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Improved outcomes for triple negative breast cancer brain metastases patients after stereotactic radiosurgery and new systemic approaches
Mashiach, Elad; Alzate, Juan Diego; De Nigris Vasconcellos, Fernando; Adams, Sylvia; Santhumayor, Brandon; Meng, Ying; Schnurman, Zane; Donahue, Bernadine R; Bernstein, Kenneth; Orillac, Cordelia; Bollam, Rishitha; Kwa, Maryann J; Meyers, Marleen; Oratz, Ruth; Novik, Yelena; Silverman, Joshua S; Harter, David H; Golfinos, John G; Kondziolka, Douglas
PURPOSE/OBJECTIVE:Although ongoing studies are assessing the efficacy of new systemic therapies for patients with triple negative breast cancer (TNBC), the overwhelming majority have excluded patients with brain metastases (BM). Therefore, we aim to characterize systemic therapies and outcomes in a cohort of patients with TNBC and BM managed with stereotactic radiosurgery (SRS) and delineate predictors of increased survival. METHODS:We used our prospective patient registry to evaluate data from 2012 to 2023. We included patients who received SRS for TNBC-BM. A competing risk analysis was conducted to assess local and distant control. RESULTS:Forty-three patients with 262 tumors were included. The median overall survival (OS) was 16 months (95% CI 13-19 months). Predictors of increased OS after initial SRS include Breast GPA score > 1 (p < 0.001) and use of immunotherapy such as pembrolizumab (p = 0.011). The median time on immunotherapy was 8 months (IQR 4.4, 11.2). The median time to new CNS lesions after the first SRS treatment was 17 months (95% CI 12-22). The cumulative rate for development of new CNS metastases after initial SRS at 6 months, 1 year, and 2 years was 23%, 40%, and 70%, respectively. Thirty patients (70%) underwent multiple SRS treatments, with a median time of 5 months (95% CI 0.59-9.4 months) for the appearance of new CNS metastases after second SRS treatment. CONCLUSIONS:TNBC patients with BM can achieve longer survival than might have been previously anticipated with median survival now surpassing one year. The use of immunotherapy is associated with increased median OS of 23 months.
PMID: 38630386
ISSN: 1573-7373
CID: 5655852
Long-term Survival From Breast Cancer Brain Metastases in the Era of Modern Systemic Therapies
Mashiach, Elad; Alzate, Juan Diego; De Nigris Vasconcellos, Fernando; Bernstein, Kenneth; Donahue, Bernadine R; Schnurman, Zane; Gurewitz, Jason; Rotman, Lauren E; Adams, Sylvia; Meyers, Marleen; Oratz, Ruth; Novik, Yelena; Kwa, Maryann J; Silverman, Joshua S; Sulman, Erik P; Golfinos, John G; Kondziolka, Douglas
BACKGROUND AND OBJECTIVES/OBJECTIVE:Median survival for all patients with breast cancer with brain metastases (BCBMs) has increased in the era of targeted therapy (TT) and with improved local control of intracranial tumors using stereotactic radiosurgery (SRS) and surgical resection. However, detailed characterization of the patients with long-term survival in the past 5 years remains sparse. The aim of this article is to characterize patients with BCBM who achieved long-term survival and identify factors associated with the uniquely better outcomes and to find predictors of mortality for patients with BCBM. METHODS:We reviewed 190 patients with breast cancer with 931 brain tumors receiving SRS who were followed at our institution with prospective data collection between 2012 and 2022. We analyzed clinical, molecular, and imaging data to assess relationship to outcomes and tumor control. RESULTS:The median overall survival from initial SRS and from breast cancer diagnosis was 25 months (95% CI 19-31 months) and 130 months (95% CI 100-160 months), respectively. Sixteen patients (17%) achieved long-term survival (survival ≥5 years from SRS), 9 of whom are still alive. Predictors of long-term survival included HER2+ status ( P = .041) and treatment with TT ( P = .046). A limited number of patients (11%) died of central nervous system (CNS) causes. A predictor of CNS-related death was the development of leptomeningeal disease after SRS ( P = .025), whereas predictors of non-CNS death included extracranial metastases at first SRS ( P = .017), triple-negative breast cancer ( P = .002), a Karnofsky Performance Status of <80 at first SRS ( P = .002), and active systemic disease at last follow-up ( P = .001). Only 13% of patients eventually needed whole brain radiotherapy. Among the long-term survivors, none died of CNS progression. CONCLUSION/CONCLUSIONS:Patients with BCBM can achieve long-term survival. The use of TT and HER2+ disease are associated with long-term survival. The primary cause of death was extracranial disease progression, and none of the patients living ≥5 years died of CNS-related disease.
