Faculty Bibliography

BACKGROUND:We evaluated the feasibility of completing 6 cycles of nab-paclitaxel (nab-P) and carboplatin (C) in a single arm prospective clinical trial for advanced/recurrent EC and safety and efficacy of day (D) 1, 8 nab-P in combination with D1 C q3weeks. METHODS:IV q21D. The trial tested the null hypothesis that subjects completing 6 cycles was ≤0.50 versus the alternative that the proportion is ≥0.75 in a single stage design with alpha = 0.05 and power = 80% with 23 subjects. Patients who completed 6 cycles (primary outcome), objective response rate (ORR) and clinical benefit rate (CBR) were estimated with exact 95% Clopper-Pearson confidence intervals. Progression free survival (PFS) and overall survival (OS) were estimated using Kaplan-Meier methods. RESULTS:From 08/2016-03/2018, 23 patients were enrolled. Nineteen patients (82.6%, 95% CI: 61.2%, 95.0%) completed 6 cycles, thus we could reject our null. Twelve patients (52.2%) experienced ≥1 grade 3/4 treatment-related adverse events including: anemia, 6 (26.1%); neutropenia, 5 (21.7%); diarrhea, 3 (13.0%). Fourteen patients (60.1%) reported grade 1 neuropathy. Of 9 patients with measurable target lesions, the ORR was 33.3% (95% CI: 7.5%, 70.1%) and CBR was 55.6% (95% CI: 21.2%, 86.3%). Median PFS in the advanced/recurrent patients was 23.2 (95% CI: 12.1, NR) months. CONCLUSIONS:The nab-P/C D1, 8 regimen met pre-specified feasibility criteria with acceptable toxicity and efficacy. Use of nab-P decreases need for steroid pre-medications, and this carboplatin doublet may prove advantageous for trials assessing combinations with immune checkpoint inhibitors in advanced EC.

Superior vena cava (SVC) syndrome is commonly caused by malignancy but is rarely associated with breast cancer. The following case series describes three female breast cancer patients who were found to have disease recurrence years after initial diagnosis, presenting as facial swelling, collateral vessel formation, and shortness of breath consistent with SVC syndrome. All patients were treated with radiation therapy, and one patient required stenting due to tumor thrombus in the SVC. These cases highlight a rare complication of breast cancer that clinicians should recognize in patients who have undergone treatment particularly for right sided breast cancer with lymph node involvement.

Current breast cancer care involves a multidisciplinary clinical approach for diagnosis and treatment including input from radiology, surgery, pathology, radiation, and medical oncology. Radiation is an integral part of the treatment for locoregionally confined breast cancer, and has well-recognized long-term risks of secondary malignancies, such as angiosarcomas. Basal cell carcinoma (BCC), a common skin malignancy, is not typically considered a radiation-induced carcinoma following breast cancer treatment. Our recent experience with 4 patients with vastly different presentations of BCC in previous radiation fields prompts the current report in order to alert clinicians to this entity.

Intraperitoneal (IP) delivery of cisplatin was developed in the 1970s based on a strong pharmacologic rationale and rodent models. Its advantage over intravenous (IV) administration was supported initially by observational studies in treating recurrent ovarian cancer and eventually by better outcomes from IP vs. IV cisplatin in randomized studies in patients undergoing optimal surgical debulking at diagnosis. In the past two decades, with the introduction of novel anticancer interventions (such as taxanes, bevacizumab, inhibitors of DNA repair, and immune check point inhibitors), advantages of IP drug delivery are less clear and concerns are raised on cisplatin's therapeutic index. The discovery of BRCA genes and their key role in DNA repair, on the other hand, have strengthened the rationale for IP drug delivery: high grade serous cancers arising in the Mullerian epithelium in association with hereditary or somatic BRCA function inactivation are linked to peritoneal spread of cells that - while initially sensitive - are prone to emergence of platinum resistance. Therefore, selection of patients based on genomic features and focusing on the better tolerated IP carboplatin are ongoing. Recent examples of leveraging the peritoneal route include (1) targeting the cell membrane copper transport receptor - that is shared by platinums - by the combination of the proteasome inhibitor bortezomib and IP carboplatin; and (2) enhancing IP 5-fluoro-2-deoxyuridine cytotoxicity when coupled with PARP inhibition.

OBJECTIVES/OBJECTIVE:We evaluated the incidence of breast cancer and overall survival in a multi-center cohort of ovarian cancer patients carrying BRCA1/2 mutations in order to assess risks and formulate optimal preventive interventions and/or surveillance. METHODS:Medical records of 502 BRCA1/2 mutation carriers diagnosed with ovarian cancer between 2000 and 2018 at 7 medical centers in Israel and one in New York were retrospectively analyzed for breast cancer diagnosis. Data included demographics, type of BRCA mutations, surveillance methods, timing of breast cancer diagnosis, and family history of cancer. RESULTS:The median age at diagnosis of ovarian cancer was 55.8 years (range, 23.9-90.1). A third (31.5%) had a family history of breast cancer and 17.1% of ovarian cancer. Most patients (67.3%) were Ashkenazi Jews, 72.9% were BRCA1 carriers. Breast cancer preceded ovarian cancer in 17.5% and was diagnosed after ovarian cancer in 6.2%; an additional 2.2% had a synchronous presentation. Median time to breast cancer diagnosis after ovarian cancer was 46.0 months (range, 11-168). Of those diagnosed with both breast cancer and ovarian cancer (n = 31), 83.9% and 16.1% harbored BRCA1 and BRCA2 mutations, respectively. No deaths from breast cancer were recorded. Overall survival did not differ statistically between patients with an ovarian cancer diagnosis only and those diagnosed with breast cancer after ovarian cancer. CONCLUSION/CONCLUSIONS:The low incidence of breast cancer after ovarian cancer in women carrying BRCA1/2 mutations suggests that routine breast surveillance, rather than risk-reducing surgical interventions, may be sufficient in ovarian cancer survivors.

Agonists of the co-stimulatory molecule OX40 (CD134) are in clinical assessment alone and in combination with other immunotherapies. Recent pre-clinical studies have suggested that concurrent administration of OX40 agonists with anti-PD1 therapy is detrimental to the efficacy of such combinations and maximal efficacy may require sequential administration of the OX40 agonist followed by anti-PD1 therapy. In this report, we detail two patients with advanced ovarian carcinoma were treated with INCAGN01949, an agonistic OX40 Ab, as part of a clinical trial until disease progression. Both patients then received the combination of ipilimumab and nivolumab and experienced unusually deep and durable responses. These cases support the hypothesis raised in pre-clinical studies and highlight the potential relevance of sequence in combinational immunotherapy.

A 66-year-old woman with a history of stage IA mixed endometrioid and serous endometrial cancer presented to our centre with 2 weeks of worsening headaches nearly 4 years after her initial surgery. At admission, she manifested bitemporal hemianopsia, difficulty walking and clinical and laboratory findings of panhypopituitarism, including diabetes insipidus. Magnetic resonance imaging of the brain revealed a 2.7 cm sellar/suprasellar mass compressing the optic chiasm and infiltrating the pituitary stalk. Computerised tomography documented mediastinal, lung, adrenal and liver involvement, including a 2.5 cm palpable left supraclavicular node that on excisional biopsy demonstrated metastatic endometrial adenocarcinoma. Due to the advanced stage of her cancer as well as the presence of multiple metastases, including lung and hepatic metastases causing post-obstructive pneumonia and coagulopathy, the sellar/suprasellar mass was treated with fractionated radiosurgery rather than surgical excision.