Shannon N. Westin

PI3K/AKT/mTOR Inhibitors in Patients With Breast and Gynecologic Malignancies Harboring PIK3CA Mutations

PURPOSE Mutations of the PIK3CA gene may predict response to phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) inhibitors. Concomitant mutations in the mitogen-activated protein kinase (MAPK) pathway may mediate resistance. PATIENTS AND METHODS Tumors from patients with breast, cervical, endometrial, and ovarian cancer referred to the Clinical Center for Targeted Therapy (Phase I Program) were analyzed for PIK3CA, KRAS, NRAS, and BRAF mutations. Patients with PIK3CA mutations were treated, whenever feasible, with agents targeting the PI3K/AKT/mTOR pathway. RESULTS Of 140 patients analyzed, 25 (18%) had PIK3CA mutations, including five of 14 patients with squamous cell cervical, seven of 29 patients with endometrial, six of 29 patients with breast, and seven of 60 patients with ovarian cancers. Of the 25 patients with PIK3CA mutations, 23 (median of two prior therapies) were treated on a protocol that included a PI3K/AKT/mTOR pathway inhibitor. Two (9%) of 23 patients had stable disease for more than 6 months, and seven patients (30%) had a partial response. In comparison, only seven (10%) of 70 patients with the same disease types but with wild-type PIK3CA treated on the same protocols responded (P = .04). Seven patients (30%) with PIK3CA mutations had coexisting MAPK pathway (KRAS, NRAS, BRAF) mutations (ovarian cancer, n = 5; endometrial cancer, n = 2), and two of these patients (ovarian cancer) achieved a response. CONCLUSION PIK3CA mutations were detected in 18% of tested patients. Patients with PIK3CA mutations treated with PI3K/AKT/mTOR inhibitors demonstrated a higher response rate than patients without mutations. A subset of patients with ovarian cancer with simultaneous PIK3CA and MAPK mutations responded to PI3K/AKT/mTOR inhibitors, suggesting that not all patients demonstrate resistance when the MAPK pathway is concomitantly activated.

Position-related injury is uncommon in robotic gynecologic surgery ☆ ☆☆

OBJECTIVE To assess the rate and risk factors for position-related injury in robotic gynecologic surgery. METHODS A prospective database from 12/2006 to 1/2014 of all planned robotic gynecologic procedures was retrospectively reviewed for patients who experienced neurologic injury, musculoskeletal injury, or vascular compromise related to patient positioning in the operating room. Analysis was performed to determine risk-factors and incidence for position-related injury. RESULTS Of the 831 patients who underwent robotic surgery during the study time period, only 7 (0.8%) experienced positioning-related injury. The injuries included minor head contusions (n=3), two lower extremity neuropathies (n=2), brachial plexus injury (n=1) and one large subcutaneous ecchymosis on the left flank and thigh (n=1). There were no long term sequelae from the positioning-related injuries. The only statistically significant risk factor for positioning-related injury was prior abdominal surgery (P=0.05). There were no significant associations between position-related injuries and operative time (P=0.232), body mass index (P=0.847), age (P=0.152), smoking history (P=0.161), or medical comorbidities (P=0.229-0.999). CONCLUSIONS The incidence of position-related injury among women undergoing robotic surgery was extremely low (0.8%). Due to the low incidence we were unable to identify modifiable risk factors for position-related injury following robotic surgery. A standardized, team-oriented approach may significantly decrease position-related injuries following robotic gynecologic surgery.

Carcinoma of the Lower Uterine Segment: A Newly Described Association With Lynch Syndrome

PURPOSE Endometrial carcinoma in the lower uterine segment (LUS) is a poorly described cancer that can be clinically confused with endocervical carcinoma. We performed a case-comparison study to document the clinicopathologic characteristics of LUS tumors and their association with risk factors for endometrial cancer. PATIENTS AND METHODS The clinical records and pathology reports from women who underwent hysterectomy at our institution for endometrial or endocervical adenocarcinoma over an 11-year interval were reviewed. The LUS group consisted of women with endometrial tumors that clearly originated between the lower uterine corpus and the upper endocervix. Immunohistochemistry and microsatellite instability and MLH1 methylation assays were performed. RESULTS Thirty-five (3.5%) of 1,009 women had endometrial carcinoma of the LUS. Compared with patients with corpus tumors, LUS patients were younger, had higher stage tumors, and had more invasive tumors. Preoperative diagnosis of the LUS tumors more frequently included the possibility of endocervical adenocarcinoma. Seventy-three percent of the LUS tumors had an immunohistochemical expression pattern typical of conventional endometrioid adenocarcinoma. Ten (29%) of 35 women with LUS tumors were confirmed to have Lynch syndrome or were strongly suspected to have Lynch syndrome on the basis of tissue-based molecular assays. CONCLUSION The prevalence of Lynch syndrome in patients with LUS endometrial carcinoma (29%) is much greater than that of the general endometrial cancer patient population (1.8%) or in endometrial cancer patients younger than age 50 years (8% to 9%). On the basis of our results, the possibility of Lynch syndrome should be considered in women with LUS tumors.

