Targeting the PI3K Pathway in Gynecologic Malignancies

Purpose of review: This review explores the PI3K pathway aberrations common in gynecologic malignancies, the relevant therapeutic targets that have been explored to date particularly given their success in endometrial cancers, and predictive biomarkers of response to therapy. Recent findings: Landmark trials have been noted involving this pathway, particularly in endometrial cancers. One phase II trial of the potent orally bioavailable mTOR inhibitor, everolimus, in combination with letrozole demonstrated an unprecedented clinical benefit rate (CBR) of 40% and high objective response rate (RR) of 32% in hormone agnostic endometrial cancers. This was followed by GOG 3007 that compared everolimus and letrozole to hormonal therapy yielding similar response rates but double progression-free survival rates. The phosphoinositide 3-kinase (PI3K) signaling pathway is implicated in tumorigenesis given its regulation over cell growth, cellular trafficking, and angiogenesis. In gynecologic malignancies, alterations in PI3K signaling are common. Therefore, developing modulators of the PI3K pathway and identifying molecular markers to predict response are of great interest for these cancer types

Feasibility Study of Neoadjuvant Olaparib for Frontline BRCA Mutant Ovarian Cancer

https://openworks.mdanderson.org/sumexp22/1095/thumbnail.jp

Exceptional Response to Pembrolizumab for Treatment of Metastatic Chemorefractory Endometrial Carcinoma in a Patient with Lynch Syndrome: A Case Report

Advanced endometrial cancer is associated with poor outcomes and few treatment options exist. Recently, the US Federal Drug Administration approved pembrolizumab for the treatment of endometrial cancers that are deficient in mismatch repair and have high microsatellite instability (MSI). Lynch syndrome is an autosomal dominant disease that causes MSI-high endometrial cancer. We report a case of a 46-year-old woman with Lynch syndrome and advanced endometrial cancer who experienced progressive disease after treatment with chemotherapy with carboplatin and paclitaxel. She was then treated with single-agent pembrolizumab and had an exceptional response. She was noted to have a significant decrease in the size of a large uterine mass extending into the vagina and vulva, as well as decrease in the size of lymphadenopathy. Data are limited at this time for patients with Lynch syndrome treated with single-agent pembrolizumab. Our case report seeks to add to the body of literature that suggests that this patient population may particularly benefit from this novel therapy

Durvalumab Plus Carboplatin/Paclitaxel Followed by Maintenance Durvalumab With or Without Olaparib as First-Line Treatment for Advanced Endometrial Cancer: The Phase III DUO-E Trial

PURPOSE Immunotherapy and chemotherapy combinations have shown activity in endometrial cancer, with greater benefit in mismatch repair (MMR)-deficient (dMMR) than MMR-proficient (pMMR) disease. Adding a poly(ADP-ribose) polymerase inhibitor may improve outcomes, especially in pMMR disease. METHODS This phase III, global, double-blind, placebo-controlled trial randomly assigned eligible patients with newly diagnosed advanced or recurrent endometrial cancer 1:1:1 to: carboplatin/paclitaxel plus durvalumab placebo followed by placebo maintenance (control arm); carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib placebo (durvalumab arm); or carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib (durvalumab + olaparib arm). The primary end points were progression-free survival (PFS) in the durvalumab arm versus control and the durvalumab + olaparib arm versus control. RESULTS Seven hundred eighteen patients were randomly assigned. In the intention-to-treat population, statistically significant PFS benefit was observed in the durvalumab (hazard ratio [HR], 0.71 [95% CI, 0.57 to 0.89]; P = .003) and durvalumab + olaparib arms (HR, 0.55 [95% CI, 0.43 to 0.69]; P < .0001) versus control. Prespecified, exploratory subgroup analyses showed PFS benefit in dMMR (HR [durvalumab v control], 0.42 [95% CI, 0.22 to 0.80]; HR [durvalumab + olaparib v control], 0.41 [95% CI, 0.21 to 0.75]) and pMMR subgroups (HR [durvalumab v control], 0.77 [95% CI, 0.60 to 0.97]; HR [durvalumab + olaparib v control] 0.57; [95% CI, 0.44 to 0.73]); and in PD-L1-positive subgroups (HR [durvalumab v control], 0.63 [95% CI, 0.48 to 0.83]; HR [durvalumab + olaparib v control], 0.42 [95% CI, 0.31 to 0.57]). Interim overall survival results (maturity approximately 28%) were supportive of the primary outcomes (durvalumab v control: HR, 0.77 [95% CI, 0.56 to 1.07]; P = .120; durvalumab + olaparib v control: HR, 0.59 [95% CI, 0.42 to 0.83]; P = .003). The safety profiles of the experimental arms were generally consistent with individual agents. CONCLUSION Carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab with or without olaparib demonstrated a statistically significant and clinically meaningful PFS benefit in patients with advanced or recurrent endometrial cancer

