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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.
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EMBASE:2005926845
ISSN: 0923-7534
CID: 4470992

Association of Diabetes and Other Clinical and Sociodemographic Factors With Guideline-concordant Breast Cancer Treatment for Breast Cancer

Gold, Heather T; Shao, Huibo; Oratz, Ruth; Yu, Onchee; Hammer, Marilyn; Richardson, Stephen; Boudreau, Denise
BACKGROUND:Women with breast cancer have worse health outcomes with co-occurring type 2 diabetes, possibly due to suboptimal breast cancer treatment. METHODS:We created a cohort of women ages 66 to 85 y with stage I to III breast cancer from 1993 to 2012 from an integrated health care delivery system (n=1612) and fee-for-service Medicare beneficiaries (n=98,915), linked to Surveillance, Epidemiology, and End Results (SEER) data (total n=100,527). We evaluated associations between type 2 diabetes and other factors with undergoing guideline-concordant cancer treatment. We estimated χ tests for univariate analysis and relative risks (RRs) using multivariable log-binomial models for outcomes of (1) overall guideline-concordant treatment, (2) definitive surgical therapy (mastectomy or lumpectomy with radiation), (3) chemotherapy if indicated, and (4) endocrine therapy. RESULTS:Our cohort included 60% of subjects with stage 1 tumors, one quarter below 70 years old, 23% had diabetes, 35% underwent overall guideline-concordant treatment, 24% chemotherapy, and 83% endocrine therapy. Women with diabetes were less likely to undergo overall guideline-concordant treatment (RR: 0.96; 95% confidence interval: 0.94-0.98), and only slightly less likely to undergo guideline-concordant definitive surgical therapy (RR: 0.99; 95% confidence interval: 0.99-1.00). No differences were found for chemotherapy or endocrine therapy. Other factors significantly associated with a lower risk of guideline-concordant care were cancer stages II to III (vs. I; RR=0.47-0.69, P<0.0001), older age (vs. 66 to 69 y; RR=0.56-0.90, P<0.0001), higher comorbidity burden, and Medicaid dual-eligibility. CONCLUSIONS:Diabetes was associated with lower adherence to overall guideline-concordant breast cancer treatment. However, higher stage, older age, higher comorbidity burden, and Medicaid insurance were more strongly associated with lower use of guideline-concordant treatment. Given the heavy burden of breast cancer and diabetes, long-term outcomes analysis should consider guideline-concordant treatment. IMPACT/CONCLUSIONS:Other factors besides diabetes are more strongly associated with guideline-concordant breast cancer treatment.
PMID: 31850918
ISSN: 1537-453x
CID: 4242682

Diabetes and differences in detection of incident invasive breast cancer

Calip, Gregory S; Yu, Onchee; Boudreau, Denise M; Shao, Huibo; Oratz, Ruth; Richardson, Stephen B; Gold, Heather T
Many women diagnosed with breast cancer have chronic conditions such as diabetes that may impact other health behaviors. Our purpose was to determine if breast cancer screening and detection differs among women with and without diabetes. We conducted a cross-sectional analysis of a retrospective cohort of women aged 52-74 years diagnosed with incident stages I-III breast cancer enrolled in an integrated health plan between 1999 and 2014 with linkage to the Surveillance, Epidemiology and End Results registry (n = 2040). Screening data were taken from electronic health records. We used multivariable modified Poisson regression models with robust standard errors to estimate relative risks (RR) and 95% confidence intervals (CI) for outcomes of (i) receipt of screening in the 2 years prior to diagnosis; (ii) symptom-detected breast cancer; and (iii) diagnosis of locally advanced stage III breast cancer. Compared to women without diabetes, women with diabetes were similar with respect to receipt of screening mammography (78% and 77%), symptom-detected breast cancer (46% and 49%), and stage III diagnosis (7% and 7%). In multivariable models adjusting for age and year of diagnosis, race, BMI, Charlson comorbidity score and depression diagnosis no differences were observed in the outcomes by presence of diabetes. Further investigation is warranted to determine how diabetes acts as a mediating factor in adverse breast cancer outcomes.
PMCID:6467528
PMID: 30949885
ISSN: 1573-7225
CID: 3826252

