Faculty Bibliography

The current study examined trends, characteristics, and outcomes of women with uterine cancer who had secondary colorectal cancer. This is a retrospective study utilizing the Surveillance, Epidemiology, and End Results Program between 1973-2013. Among uterine cancer (n = 246,272) and colorectal cancer (n = 421,312) cohorts, women with both diagnoses were identified, and clinico-pathological factors and survival were extracted and analyzed. There were 6862 women with both cancer diagnoses, representing 2.8% of the uterine cancer cohort and 1.6% of the colorectal cancer cohort. Among 123,940 women with uterine cancer survivors, the number with postcedent colorectal cancer decreased from 5.3% to 0.7% between 1981-2008 (relative risk reduction 87.0% p < 0.001). Similarly, of 141,801 women with colorectal cancer survivors, the number with postcedent uterine cancer decreased from 1.7% to 0.5% between 1973-2008 (relative risk reduction 71.6%, p < 0.001). In the uterine cancer cohort, women with antecedent/synchronous colorectal cancer had more high-grade tumors and advanced-stage disease resulting in poorer survival, whereas those who had postcedent colorectal cancer had more low-grade tumors and early-stage disease resulting in superior survival compared to those without secondary colorectal cancer (all, p < 0.05). In conclusion, the development of postcedent colorectal cancer following uterine cancer has decreased in recent years in the United States.

OBJECTIVES/OBJECTIVE:Neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) is a treatment strategy for ovarian cancer patients with unresectable disease or poor performance status (PS). This strategy has been used in the treatment of advanced endometrial cancer and a survival benefit has been shown in patients who are subsequently able to undergo interval cytoreduction. This study sought to review our single institution experience with NACT for advanced endometrial cancer. METHODS:We conducted a retrospective review of all patients who received NACT for advanced endometrial cancer at two institutions in New York City between 2002 and 2016. RESULTS:We identified 39 patients (median age 61, range 35-89). The histologic subtype distribution was: serous (44%), endometrioid (28%), carcinosarcoma (10%), clear cell (8%), mixed (8%), neuroendocrine (3%). Contraindications to primary surgery included: unresectable disease (72%), poor PS (15%), unresectable disease and poor PS (13%). Twenty-three patients (59%) did not undergo IDS due to: progression of disease (70%), medical ineligibility (4%), unresectable disease (17%), lost to follow-up (4%), death (4%). Sixteen patients (41%) underwent IDS, 81% had an optimal cytoreduction. Disease status at NACT completion was: partial response (56%), stable disease (3%) and progression of disease (41%). There were no complete responses. Patients who responded to NACT had a significantly longer overall survival than those who did not (15 vs. 5 months. P = 0.015). IDS was also associated with an improvement in overall survival versus no surgery (16 vs. 6 months, P = 0.04). CONCLUSIONS:Unlike ovarian cancer, less than half of the patients undergoing NACT for endometrial cancer underwent IDS, none had a complete response, and 41% had disease progression during NACT. However, endometrial cancer patients who underwent IDS had a high rate of optimal cytoreduction. Both response to NACT and IDS were associated with improved survival.

Over the last two decades, discoveries related to the breast cancer susceptibility genes 1 and 2 (BRCA1 and BRCA2) have profoundly changed our understanding and management of hereditary breast and ovarian cancers. The concept of synthetic lethality, which arises when cells become vulnerable to a combination of deficiencies in DNA repair, has driven the expanding roles of poly (adenosine diphosphate (ADP)-ribose) polymerase inhibitors in breast and ovarian cancers, and prevention strategies are taking into account the tissue specificity, natural history (fallopian tube origin of some high-grade serous ovarian cancers) and hormone sensitivity of BRCA-associated cancers. Current research has focussed on further elucidating the roles of BRCA proteins in DNA repair, investigating other key DNA repair processes and proteins and linking aberrant DNA repair with carcinogenesis. The ultimate goal is to translate this evolving knowledge into improving the clinical care and treatment of patients with pathogenic BRCA variants or other deficiencies in homologous recombination (HR). In this review, we will discuss 1) the role of BRCA proteins in DNA repair; 2) emerging concepts in the biology of HR deficiency and 3) implications for prevention and treatment.

