Diagnostic challenges and individualized treatment of cervical adenocarcinoma metastases to the breast: A case report.

BACKGROUND: Cervical cancer is a rare primary tumor resulting in metastases to the breast with few cases reported in literature. Breast metastases are associated with poor prognosis. The following case highlights the diagnostic challenges associated with metastatic cervical cancer to the breast along with individualized treatment. CASE SUMMARY: A 44-year-old G7P5025 with no significant past medical or surgical history presented with heavy vaginal to an outside emergency department where an exam and a pelvic magnetic resonance imaging showed a 4.5 cm heterogenous lobulated cervical mass involving upper two thirds of vagina, parametria and lymph node metastases. Cervical biopsies confirmed high grade adenocarcinoma with mucinous features. A positron emission tomography/computed tomography (PET/CT) did not show evidence of metastatic disease. She received concurrent cisplatin with external beam radiation therapy. Follow up PET/CT scan three months later showed no suspicious fluorodeoxyglucose uptake in the cervix and no evidence of metastatic disease. Patient was lost to follow up for six months. She was re-imaged on re-presentation and found to have widely metastatic disease including breast disease. Breast biopsy confirmed programmed death-ligand 1 positive metastatic cervical cancer. The patient received six cycles of carboplatin and paclitaxel with pembrolizumab. Restaging imaging demonstrated response. Patient continued on pembrolizumab with disease control. CONCLUSION: Metastatic cervical cancer to the breast is uncommon with nonspecific clinical findings that can make diagnosis challenging. Clinical history and immunohistochemical evaluation of breast lesion, and comparison to primary tumor can support diagnosis of metastatic cervical cancer to the breast. Overall, the prognosis is poor, but immunotherapy can be considered in select patients and may result in good disease response.

The Intersection of Palliative Care and Genetic Counseling in Cancer Care: A Case Discussion.

Up to 10% of cancers have a strong hereditary component. The diagnosis of a hereditary cancer may alter treatment recommendations for the patient. However, the optimal timing and best practices for integrating genetic counseling and testing into the care of women diagnosed with cancer remains unclear. In this study, we demonstrate the potential benefits of discussing genetic testing and counseling in the context of palliative care through two cases. Incorporating referrals for genetic testing into the palliative care context is important. This provides an opportunity to perform previously missed genetic testing. It is also a chance for the patient to leave a legacy while also potentially allowing for alternate targeted treatment possibilities that may be well tolerated and provide a better quality of life for the patients themselves. The benefits of referral to palliative care by the genetics team includes assisting patients with the management of not only physical but also psychological symptoms as well as conducting advanced care planning in patients and families with hereditary mutations.

Role of brachytherapy in stage III endometrial cancer treated with adjuvant chemotherapy: Identifying factors predictive of a survival benefit.

OBJECTIVES: To determine which patients with stage III endometrial cancer receiving adjuvant chemotherapy derive benefit from the addition of vaginal brachytherapy, as stage III is a highly heterogeneous population with substantial variations in practice. METHODS: Patients with FIGO stage III endometrial carcinoma diagnosed 2004-2016 who underwent at least total hysterectomy and adjuvant multiagent chemotherapy were identified in the National Cancer Database. The primary outcome was overall survival according to receipt of brachytherapy, stratified by histologic type, pathological features, and status of pelvic external beam radiotherapy (EBRT), and analyzed using the Kaplan-Meier method and Cox multivariable regression. RESULTS: In total, 9369 patients were identified (24% stage IIIA, 5% stage IIIB, 71% stage IIIC; 61% endometrioid, 39% nonendometrioid histology), and 28% received brachytherapy. In the endometrioid cohort, brachytherapy was associated with a 5% absolute increase in 3-year overall survival (87% vs. 82%, p < 0.0001), which persisted in multivariable analysis (adjusted hazard ratio 0.74, 95% confidence interval 0.64-0.84, p < 0.0001). The benefit of brachytherapy was greater in patients not also receiving EBRT, and in patients with vaginal/parametrial extension, grade 3 disease, lymphovascular invasion, and/or deep myometrial invasion. In the nonendometrioid cohort, brachytherapy was associated with a significant survival benefit in univariable but not multivariable analysis, regardless of EBRT status or pathological features. CONCLUSIONS: Factors predictive of brachytherapy benefit were endometrioid histology and pathological risk factors for local recurrence. Additionally, brachytherapy appeared more beneficial in patients not already receiving pelvic EBRT. Further research is warranted to determine which stage III patients may be best served by brachytherapy, EBRT, or both.

