veliparib with carboplatin/paclitaxel (VCP) or temozolomide (VT) in patients with BRCA1/2-mutated breast cancer., Patients and Methods: Eligible patients ≥18 years with locally recurrent or metastatic breast cancer and a deleterious BRCA1/2 germline mutation were randomized 1 : 1 : 1 to VCP, VT, or placebo plus carboplatin/paclitaxel (PCP). Primary end point was progression-free survival (PFS); secondary end points included overall survival (OS) and overall response rate (ORR)., Results: Of 290 randomized patients, 284 were BRCA+, confirmed by central laboratory. For VCP versus PCP, median PFS was 14.1 and 12.3 months, respectively [hazard ratio (HR) 0.789; 95% CI 0.536-1.162; P = 0.227], interim median OS 28.3 and 25.9 months (HR 0.750; 95% CI 0.503-1.117; P = 0.156), and ORR 77.8% and 61.3% (P = 0.027). For VT (versus PCP), median PFS was 7.4 months (HR 1.858; 95% CI 1.278-2.702; P = 0.001), interim median OS 19.1 months (HR 1.483; 95% CI 1.032-2.131; P = 0.032), and ORR 28.6% (P < 0.001). Safety profile was comparable between carboplatin/paclitaxel arms. Adverse events (all grades) of neutropenia, anemia, alopecia, and neuropathy were less frequent with VT versus PCP., Conclusion: Numerical but not statistically significant increases in both PFS and OS were observed in patients with BRCA1/2-mutated recurrent/metastatic breast cancer receiving VCP compared with PCP. The addition of veliparib to carboplatin/paclitaxel significantly improved ORR. There was no clinically meaningful increase in toxicity with VCP versus PCP. VT was inferior to PCP. An ongoing phase III trial is evaluating VCP versus PCP, with optional continuation single-agent therapy with veliparib/placebo if chemotherapy is discontinued without progression, in this patient population., Clinical Trial Information: NCT01506609., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose African American women with breast cancer have higher cancer-specific and overall mortality rates. Obesity is common among African American women and contributes to breast cancer progression and numerous chronic conditions. Weight loss interventions among breast cancer survivors positively affect weight, behavior, biomarkers, and psychosocial outcomes, yet few target African Americans. This article examines the effects of Moving Forward, a weight loss intervention for African American breast cancer survivors (AABCS) on weight, body composition, and behavior. Patients and Methods Early-stage (I-III) AABCS were randomly assigned to a 6-month interventionist-guided (n = 125) or self-guided (n = 121) weight loss program supporting behavioral changes to promote a 5% weight loss. Anthropometric, body composition, and behavioral data were collected at baseline, postintervention (6 months), and follow-up (12 months). Descriptive statistics and mixed models analyses assessed differences between groups over time. Results Mean (± standard deviation) age, and body mass index were 57.5 (± 10.1) years and 36.1 (± 6.2) kg/m 2 , respectively, and 82% had stage I or II breast cancer. Both groups lost weight. Mean and percentage of weight loss were greater in the guided versus self-guided group (at 6 months: 3.5 kg v 1.3kg; P < .001; 3.6% v 1.4%; P < .001, respectively; at 12 months: 2.7 kg v 1.6 kg; P < .05; 2.6% v 1.6%; P < .05, respectively); 44% in the guided group and 19% in the self-guided group met the 5% goal. Body composition and behavioral changes were also greater in the interventionist-guided group at both time points. Conclusion The study supports the efficacy of a community-based interventionist-guided weight loss program targeting AABCS. Although mean weight loss did not reach the targeted 5%, the mean loss of > 3% at 6 months is associated with improved health outcomes. Affordable, accessible health promotion programs represent a critical resource for AABCS.

Exposure to estrogen has long been associated with an increased risk of developing breast cancer. However, how estrogen signaling promotes breast carcinogenesis remains elusive. Senescence is known as an important protective response to oncogenic events. We aimed to elucidate the role of estrogen receptor alpha (ERα) on senescence in transformed human mammary epithelial cells and breast cancer cells. Our results show that ectopic expression of oncoprotein H-ras-V12 in immortalized human mammary epithelial cells (HMEC) significantly inhibited the phosphorylation of the retinoblastoma protein (Rb) and increased the activity of the senescence-associated beta-galactosidase (SA-β-Gal). These senescence-like phenotypes were reversed by ectopic expression of ERα. Similar inhibition of the H-ras-V12-induced SA-β-Gal activity by ERα was also observed in the human mammary epithelial MCF-10A cells. Co-expression of ERα and H-ras-V12 resulted in HMEC anchorage-independent growth in vitro and tumor formation in vivo. Furthermore, inhibition of ERα expression induced senescence-like phenotypes in ERα positive human breast cancer cells such as increased activity of SA-β-Gal, decreased phosphorylation of RB, and loss of mitogenic activity. Thus, the suppression of cellular senescence induced by oncogenic signals may be a major mechanism by which ERα promotes breast carcinogenesis., Competing Interests: There is no conflict of interest.