OBJECTIVE:on day 1, repeated every 4 weeks) after first-line salvage chemotherapy for platinum-sensitive recurrent epithelial ovarian cancer. METHODS:This retrospective cohort study examined women with a first recurrence of platinum-sensitive epithelial ovarian cancer diagnosed between 2005 and 2015. Eligible cases had PLD maintenance following the first-line salvage chemotherapy (n = 28). Outcomes of interest included adverse events related to PLD maintenance therapy and survival outcome after the first recurrence. RESULTS:). No women developed cardiotoxicity or secondary malignancies. There were 16 (57%) women who developed any grade of adverse events, including 3 (11%) women who developed grade 3 adverse events. There were no grade 4 adverse events. The most common adverse event was mucositis (n = 7, 25%). Dose reduction due to adverse events occurred in 14 (50%) women including 3 (11%) women with discontinuation due to toxicity. Median progression-free survival and overall survival after the initiation of PLD maintenance was 14.5 months (2-year rate 21.1%) and 51.2 months (5-year rate 43.4%), respectively. CONCLUSION/CONCLUSIONS:Our study suggests that PLD maintenance therapy for platinum-sensitive recurrent ovarian cancer is relatively well tolerated with the use of dose reduction to manage toxicity. Our study suggests that PLD maintenance therapy may be effective for women with platinum-sensitive recurrent epithelial ovarian cancer.

OBJECTIVE:To analyze clinical prognostic factors for survival after recurrence of high-grade, advanced-stage ovarian-peritoneal-tubal carcinoma and to develop a nomogram to predict individual survival after recurrence. METHODS:We retrospectively analyzed patients treated in multicenter Gynecologic Oncology Group protocols for stage III and IV ovarian-peritoneal-tubal carcinoma who underwent primary debulking surgery, received chemotherapy with paclitaxel and a platinum compound, and subsequently developed recurrence. Prognostic factors affecting survival were identified and used to develop a nomogram, which was both internally and externally validated. RESULTS:There were 4,739 patients included in this analysis, of whom, 84% had stage III and 16% had stage IV ovarian carcinoma. At a median follow-up of 88.8 months (95% CI 86.2-92.0 months), the vast majority of patients (89.4%) had died. The median survival after recurrence was 21.4 months (95% CI 20.5-21.9 months). Time to recurrence after initial chemotherapy, clear cell or mucinous histology, performance status, stage IV disease, and age were significant variables used to develop a nomogram for survival after recurrence, which had a concordance index of 0.67. The time to recurrence alone accounted for 85% of the prognostic information. Similar results were found for patients who underwent second look laparotomy and had a complete pathologic response or received intraperitoneal chemotherapy. CONCLUSION/CONCLUSIONS:For individuals with advanced-stage ovarian carcinoma who recur after standard first-line therapy, estimated survivals after recurrence are closely related to the time to recurrence after chemotherapy and prognostic variables can be used to predict subsequent survival. CLINICAL TRIAL REGISTRATION/BACKGROUND:ClinialTrials.gov, NCT00002568, NCT00837993, NCT00002717, NCT01074398, and NCT00011986.

Background Although the lifetime risk of both ovarian cancer (oc) and breast cancer (bca) is a high in BRCA mutation carriers (61%-79% bca risk, and 11%-53% oc risk), synchronous cancers, defined as the diagnosis of both cancers in the same patient within 6 months of each other, are rare, with only a few cases being reported in the literature. In 2008, we reported a case series of 8 BRCA-mutated patients who had both bca and oc, and we highlighted the unusual features and variable management of both synchronous and metachronous cancers. We now focus on synchronous presentations. Methods 6 patients with BRCA germline mutations and synchronous diagnoses of bca and oc were identified at New York University Langone Medical Center and Tel Aviv Sourasky Medical Center. Their clinical presentations and outcomes to date were analyzed. Results In 3 of 6 patients, the diagnoses of synchronous bca and oc were a result of risk-reducing surgeries or initial staging imaging. The bcas were all early-stage disease (i and ii); the ocs were high-grade, primarily serous, and advanced even if detected incidentally during the bca work-up. All 6 patients received chemotherapy with platinum and a taxane initially, aregimen that doubled as adjuvant or neoadjuvant treatment for bca. All 6 patients had excellent local and systemic control of bca, but the eventual progression in their oc or the occurrence of another primary cancer resulted in unfavourable outcomes. Conclusions Synchronous bca and oc diagnoses in BRCA-mutated women might become more common because of widespread genetic testing, use of staging imaging, and prophylactic surgeries. Platinum- and taxane-based chemotherapy directed at oc, coupled with local and systemic treatments, appears to adequately deal with bca, but long-term outlook is driven primarily by risk of oc recurrence or unrelated cancers. Dual primaries might provide a further rationale for consolidation with parp inhibitors