End-of-Life Care, Palliative Care Consultation, and Palliative Care Referral in the Emergency Department: A Systematic Review.

CONTEXT: There is growing interest in providing palliative care (PC) in the emergency department (ED), but relatively little is known about the efficacy of ED-based PC interventions. A 2016 systematic review on this topic found no evidence that ED-based PC interventions affect patient outcomes or health care utilization, but new research has emerged since the publication of that review. OBJECTIVES: This systematic review provides a concise summary of current literature addressing the impact of ED-based PC interventions on patient-reported or family reported outcomes, health care utilization, and survival. METHODS: We searched PubMed, Embase, Web of Science, Scopus, and the Cumulative Index to Nursing and Allied Health Literature from inception until September 1, 2018 and reviewed references. Eligible articles evaluated the effects of PC interventions in the ED on patient-reported or family reported outcomes, health care utilization, or survival. RESULTS: We screened 3091 abstracts and 98 full-text articles with 13 articles selected for final inclusion. Two articles reported the results of a single randomized controlled trial, whereas the remaining 11 studies were descriptive or quasi-experimental cohort studies. More than half of the included articles were published after the previous systematic review on this topic. Populations studied included older adults, patients with advanced malignancy, and ED patients screening positive for unmet PC needs. Most interventions involved referral to hospice or PC or PC provided directly in the ED. Compared with usual care, ED-PC interventions improved quality of life, although this improvement was not observed when comparing ED-PC to inpatient PC. ED-PC interventions expedited PC consultation; most studies reported a concomitant reduction in hospital length of stay and increase in hospice utilization, but some data were conflicting. Short-term mortality rates were high across all studies, but ED-PC interventions did not decrease survival time compared with usual care. CONCLUSION: Existing data support that PC in the ED is feasible, may improve quality of life, and does not appear to affect survival.

Defining the survival benefit of adjuvant pelvic radiotherapy and chemotherapy versus chemotherapy alone in stages III-IVA endometrial carcinoma.

OBJECTIVES: To determine which patients with locoregionally advanced endometrial cancer may benefit from pelvic external beam radiotherapy (EBRT) in addition to chemotherapy compared to chemotherapy alone. METHODS: Patients with FIGO stages III-IVA endometrial carcinoma between 2004 and 2016 who underwent at least total hysterectomy and adjuvant multiagent chemotherapy were identified in the National Cancer Database. The primary outcome was overall survival according to receipt of pelvic EBRT, analyzed using the Kaplan-Meier method and Cox multivariable regression. RESULTS: In total, 13,270 patients were identified (62% pure endometrioid, 38% serous/clear cell or mixed histology; 22.6% stage IIIA, 4.7% stage IIIB, 71.2% stage IIIC, 1.5% stage IVA), of whom 40% received pelvic EBRT. In univariable analysis, EBRT was associated with absolute 5-year survival increases of 5% and 9% in the endometrioid and non-endometrioid cohorts, respectively (P < 0.0001). In multivariable analyses stratified by stage and histology, patients with a significant benefit from EBRT were stage IIIC (specifically IIIC2) endometrioid (adjusted hazard ratio [HR] 0.73, P = 0.01) and stages IIIB and IIIC non-endometrioid (adjusted HR 0.52, P = 0.01 and adjusted HR 0.79, P < 0.0001). The benefit of EBRT in node-positive patients persisted in those who underwent more extensive lymphadenectomy. CONCLUSIONS: Stages III-IVA endometrial cancer comprised a heterogeneous population with respect to the added benefit of radiotherapy compared to chemotherapy alone. Patients with stage IIIC2 endometrioid and stages IIIB-C non-endometrioid cancer may be most likely to benefit from pelvic EBRT.