PMID: 37581437
ISSN: 1524-4040
CID: 5599542
Randomized Phase II Trial of Endocrine Therapy With or Without Ribociclib After Progression on Cyclin-Dependent Kinase 4/6 Inhibition in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer: MAINTAIN Trial
Kalinsky, Kevin; Accordino, Melissa K; Chiuzan, Codruta; Mundi, Prabhjot S; Sakach, Elizabeth; Sathe, Claire; Ahn, Heejoon; Trivedi, Meghna S; Novik, Yelena; Tiersten, Amy; Raptis, George; Baer, Lea N; Oh, Sun Y; Zelnak, Amelia B; Wisinski, Kari B; Andreopoulou, Eleni; Gradishar, William J; Stringer-Reasor, Erica; Reid, Sonya A; O'Dea, Anne; O'Regan, Ruth; Crew, Katherine D; Hershman, Dawn L
PURPOSE/OBJECTIVE:Cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) with endocrine therapy (ET) improves progression-free survival (PFS) and overall survival (OS) in hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). Although preclinical and clinical data demonstrate a benefit in changing ET and continuing a CDK4/6i at progression, no randomized prospective trials have evaluated this approach. METHODS:In this investigator-initiated, phase II, double-blind placebo-controlled trial in patients with HR+/HER2- MBC whose cancer progressed during ET and CDK4/6i, participants switched ET (fulvestrant or exemestane) from ET used pre-random assignment and randomly assigned 1:1 to the CDK4/6i ribociclib versus placebo. PFS was the primary end point, defined as time from random assignment to disease progression or death. Assuming a median PFS of 3.8 months with placebo, we had 80% power to detect a hazard ratio (HR) of 0.58 (corresponding to a median PFS of at least 6.5 months with ribociclib) with 120 patients randomly assigned using a one-sided log-rank test and significance level set at 2.5%. RESULTS:= .006. At 6 and 12 months, the PFS rate was 41.2% and 24.6% with ribociclib, respectively, compared with 23.9% and 7.4% with placebo. CONCLUSION/CONCLUSIONS:In this randomized trial, there was a significant PFS benefit for patients with HR+/HER2- MBC who switched ET and received ribociclib compared with placebo after previous CDK4/6i and different ET.