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

INTRAVITREAL BEVACIZUMAB IN THE MANAGEMENT OF BREAST CANCER IRIS METASTASIS

Seidman, Carly J; Finger, Paul T; Silverman, Joshua S; Oratz, Ruth
PURPOSE: To report a case of neovascular and angle closure glaucoma secondary to breast cancer metastatic to the iris that was successfully treated with injections of intravitreal bevacizumab (Avastin) 1.25 mg/0.05 mL. METHODS: Case report. PATIENTS: A 47-year-old woman with metastatic breast cancer presented to The New York Eye Cancer Center with left ocular pain, photosensitivity, vision loss, and multiple iris nodules. Her intraocular pressure was uncontrolled. Gonioscopy revealed neovascularization of the iris and angle; no choroidal neovascularization was noted. Ultrasound biomicroscopy demonstrated tumor invasion of iris stroma with marked anterior uveal thickening and narrowed angles. RESULTS: Three monthly injections of intravitreal bevacizumab resulted in nearly complete resolution of iris neovascularization, reduction of intraocular pressure, and control of tumor (although a small amount of residual tumor remained). CONCLUSION: Intravitreal anti-vascular endothelial growth factor therapy for breast cancer metastatic to the iris with secondary neovascular glaucoma provided good local control for a limited follow-up period, because the patient died because of systemic complications of her disease.
PMID: 26862924
ISSN: 1937-1578
CID: 2044842

Phase II trial of exemestane with immunomodulatory oral cyclophosphamide in metastatic hormone receptor (HR)-positive breast cancer: Prolonged progression-free survival (PFS) in patients with distinct T regulatory cell (Treg) profile [Meeting Abstract]

Kwa, M; Novik, Y; Oratz, R; Jhaveri, K; Wu, J; Gu, P; Meyers, M; Muggia, F; Bonakdar, M; Abidoglu, C; Kozhaya, L; Li, X; Joseph, B; Iwano, A; Friedman, K; Goldberg, JD; Unutmaz, D; Adams, S
ISI:000375622400315
ISSN: 1538-7445
CID: 2411072

A Phase I-II Study of Adjuvant Concurrent Carboplatin and Accelerated Radiation Therapy for Triple Negative Breast Cancer: Updated Results [Meeting Abstract]

Golden, EB; Chhabra, AM; Fenton-Kerimian, MB; Novik, Y; Oratz, R; Speyer, J; Formenti, SC
ISI:000373215300094
ISSN: 1879-355x
CID: 2097822

Clinical Trial Evidence of the Antitumor Activity of Topical Imiquimod for Breast Cancer Skin Metastases [Letter]

Adams, Sylvia; Novik, Yelena; Oratz, Ruth; Axelrod, Deborah; Speyer, James; Tiersten, Amy; Goldberg, Judith D; Bhardwaj, Nina; Unutmaz, Derya; Demaria, Sandra; Formenti, Silvia
PMID: 25092780
ISSN: 0732-183x
CID: 1105352

Cancer Risk Assessment Using Genetic Panel Testing: Considerations for Clinical Application

Hiraki, Susan; Rinella, Erica S; Schnabel, Freya; Oratz, Ruth; Ostrer, Harry
With the completion of the Human Genome Project and the development of high throughput technologies, such as next-generation sequencing, the use of multiplex genetic testing, in which multiple genes are sequenced simultaneously to test for one or more conditions, is growing rapidly. Reflecting underlying heterogeneity where a broad range of genes confer risks for one or more cancers, the development of genetic cancer panels to assess these risks represents just one example of how multiplex testing is being applied clinically. There are a number of issues and challenges to consider when conducting genetic testing for cancer risk assessment, and these issues become exceedingly more complex when moving from the traditional single-gene approach to panel testing. Here, we address the practical considerations for clinical use of panel testing for breast, ovarian, and colon cancers, including the benefits, limitations and challenges, genetic counseling issues, and management guidelines.
PMID: 24599651
ISSN: 1059-7700
CID: 958122