National patterns of care and cancer-specific outcomes of adjuvant treatment in patients with serous and clear cell endometrial carcinoma.

OBJECTIVES: To investigate outcomes of adjuvant therapy for serous and clear cell endometrial carcinoma, as prior studies are limited by sample size and/or patient heterogeneity. National guidelines permit substantial variations in treatment, suggesting the need for additional data. METHODS: Patients with FIGO stages I-III serous or clear cell uterine carcinoma who underwent at least total hysterectomy were identified in SEER-Medicare. Adjuvant external beam radiation, brachytherapy, and chemotherapy were determined using SEER fields and Medicare claims. The primary outcome was death from endometrial cancer (cancer-specific mortality [CSM]) evaluated using Gray's test (univariable analysis, UVA) and Fine-Gray regression (multivariable analysis, MVA). RESULTS: A total of 1789 patients (1437 serous, 352 clear cell) were identified. In stages I-II patients (n = 1188), brachytherapy was significant for survival in UVA (P = 0.03) and MVA (P = 0.02). Additionally, in the subset with serous histology (n = 947), chemotherapy was also significant in UVA (P = 0.002) and approached significance in MVA (P = 0.05). The 4-year CSM for stages I-II serous cancers was 25% without brachytherapy or chemotherapy, 15% with one, and 9% with both (P ≤ 0.05 for all pairwise comparisons). In stage III patients (n = 601), chemotherapy was significant in UVA (P = 0.002) and MVA (P = 0.006). Most (81%) patients underwent lymph node dissection, which predicted lower CSM in stage III (P = 0.001) but not stages I-II patients. CONCLUSIONS: Our results suggest brachytherapy benefits stages I-II serous/clear cell cancers, chemotherapy benefits stage III serous/clear cell cancers, and both chemotherapy and brachytherapy benefit stages I-II serous cancers.

Racial disparities in outcomes for high-grade uterine cancer: A California cancer registry study.

BACKGROUND: Endometrial cancer (EC) is the most common gynecologic malignancy. We examined factors affecting overall prognosis and survival among different racial groups diagnosed with high-grade EC. METHODS: We utilized the California Cancer Registry database (CCR) to identify women with high-grade II EC from 1998 to 2009. Using the Kaplan-Meier method, we described disease-specific survival. Survival by stage, race, and time to treatment category was compared using the log-rank test. The associations of race with disease-specific survival were modeled using Cox proportional hazards regression. Covariates were selected a priori. RESULTS: A total of 10 647 patients met study eligibility criteria. The majority of patients in this cohort of high-grade EC were non-Hispanic (NH) white (64.1%), followed by Hispanic (15.7%), Asian (10.4%), and NH black (9.8%). NH black women had higher incidence of certain aggressive histologic subtypes in comparison with NH whites, including serous carcinomas and carcinosarcoma. Non-Hispanic black patients had a worse 5-year disease-specific survival (DSS) when compared to other racial groups. The five-year DSS for NH black women was 54% (51%-57%), compared to NH white women 66% (65%-67%), Hispanic 67% (64%-69%), and Asians 69% (67%-72%) (P < 0.0001). This clear survival disadvantage of NH black women persisted when controlling for other factors. CONCLUSIONS: Non-Hispanic black women have a higher incidence of more aggressive histologic subtypes even among a cohort of women high-grade EC and have a disproportionately worse disease-specific survival after controlling for factors such as age, histologic subtype, stage, time to treatment, and type of treatment.

Platinum desensitization in patients with carboplatin hypersensitivity: A single-institution retrospective study.