PMID: 37207300
ISSN: 1527-7755
CID: 5508142
Outcomes of Breast Cancer Patients Treated with Chemotherapy, Biologic Therapy, Endocrine Therapy, or Active Surveillance During the COVID-19 Pandemic
Marks, Douglas K; Budhathoki, Nibash; Kucharczyk, John; Fa'ak, Faisal; D'Abreo, Nina; Kwa, Maryann; Plasilova, Magdalena; Dhage, Shubhada; Soe, Phyu Phyu; Becker, Daniel; Hindenburg, Alexander; Lee, Johanna; Winner, Megan; Okpara, Chinyere; Daly, Alison; Shah, Darshi; Ramdhanny, Angela; Meyers, Marleen; Oratz, Ruth; Speyer, James; Novik, Yelena; Schnabel, Freya; Jones, Simon A; Adams, Sylvia
PURPOSE:Provide real-world data regarding the risk for SARS-CoV-2 infection and mortality in breast cancer (BC) patients on active cancer treatment. METHODS:Clinical data were abstracted from the 3778 BC patients seen at a multisite cancer center in New York between February 1, 2020 and May 1, 2020, including patient demographics, tumor histology, cancer treatment, and SARS-CoV-2 testing results. Incidence of SARS-CoV-2 infection by treatment type (chemotherapy [CT] vs endocrine and/or HER2 directed therapy [E/H]) was compared by Inverse Probability of Treatment Weighting. In those diagnosed with SARS-CoV-2 infection, Mann-Whitney test was used to a assess risk factors for severe disease and mortality. RESULTS:Three thousand sixty-two patients met study inclusion criteria with 641 patients tested for SARS-COV-2 by RT-PCR or serology. Overall, 64 patients (2.1%) were diagnosed with SARS-CoV-2 infection by either serology, RT-PCR, or documented clinical diagnosis. Comparing matched patients who received chemotherapy (n = 379) with those who received non-cytotoxic therapies (n = 2343) the incidence of SARS-CoV-2 did not differ between treatment groups (weighted risk; 3.5% CT vs 2.7% E/H, P = .523). Twenty-seven patients (0.9%) expired over follow-up, with 10 deaths attributed to SARS-CoV-2 infection. Chemotherapy was not associated with increased risk for death following SARS-CoV-2 infection (weighted risk; 0.7% CT vs 0.1% E/H, P = .246). Advanced disease (stage IV), age, BMI, and Charlson's Comorbidity Index score were associated with increased mortality following SARS-CoV-2 infection (P ≤ .05). CONCLUSION:BC treatment, including chemotherapy, can be safely administered in the context of enhanced infectious precautions, and should not be withheld particularly when given for curative intent.
PMID: 35641208
ISSN: 1549-490x
CID: 5235912
"Bridge" Neoadjuvant Endocrine Therapy for Early Stage Breast Cancer Patients During COVID-19 at an Academic Hospital in NYC: Lessons Learned and Future Directions
Feinberg, Joshua; Cen, Cindy; Schnabel, Freya; Adams, Sylvia; Plasilova, Magdalena; Yeh, Janet; Meyers, Marleen; Speyer, James; Belenkov, Elliot; Kwa, Maryann; Novik, Yelena; Katz, Elena; Guth, Amber Azniv
ORIGINAL:0015541
ISSN: 2578-9503
CID: 5192472
Phase II study of pembrolizumab and nab-paclitaxel in HER2-negative metastatic breast cancer: Hormone receptor-positive cohort [Meeting Abstract]
Novik, Y; Klar, N; Zamora, S; Kwa, M; Speyer, J; Oratz, R; Muggia, F; Meyers, M; Hochman, T; Goldberg, J; Adams, S
Background: PD-1/PD-L1 checkpoint blockade in combination with chemotherapy has improved outcomes in triple-negative breast cancer, but its role in hormone receptor-positive (HR+) metastatic breast cancer (MBC) is less clear. We report the results of the HR+ cohort of a HER2-negative MBC trial.
Method(s): Prospective phase 2 trial where 20 HR+/HER2- MBC patients (pts) received nab-paclitaxel (A) (100mg/m2 IV d1/8, q 3 wks) and pembrolizumab (P) (200mg IV d1, q 3 wks, starting with cycle 2). Eligibility: ER/PR >=1%, HER2 negative, maximum of 2 lines of cytotoxic therapy for MBC, pts could have received prior endocrine and/or targeted therapy. Primary endpoint: best overall response rate (BORR) by RECIST v1.1; secondary endpoints: safety, PFS, clinical benefit rate (CBR), duration of response (DOR), and overall survival (OS). Biomarker analyses are ongoing.