Radical hysterectomy: A comparison of surgical approaches after adoption of robotic surgery in gynecologic oncology

OBJECTIVE To compare intra-operative, postoperative and pathologic outcomes of three surgical approaches to radical hysterectomy and bilateral pelvic lymph node dissection over a three year time period during which all three approaches were used. METHODS We reviewed all patients who underwent radical hysterectomy with pelvic lymph node dissection between 1/2007 and 11/2010. Comparison was made between robotic, laparoscopic and open procedures in regard to surgical times, complication rates, and pathologic findings. RESULTS A total of 95 radical hysterectomy procedures were performed during the study period: 30 open (RAH), 31 laparoscopic (LRH) and 34 robotic (RRH). There were no differences in age, body mass index or other demographic factors between the groups. Operative time was significantly shorter in the RAH compared to LRH and RRH (265 vs 338 vs 328min, p=0.002). Estimated blood loss was significantly lower in LRH and RRH compared with RAH (100 vs 100 vs 350mL, p<0.001). Thirteen (24%) of RAH required blood transfusion. Conversion rates were higher in the LRH (16%) compared to RRH (3%) although not significant (p=0.10). Median length of stay was significantly shorter in RRH (1day) vs LRH or RAH (2 vs 4days, p<0.01). Pathologic findings were similar among all groups. CONCLUSION Minimally invasive surgery has made a significant impact on patients undergoing radical hysterectomy including decrease in blood loss and transfusion rates however; operative times were significantly longer compared to open radical hysterectomy. Our findings suggest that the robotic approach may have the added benefit of even shorter length of stay compared to traditional laparoscopy.

Enhanced estrogen-induced proliferation in obese rat endometrium

OBJECTIVE We tested the hypothesis that the proliferative estrogen effect on the endometrium is enhanced in obese vs lean animals. STUDY DESIGN Using Zucker fa/fa obese rats and lean control, we examined endometrial cell proliferation and the expression patterns of certain estrogen-regulated proproliferative and antiproliferative genes after short-term treatment with estradiol. RESULTS No significant morphologic/histologic difference was seen between the obese rats and the lean rats. Estrogen-induced proproliferative genes cyclin A and c-Myc messenger RNA expression were significantly higher in the endometrium of obese rats compared with those of the lean control. Expression of the antiproliferative gene p27Kip1 was suppressed by estrogen treatment in both obese and lean rats; however, the decrease was more pronounced in obese rats. Estrogen more strongly induced the antiproliferative genes retinaldehyde dehydrogenases 2 and secreted frizzled-related protein 4 in lean rats but had little or no effect in obese rats. CONCLUSION Enhancement of estrogen-induced endometrial proproliferative gene expression and suppression of antiproliferative gene expression was seen in the endometrium of obese vs lean animals.

Targeted therapy by combined inhibition of the RAF and mTOR kinases in malignant spindle cell neoplasm harboring the KIAA1549-BRAF fusion protein

BackgroundOncologic patients who are extreme responders to molecularly targeted therapy provide an important opportunity to better understand the biologic basis of response and, in turn, inform clinical decision making. Malignant neoplasms with an uncertain histologic and immunohistochemical characterization present challenges both on initial diagnostic workups and then later in management, as current treatment algorithms are based on a morphologic diagnosis. Herein, we report a case of a difficult to characterize sarcoma-like lesion for which genomic profiling with clinical next generation sequencing (NGS) identified the molecular underpinnings of arrested progression(stable disease) under combination targeted therapy within a phase I clinical trial.MethodsGenomic profiling with clinical next generation sequencing was performed on the FoundationOne™ platform (Foundation Medicine, Cambridge MA). Histopathology and immunohistochemical studies were performed in the Department of Pathology, MD Anderson Cancer Center (Houston, TX). Treatment was administered in the context of a phase I clinical trial ClinicalTrials.gov Identifier: (NCT01187199).ResultsThe histology of the tumor was that of a spindle cell neoplasm, grade 2 by FNCLCC standards. Immunohistochemical staining was positive for S100 and CD34. Genomic profiling identified the following alterations: a KIAA1549-BRAF gene fusion resulting from a tandem duplication event, a homozygous deletion of PTEN, and frameshift insertion/deletions in CDKN2A A68fs*51, SUFU E283fs*3, and MAP3K1 N325fs*3. The patient had a 25% reduction in tumor (RECIST v1.1) following combination therapy consisting of sorafenib, temsirolimus, and bevazicumab within a phase I clinical trial.ConclusionsThe patient responded to combination targeted therapy that fortuitously targeted KIAA1549-BRAF and PTEN loss within a spindle cell neoplasm, as revealed by genomic profiling based on NGS. This is the first report of a tumor driven by a KIAA1549-BRAF fusion responding to sorafenib-based combination therapy.