Adult-type granulosa cell tumors (GCTs), although rare, are the most commonly diagnosed neoplasms arising in the endocrine-active ovarian stroma. They are characterized by excessive production of estrogens, antimullerian hormone and inhibins. In 2009, a specific mutation in FOXL2 was identified to be pathognomonic of GCTs. How dysregulation of this transcription factor, resulting in upregulation of aromatase, leads to unchecked proliferation, and progression to a malignancy, remains unclear. The key pathological and clinical feature of GCTs that affects their usually favorable outcomes is a diagnosis of greater than Stage 1 disease at presentation. Chemotherapy is given as adjuvant upon an advanced stage diagnosis; however, its effect on survival upon recurrence is modest. On the other hand, aromatase inhibitors also lead to tumor regression and are suitable for long-term maintenance.

The carboplatin/paclitaxel doublet remains the chemotherapy backbone for the initial treatment of ovarian cancer. This two-drug regimen, with carboplatin dosed using the Calvert formula, yielded convincing noninferior outcomes when compared with the prior, more toxic, regimen of cisplatin/paclitaxel. Carboplatin's dose-limiting toxicity is thrombocytopenia; however, when this drug is properly dosed and combined with paclitaxel, the doublet's cycle 1 dose in chemotherapy-naive women is generally safe. Carboplatin (unlike cisplatin) contributes minimally to the cumulative sensory neuropathy of paclitaxel, thus ensuring noticeable reversibility of neuropathy symptoms following completion of 6 cycles and only occasionally requiring cessation or substitution of the taxane. Paclitaxel is responsible for the hair loss associated with the carboplatin/paclitaxel doublet; preventive measures must be considered for patients who would otherwise refuse treatment. Several first-line phase III trials, as well as ongoing trials for which only preliminary results have been published, have fueled debates on the optimal dose and schedule; these have focused not only on weekly vs q3-weeks paclitaxel, but also on other modifications and the advisability of adding bevacizumab. Our view is that results of this doublet in the first-line treatment of ovarian cancer are driven primarily by carboplatin, given that ovarian cancer is a platinum-sensitive disease. Consequently, the roles of the accompanying paclitaxel dose and schedule and the addition of bevacizumab are currently unsettled, and questions regarding these issues should be decided based on patient tolerance and comorbidities until additional data are available.

Could hydroxychloroquine and quinacrine antimalarial therapy for dermatomyositis later attributed to a paraneoplasic manifestation of an ovarian cancer enhance its subsequent response to chemotherapy? Five months after being diagnosed with dermatomyositis, while somewhat improved with hydroxychloroquine, quinacrine and methotrexate, this 63-year-old woman presented with an advanced intra-abdominal epithelial ovarian cancer documented (but not resected) at laparotomy. Neoadjuvant carboplatin/paclitaxel resulted in remarkable improvement of symptoms, tumour markers and imaging findings leading to thorough cytoreductive surgery at completion of five cycles. No tumour was found in the resected omentum, gynaecologic organs, as well as hepatic and nodal sampling thus documenting a complete pathologic response; a subcutaneous port and an intraperitoneal (IP) catheter were placed for two cycles of IP cisplatin consolidation. She remains free of disease 3 years after such treatment and her dermatomyositis is in remission in the absence of any treatment. We discuss a possible role of autophagy in promoting tumour cell survival and chemoresistance that is potentially reversed by antimalarial drugs. Thus, chemotherapy following their use may subsequently lead to dramatic potentiation of anticancer treatment.