Result(s): In this 20-patient cohort, the median age was 56 (34-75), median lines of cytotoxic chemotherapy was 1 (0-2), 70% (14/20) were ER>10%, 80% (16/20) received prior hormone therapy, and 60% (12/20) received prior CDK 4/6 inhibitors. BORR was partial response (PR) in 5/20, stable disease (SD) in 7/20, and progressive disease (PD) in 7/20. CBR was 35% (7/20). Median PFS was 5.6 mos (95%CI 2.07-8.18), median OS 15.7 mos (95%CI 3.88-27.70) and median DOR was 3.9 mos (95%CI 2.07-not yet reached). Out of 5 pts who achieved PR, 4 (80%) received prior CDK 4/6 inhibitors. The most common related adverse events (AE) were anemia (50%), diarrhea, nausea and ALT abnormalities (40% each). 14 pts experienced grade 3 AEs, the most common being neutropenia, 1 pt had grade 4 AEs (pneumonitis, blood/lymphatics, hyponatremia), and no grade 5 AEs. [Formula presented]
Conclusion(s): P plus A was efficacious with PR in 5/20 and SD in 7/20 pts with a manageable toxicity profile. Importantly, responses were observed in patients previously treated with CDK 4/6 inhibitors. Further investigation of this regimen in HR+/HER2- MBC is warranted. Clinical trial identification: NCT02752685. Legal entity responsible for the study: NYU Langone Health.
Funding(s): Merck (drug-pembrolizumab and financial funding); Celgene (drug-nab-paclitaxel). Disclosure: F. Muggia: Advisory/Consultancy, Member of data safety monitoring committee of Pembrolizumab trials run by Merck: Merck. S. Adams: Advisory/Consultancy, Research grant/Funding (institution), consultant (uncompensated): Merck; Research grant/Funding (institution): Celgene. All other authors have declared no conflicts of interest.
Copyright
EMBASE:2005926845
ISSN: 0923-7534
CID: 4470992
Phase II trial of nivolumab with chemotherapy as neoadjuvant treatment in inflammatory breast cancer. [Meeting Abstract]
Kwa, Maryann J.; Tray, Nancy; Esteva, Francisco J.; Novik, Yelena; Speyer, James L.; Oratz, Ruth; Meyers, Marleen Iva; Muggia, Franco; Ty, Victor; Troxel, Andrea; Schneider, Robert; Adams, Sylvia
ISI:000487345803405
ISSN: 0732-183x
CID: 5197792
Serial immunological parameters in a phase II trial of exemestane and low-dose oral cyclophosphamide in advanced hormone receptor-positive breast cancer
Kwa, Maryann; Li, Xiaochun; Novik, Yelena; Oratz, Ruth; Jhaveri, Komal; Wu, Jennifer; Gu, Ping; Meyers, Marleen; Muggia, Franco; Speyer, James; Iwano, Alyssa; Bonakdar, Maryam; Kozhaya, Lina; Tavukcuoglu, Ece; Budan, Bahar; Raad, Roy; Goldberg, Judith D; Unutmaz, Derya; Adams, Sylvia
BACKGROUND AND PURPOSE: Resistance to endocrine therapies in hormone receptor (HR)-positive breast cancer is a significant challenge. Prior studies have shown that low-dose oral cyclophosphamide can transiently deplete regulatory T cells (Tregs) and improve anti-tumor immunity. We investigated the combination of exemestane with cyclophosphamide in patients with advanced HR-positive breast cancer and assessed changes in circulating immune cell subsets. METHODS: This was a single-arm phase II trial of exemestane with cyclophosphamide in patients with metastatic HR-positive/HER2-negative breast cancer who had progressed on prior endocrine therapy (ClinicalTrials.gov: NCT01963481). Primary endpoint was progression-free survival (PFS) at 3 months (RECIST 1.1). Secondary objectives included median PFS, objective response rate, duration of response, and safety. Circulating Tregs (FOXP3+Helios+) and other immune cell subsets were monitored during treatment and compared with healthy controls. RESULTS: Twenty-three patients were enrolled. Treatment was well tolerated, without grade 4/5 toxicities. Objective responses were seen in 6/23 patients (26.1%; 