Personalized therapy in endometrial cancer: Challenges and opportunities

Early stage endometrial cancer is generally curable. However, progress in the treatment of advanced and recurrent endometrial cancer has been limited. This has led to a shift from the use of traditional chemotherapeutic agents and radiotherapy regimens to the promising area of targeted therapy, given the large number of druggable molecular alterations found in endometrial cancer. To maximize the effects of directed targeted therapy, careful molecular characterization of the endometrial tumor is necessary. This represents an important difference in the use of targeted therapy vs. traditional chemotherapy or radiation treatment. This review will discuss relevant pathways to target in endometrial cancer as well as the challenges that arise during development of a personalized oncology approach.

Optimization of MR Imaging for Pretreatment Evaluation of Patients with Endometrial and Cervical Cancer

Endometrial and cervical cancer are the most common gynecologic malignancies in the world. Accurate staging of cervical and endometrial cancer is essential to determine the correct treatment approach. The current International Federation of Gynecology and Obstetrics (FIGO) staging system does not include modern imaging modalities. However, magnetic resonance (MR) imaging has proved to be the most accurate noninvasive modality for staging endometrial and cervical carcinomas and often helps with risk stratification and making treatment decisions. Multiparametric MR imaging is increasingly being used to evaluate the female pelvis, an approach that combines anatomic T2-weighted imaging with functional imaging (ie, dynamic contrast material-enhanced and diffusion-weighted imaging). MR imaging helps guide treatment decisions by depicting the depth of myometrial invasion and cervical stromal involvement in patients with endometrial cancer and tumor size and parametrial invasion in those with cervical cancer. However, its accuracy for local staging depends on technique and image quality, namely thin-section high-resolution multiplanar T2-weighted imaging with simple modifications, such as double oblique T2-weighting supplemented by diffusion weighting and contrast enhancement.

Overall survival after pelvic exenteration for gynecologic malignancy

BACKGROUND Five-Year survival after pelvic exenteration for gynecologic malignancies has been reported as high as 60%. The objective of this study was to determine overall survival (OS) after pelvic exenteration and evaluate factors impacting outcome. METHODS A retrospective review of all women who underwent pelvic exenteration at our institution between February 1993 and December 2010 was performed. OS was defined as time from exenteration to date of death or last contact. Survival analysis was performed using the Kaplan Meyer method. Multivariate analysis was performed to determine the impact of clinical and pathologic factors on survival outcomes. RESULTS One hundred sixty patients with gynecologic malignancy underwent pelvic exenteration. Five-year recurrence free survival (RFS) was 33% (95%CI 0.25-0.40). Factors which negatively impacted RFS included shorter treatment-free interval (p=.050), vulvar primary (p=.032), positive margins (p<.001), lymphovascular space invasion (LVSI, p<.001), positive lymph nodes (p<.001) and perineural invasion (p=0.030). In multivariate analysis, positive margins (p=.040), positive nodes (p<.001) and lymphovascular space invasion (LVSI, p=.003) retained a significant impact on RFS. Five-year OS was 40% (95% CI 0.32-0.48). Factors which negatively impacted OS included vulvar primary (p=.04), positive margins (p<.001), LVSI (p<.001), positive lymph nodes (p<.001) and perineural invasion (p=.008). In multivariate analysis, positive nodes (p=.001) and LVSI (p=.001) retained a significant impact on OS. CONCLUSION Five-year OS after pelvic exenteration was 40%. Survival outcomes have not significantly improved despite improvements in technique and patient selection. Multiple non-modifiable factors at the time of exenteration are associated with poor survival.

Perception of screening and risk reduction surgeries in patients tested for a BRCA deleterious mutation

Women at a high risk for breast cancer are offered choices for screening or prophylactic surgeries. The aim of this study was to evaluate opinions regarding screening and surgical strategies in high‐risk women.