Mutations of the BRCA1/2 genes have been described in association with a number of malignancies including cancers of the breast, ovary, prostate and stomach, but have never been described in relation to gastrointestinal stromal tumours (GIST). We describe a patient with a BRCA2 8642del3insC mutation who developed prostate cancer, breast cancer and GIST. GIST has been shown to be associated with a number of malignancies, including some of the common BRCA1/2-related cancers, but it has never been associated with BRCA1/2 gene mutations. This report highlights the potential association between BRCA1/2 mutations and GIST, and aims to raise awareness for further genetic screening in GIST patients., (2015 BMJ Publishing Group Ltd.)

During the past few years, several genetic aberrations that may contribute to increased risks for development of breast and/or ovarian cancers have been identified. The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast and Ovarian focus specifically on the assessment of genetic mutations in BRCA1/BRCA2, TP53, and PTEN, and recommend approaches to genetic testing/counseling and management strategies in individuals with these mutations. This portion of the NCCN Guidelines includes recommendations regarding diagnostic criteria and management of patients with Cowden Syndrome/PTEN hamartoma tumor syndrome., (Copyright © 2014 by the National Comprehensive Cancer Network.)

Special consideration is required when prescribing antipsychotic drugs for patients with an existing diagnosis of breast cancer. The package inserts of all approved antipsychotics contain precautions regarding their administration in this patient group. These drugs are well known to elevate serum prolactin levels to varying degrees. Overexpression of the prolactin receptor is seen in more than 95% of human breast cancers. Many genes that are activated by the prolactin receptor are associated with tumorigenesis and cancer cell proliferation. The authors discuss the pathophysiology, clinical implications, and pertinent preclinical data and make specific recommendations regarding the use of antipsychotics in patients with breast cancer.

Purpose: We assessed adding the multikinase inhibitor sorafenib to gemcitabine or capecitabine in patients with advanced breast cancer whose disease progressed during/after bevacizumab., Experimental Design: This double-blind, randomized, placebo-controlled phase IIb study (ClinicalTrials.gov NCT00493636) enrolled patients with locally advanced or metastatic human epidermal growth factor receptor 2 (HER2)-negative breast cancer and prior bevacizumab treatment. Patients were randomized to chemotherapy with sorafenib (400 mg, twice daily) or matching placebo. Initially, chemotherapy was gemcitabine (1,000 mg/m(2) i.v., days 1, 8/21), but later, capecitabine (1,000 mg/m(2) orally twice daily, days 1-14/21) was allowed as an alternative. The primary endpoint was progression-free survival (PFS)., Results: One hundred and sixty patients were randomized. More patients received gemcitabine (82.5%) than capecitabine (17.5%). Sorafenib plus gemcitabine/capecitabine was associated with a statistically significant prolongation in PFS versus placebo plus gemcitabine/capecitabine [3.4 vs. 2.7 months; HR = 0.65; 95% confidence interval (CI): 0.45-0.95; P = 0.02], time to progression was increased (median, 3.6 vs. 2.7 months; HR = 0.64; 95% CI: 0.44-0.93; P = 0.02), and overall response rate was 19.8% versus 12.7% (P = 0.23). Median survival was 13.4 versus 11.4 months for sorafenib versus placebo (HR = 1.01; 95% CI: 0.71-1.44; P = 0.95). Addition of sorafenib versus placebo increased grade 3/4 hand-foot skin reaction (39% vs. 5%), stomatitis (10% vs. 0%), fatigue (18% vs. 9%), and dose reductions that were more frequent (51.9% vs. 7.8%)., Conclusion: The addition of sorafenib to gemcitabine/capecitabine provided a clinically small but statistically significant PFS benefit in HER2-negative advanced breast cancer patients whose disease progressed during/after bevacizumab. Combination treatment was associated with manageable toxicities but frequently required dose reductions., (©2013 AACR)

Brain metastases (BM) and leptomeningeal metastases (LM) are devastating neurologic complications. Pemetrexed is a multi-targeted anti-folate agent approved for treatment of nonsquamous non-small cell lung cancer but has anti-tumor activity in other solid tumors. We performed two trials using pemetrexed in patients with BM and LM to assess CSF penetration and anti-tumor activity. Patients were treated with intravenous pemetrexed at doses of 500 (n = 3), 750 (n = 3), 900 (n = 12) or 1,050 mg/m(2) (n = 3) every 3 weeks. Neuro-imaging was done every 6 weeks. Matched CSF and plasma samples were obtained serially from three patients with Ommaya reservoirs; the remaining patients had a single paired collection. Twenty-one patients (15 women and six men) with median age of 50 years and median KPS of 90 were treated. Primary tumors included breast (13), lung (4), colorectal (1), endometrial (1), esophageal (1) and pinealoblastoma (1). Nine patients had prior whole brain RT and median number of prior chemotherapies was two including prior methotrexate in four patients. Median pemetrexed doses administered was three (range 1-14). Responses included one partial response, ten stable disease and ten progressive disease. Median time to progression and survival was 2.7 and 7.3 months; PFS six was 22 %. No major toxicities were seen. Pemetrexed distributed from the plasma to the CSF within 1-4 h with the resulting CSF concentrations < 5 % of plasma. Pemetrexed was tolerated in solid tumor patients with CNS metastases. Limited anti-tumor activity was seen, which might have been due to low CSF concentrations, although some patients displayed prolonged benefit.