95% CI 10.2-48.4%) and were durable (median 11.6 months). Three-month PFS rate was 50.1% (95% CI 33.0-76.0%); median PFS was 4.23 months (95% CI 2.8-11.7). No treatment-related decrease in Tregs was observed. However, elevated baseline levels of Naive Tregs [greater than 2.5 (the median of the naive Tregs)] were associated with relative risk of disease progression or death [hazard ratio 11.46 (95% CI 2.32-56.5)]. In addition, the baseline levels of Naive Tregs (adj-p = 0.04), Memory Tregs (adj-p = 0.003), CD4 + Central Memory T cells (adj-p = 0.0004), PD-1 + CD4 + Central Memory T cells (adj-p = 0.008), and PD-1 + CD4 + Effector Memory T cells (adj-p = 0.009) were significantly greater in the patients than in the healthy controls; the baseline levels of %CD4 + Naive T cells (adj-p = 0.0004) were significantly lower in patients compared with healthy controls (n = 40). CONCLUSION: Treg depletion was not observed with low-dose cyclophosphamide when assessed by the specific marker FOXP3 + Helios +; however, baseline naive Tregs were associated with 3-month PFS. Exemestane/cyclophosphamide combination had favorable safety profile with evidence of clinical activity in heavily pretreated patients.
PMID: 29124456
ISSN: 1573-7217
CID: 2772912
Phase II trial of pembrolizumab in combination with nab-paclitaxel in patients with metastatic HER2-negative breast cancer [Meeting Abstract]
Kwa, Maryann J.; Iwano, Alyssa; Esteva, Francisco J.; Novik, Yelena; Speyer, James L.; Oratz, Ruth; Meyers, Marleen Iva; Axelrod, Deborah M.; Hogan, Rebecca; Mendoza, Sandra; Goldberg, Judith D.; Muggia, Franco; Adams, Sylvia
ISI:000411895702072
ISSN: 0732-183x
CID: 3726432
Results of a phase I-II study of adjuvant concurrent carboplatin and accelerated radiotherapy for triple negative breast cancer
Formenti, Silvia C; Golden, Encouse B; Goldberg, Judith D; Li, Xiaochun; Taff, Jessica; Fenton-Kerimian, Maria B; Chandrasekhar, Sharanya; Demaria, Sandra; Novik, Yelena
Purpose: To determine feasibility and explore the clinical efficacy of concurrent radiotherapy and carboplatin as adjuvant treatment of triple negative breast cancer (TNBC). Patients and Methods: Women with Stage I-II TNBC were treated after surgery in a phase I-II prospective trial [NCT01289353]. Weekly carboplatin (AUC = 2.0) was delivered for 6 weeks. Concurrent radiotherapy was delivered in the prone position during weeks 2-4, for a total dose of 40.5 Gy in 15 fractions to the breast, and 46.5 Gy in 17 fractions to the tumor bed. Adverse events (AE) were assessed weekly during treatment, once at 45-60 d, and every 6 mo thereafter, using the Common Terminology Criteria for AE (CTCAE) v3.0. Results: A total of 39 patients accrued and 36 received treatment. Eight patients (22%, exact 95% CI: 10%, 39%) developed grade 2 or greater acute radiation dermatitis. Overall, grade 2 AE were seen in nine and grade 3 in two patients. Twenty-three patients (64%) received additional adjuvant chemotherapy. With a median follow-up of 48 mo, 34/36 (94%) are alive and disease free. One patient died of pulmonary failure with possible but unproven breast cancer recurrence, and one patient died of pelvic malignancy. One patient recurred locally and is alive and disease free after surgical management. Brisk lymphocytic infiltrate was present pre-treatment in 39% of 18 patients with evaluable tumor. Conclusions: Adjuvant concurrent carboplatin and prone accelerated radiotherapy is a well-tolerated and promising treatment of early stage TNBC. The observed 3% compares favorably with the expected 30% recurrence rate within 1-4 y from treatment, warranting further studies.
PMCID:5384379
PMID: 28405497
ISSN: 2162-4011
CID: 2527872