Faculty Bibliography

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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PURPOSE/OBJECTIVE:To examine trends, characteristics and outcomes of women who develop both ovarian and breast cancers. METHODS:This is a retrospective study examining the Surveillance, Epidemiology, and End Results Program from 1973 to 2013. Among ovarian cancer (n = 133,149) and breast cancer (n = 1,143,219) cohorts, women with both diagnoses were identified and temporal trends, tumor characteristics and survival were examined. RESULTS:There were 6446 women with both malignancies, representing 4.8% of the ovarian cancer cohort and 0.6% of the breast cancer cohort. Women with ovarian cancer who had secondary breast cancer were younger than those without secondary breast cancer early in the study period (52.3 versus 59.2 in 1973) but older in more recent years (68.5 versus 62.1 in 2013, P < 0.001). The number of breast cancer survivors who developed postcedent ovarian cancer decreased from 1.5 to 0.2% from 1979 to 2008 (relative risk reduction 90.0%, P < 0.05). Similarly, the number of ovarian cancer survivors who developed postcedent breast cancer decreased from 7.2 to 2.0% from 1973 to 2008 (relative risk reduction 72.4%, P < 0.05). Tumor characteristics were more likely to be favorable in women with ovarian cancer who developed postcedent breast cancer but unfavorable in those who had antecedent breast cancer (all, P < 0.05). Women with ovarian cancer who had secondary breast cancer had superior cause-specific survival compared to those who did not develop breast cancer regardless of breast cancer timing (P < 0.05). CONCLUSION/CONCLUSIONS:Our study demonstrated that the demographics of women who develop breast cancer and ovarian cancer have changed over time and diagnosis of secondary breast cancer after ovarian cancer has decreased.

OBJECTIVE:Poly(ADP-ribosyl) polymerases (PARPs) are nuclear enzymes with roles in DNA damage recognition and repair. PARP1 inhibition enhances the effects of DNA-damaging agents like doxorubicin. We sought to determine the recommended phase two dose (RP2D) of veliparib with pegylated liposomal doxorubicin (PLD) in breast and recurrent gynecologic cancer patients. METHODS:on day 1 of a 28-day cycle. Dose escalation proceeded in two strata: A (prior PLD exposure) and B (no prior PLD exposure). Patients underwent limited pharmacokinetic (PK) sampling; an expansion PK cohort was added. RESULTS:44 patients with recurrent ovarian or triple negative breast cancer were enrolled. Median age 56 years; 23 patients BRCA mutation carriers; median prior regimens four. Patients received a median of four cycles of veliparib/PLD. Grade 3/4 toxicities were observed in 10% of patients. Antitumor activity was observed in both sporadic and BRCA-deficient cancers. Two BRCA mutation carriers had complete responses. Two BRCA patients developed oral squamous cell cancers after completing this regimen. PLD exposure was observed to be higher when veliparib doses were > 200 mg BID. CONCLUSIONS:PLD on day 1 of a 28-day cycle. Anti-tumor activity was seen in both strata. However, given development of long-term squamous cell cancers and the PK interaction observed, efforts should focus on other targeted combinations to improve efficacy.

OBJECTIVES/HYPOTHESIS/OBJECTIVE:Advances in cancer treatment have increased survival for many patients, prompting a need for greater recognition of the long-term complications of treatment. Chemotherapy agents have the potential to induce carcinogenesis and can increase the risk of secondary malignancy. Pegylated liposomal doxorubicin (PLD) used for maintenance treatment of recurrent high-grade serous cancers has been associated with the development of oral cavity squamous cell carcinoma (SCC). STUDY DESIGN/METHODS:Retrospective review. METHODS:Cases of oral cavity SCC in patients with recurrent high-grade serous cancer treated with PLD between 1997 and 2017 at a single institution were reviewed. RESULTS:). Seven patients tested positive for BRCA mutations (four BRCA 1+, three BRCA 2+). No patients had a history of alcohol or tobacco use. All had early-stage oral cavity disease; five were T1N0, two were T2N0, and one had carcinoma in situ. All patients underwent surgery, and two received adjuvant radiation. Four developed locoregional recurrence requiring additional treatment. Of these, one patient died from complications of oral SCC, one developed recurrent ovarian cancer, and two had no evidence of disease of the oral cavity or ovarian cancer at the last follow-up. CONCLUSIONS:Long-term PLD therapy may be associated with the development of oral cavity SCC. A high index of suspicion and routine head and neck examination should be included in follow-up for exposed patients. LEVEL OF EVIDENCE/METHODS:4 Laryngoscope, 2019.