Breast-Specific Sensuality and Sexual Function in Cancer Survivorship: Does Surgical Modality Matter?

More early-staged breast cancer patients are choosing mastectomy. No studies have addressed breast-specific sensuality (BSS), defined as the breast's role during intimacy. We explored BSS among women undergoing lumpectomy (L), mastectomy alone (M), or with reconstruction (MR) and analyzed the association of surgical modality with sexual function. Women undergoing breast cancer surgery between 2000 and 2013 were eligible for survey using investigator-generated questions and the Female Sexual Function Index (FSFI). Demographic and surgical data were collected by chart review. The Kruskal-Wallis test was used to analyze FSFI scores, and chi (2) or Fisher's exact tests were used for categorical data. Of 453 invited participants, 268 (59%) completed the survey. Of these, 69.4, 22.4, and 8.2% underwent L, MR, or M, respectively. The importance of the breast/chest wall during intimacy declined significantly regardless of surgical modality (L 83-74%, p = 0.0006; M 95-47%, p = 0.003; MR 93-77%, p = 0.002). No difference in sexual function was found between L, MR, and M (median FSFI score 28.2, 27.5, 25.9, respectively; p = 1.0). Comparing L versus MR, higher FSFI scores resulted with appearance satisfaction (29.0 vs. 22.6 p = 0.002) and preserved BSS as pleasurable breast caress (28.8 vs. 26.5, p = 0.04) and the breast as part of intimacy (28.8 vs. 24.8, p = 0.1). Breast cancer surgery is associated with lowered BSS. However, BSS and appearance satisfaction scores are better for L and appear to correlate with improved sexual function postoperatively. These data may guide surgical counseling and contribute to survivorship outcomes

Influential Forces in Breast Cancer Surgical Decision Making and the Impact on Body Image and Sexual Function

BACKGROUND: Shared decision making with one\u27s partner and body image satisfaction may affect surgical choices of breast cancer patients. This study analyzed whether partner opinion was associated with choice of operation and whether comfort level with one\u27s partner was altered postoperatively. METHODS: A prospective anonymous survey was administered to breast cancer patients who underwent breast surgery between 2000 and 2014. Categorical variables were compared by chi (2) or Fisher\u27s exact test. RESULTS: Women who elected to undergo mastectomy with reconstruction (MR) placed greater emphasis on their own decision making than on input from their partner, surgeon, or others (56.5 vs. 8.3 vs. 23.2 vs. 12, respectively), whereas those who chose lumpectomy (L) placed similar weight on surgeon input and self-input (44.2 vs. 42.7 %). Only 7.5 % of all patients identified their partner as the greatest influence on their surgical choice. Preoperatively, the L group was the most comfortable with their partner seeing their chest (91.9 % L vs. 83.9 % MR vs. 75.9 % mastectomy alone (M); p = 0.01), and postoperatively, the comfort levels for all were remarkably decreased. Furthermore, if a patient was a candidate for L but chose MR, the role her chest played in intimacy dropped more compared with those who chose L (83.8 % L vs. 91.7 % MR; p = 0.3 preoperatively to 65.1 % L vs. 42.9 % MR; p = 0.01 postoperatively). CONCLUSIONS: When making surgical decisions, most patients indicate that they value their own opinion over that of others. Mastectomy, regardless of reconstruction, leads to a significant reduction in comfort with one\u27s partner postoperatively compared with lumpectomy. This information may be helpful in counseling couples at the time of consultation for breast cancer treatment