Objective: Few effective treatment options exist for women with advanced or recurrent endometrial cancer (EC). To explore a modification of the standard systemic treatment for advanced or recurrent EC, we sought to determine the feasibility of completing 6 cycles of nab-paclitaxel (Nab-P) and carboplatin. Unlike paclitaxel, Nab-P does not require any steroid or other premedication, an important consideration for patients with diabetes mellitus and in the investigation of combinations with immunotherapy. We prospectively evaluated safety and efficacy of a day 1, 8-dose schedule of Nab-P in combination with carboplatin day 1 q3weeks in patients with chemotherapy naive EC.
Method(s): Patients with early-stage and high-risk, advanced primary, or recurrent EC with no prior platinum and taxane exposure were enrolled at a single institution. Patients received 6 cycles of day 1 Nab-P 100 mg/m² IV with carboplatin AUC 6 IV and day 8 Nab-P 100 mg/m² IV q21days. We evaluated percentage completion of 6 cycles with standard dose reductions, as well as toxicity per CTCAE v.4. Measurable disease was not required, and efficacy was assessed by PFS rate at 6 months.
Result(s): From 2016 to 2018, 23 subjects were enrolled; median age was 65 (43-73) years. Nineteen (82%) completed 6 cycles of the doublet therapy. Eight subjects (35%) were dose-reduced 1 level, and 5 (22%) were reduced 2 levels; only 1 subject withdrew due to toxicity. Twelve subjects (52%) had at least 1 grade 3/4 treatment-related adverse event, the most common being anemia, 6 (26%); neutropenia, 4 (17%); and diarrhea, 2 (9%). Pre-existing neuropathy was an exclusion criteria, and 13 (57%) reported at least grade 1 neuropathy with treatment. After treatment, 3 (13%) deaths occurred with 2 due to disease progression and 1 to pulmonary embolism. At 6 months after treatment initiation, 19 (83%) had no evidence of disease or its progression; 4 (17%) had progressed. Kaplan-Meier analysis revealed a 6-month PFS rate of 80.5% (95% CI 65.1%-99.7%) (Figure 1).
Conclusion(s): The Nab-P/carboplatin day 1, 8 regimen met the prespecified criteria of feasibility with acceptable toxicity and efficacy. Use of Nab-P obviates steroid premedications, ideal for immune checkpoint inhibitors that target mismatch repair deficient advanced EC. A future phase II feasibility trial combining an anti-PD-1 agent with Nab-P and carboplatin is planned. [Figure presented]
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OBJECTIVE:To report population-based statistics of women with uterine cancer and a history of prior breast cancer. METHODS:This is a retrospective study examining the Surveillance, Epidemiology, and End Results Program between 1973 and 2013. Temporal trends, clinico-pathological characteristics, and survival of women with uterine cancer who had prior breast cancer were assessed. RESULTS:Among 237,686 women with uterine cancer, 8235 (3.5%) women had antecedent breast cancer. The number of women with uterine cancer who had a history of breast cancer increased between 1975 and 1989 (21.1-fold relative risk-increase, P < 0.001) and then decreased between 1989 and 2013 (relative risk-reduction [RRR] 11.1%, P = 0.008). The number of uterine cancer among breast cancer survivors decreased between 1990 and 2008 (RRR, 86.0%, P < 0.001). Women with uterine cancer and antecedent breast cancer were more likely to be older and white compared to those without a history of breast cancer (P < 0.05). Uterine tumors after breast cancer were more likely to have serous (10.5% versus 5.7%), carcinosarcoma (8.9% versus 4.4%), or clear cell (2.1% versus 1.2%) histology and present with grade 3 (30.8% versus 21.5%) and stage I disease (64.6% versus 62.5%) compared to tumors in women without breast cancer (all, P < 0.05). After propensity score matching, women with uterine cancer after breast cancer were less likely to die from uterine cancer (adjusted-hazard ratio [HR] 0.675) but more likely to die from other malignancies (adjusted-HR 4.090), particularly breast cancer, and had poorer overall survival (adjusted-HR 1.154) compared to those without breast cancer. CONCLUSION/CONCLUSIONS:The diagnosis of uterine cancer after breast cancer is decreasing. While uterine tumors following breast cancer are associated with high-risk tumor characteristics, women with uterine cancer after breast cancer are more likely to die from other malignancies.