OBJECTIVES: The carboplatin desensitization (CD) protocol presented here allows patients with either a positive skin test or a prior hypersensitivity reaction (HSR) to safely, rapidly and effectively continue with carboplatin infusions. Newly described factors can identify patients at risk for developing adverse events during CD. METHODS: A retrospective review was performed on patients with gynecologic cancer who underwent CD between 2005 and 2014. The CD protocol uses a four-step dilution process over 3.5h. RESULTS: 129 patients underwent CD and completed a total of 788cycles. The desensitization protocol prevented HSRs in 96% (753 out of 788) of these cycles. Patients achieved an average of 6.1cycles (SD±4.55, range 0-23) with CD. The CD protocol allowed 73% (94 of 129) of the patients to undergo carboplatin infusion without reaction. Patients with moderate to life-threatening HSRs (grade 2 through 4) were 10.5years younger at initial CD than patients with grades 0 or 1 HSRs (52.3 vs. 63, P = 0.0307). One patient death occurred during her thirteenth desensitization cycle. The HSR in this case was complicated by pre-exisiting pulmonary hypertension. CONCLUSIONS: This is the largest study of its kind showing a safe, effective and rapid (3.5h) CD protocol. The majority of patients with a history of either carboplatin hypersensitivity reaction or a positive skin test completed the CD protocol without HSRs. Age was identified as a risk factor for HSR severity during CD. Age can be employed along with pre-load dependent cardiac conditions as a way to help risk stratify patients undergoing CD.

Mutational landscape of uterine and ovarian carcinosarcomas implicates histone genes in epithelial-mesenchymal transition.

Carcinosarcomas (CSs) of the uterus and ovary are highly aggressive neoplasms containing both carcinomatous and sarcomatous elements. We analyzed the mutational landscape of 68 uterine and ovarian CSs by whole-exome sequencing. We also performed multiregion whole-exome sequencing comprising two carcinoma and sarcoma samples from six tumors to resolve their evolutionary histories. The results demonstrated that carcinomatous and sarcomatous elements derive from a common precursor having mutations typical of carcinomas. In addition to mutations in cancer genes previously identified in uterine and ovarian carcinomas such as TP53, PIK3CA, PPP2R1A, KRAS, PTEN, CHD4, and BCOR, we found an excess of mutations in genes encoding histone H2A and H2B, as well as significant amplification of the segment of chromosome 6p harboring the histone gene cluster containing these genes. We also found frequent deletions of the genes TP53 and MBD3 (a member with CHD4 of the nucleosome remodeling deacetylase complex) and frequent amplification of chromosome segments containing the genes PIK3CA, TERT, and MYC Stable transgenic expression of H2A and H2B in a uterine serous carcinoma cell line demonstrated that mutant, but not wild-type, histones increased expression of markers of epithelial-mesenchymal transition (EMT) as well as tumor migratory and invasive properties, suggesting a role in sarcomatous transformation. Comparison of the phylogenetic relationships of carcinomatous and sarcomatous elements of the same tumors demonstrated separate lineages leading to these two components. These findings define the genetic landscape of CSs and suggest therapeutic targets for these highly aggressive neoplasms.

Chlamydia Peritonitis and Ascites Mimicking Ovarian Cancer.

Background. Pelvic inflammatory disease (PID) rarely results in diffuse ascites. Severe adhesive disease secondary to PID may lead to the formation of inclusion cysts and even pelvic peritoneal nodularity due to postinflammatory scarring and cause an elevation of serum CA-125 levels. The constellation of these findings may mimic an ovarian neoplasm. Case. We report a case of a 22-year-old female who presented with multiple pelvic cysts and diffuse ascites due to Chlamydia trachomatis infection. The initial gynecologic exam did not reveal obvious evidence of PID; however, a positive Chlamydia trachomatis test, pathologic findings, and the exclusion of other etiologies facilitated the diagnosis. Conclusion. Chlamydia trachomatis and other infectious agents should be considered in the differential diagnosis of a young sexually active female with abdominal pain, ascites, and pelvic cystic masses. Thorough workup in such a population may reduce the number of more invasive procedures as well as unnecessary repeat surgical procedures.

Molecular diagnosis and molecular profiling to detect treatment-resistant ovarian cancer.

INTRODUCTION: Epithelial ovarian cancer remains the gynecologic tumor with the highest rate of recurrence after initial optimal cytoreductive surgery followed by adjuvant chemotherapy. Unfortunately, with the development of recurrent ovarian cancer often comes the discovery of chemo-resistant disease. The absence of improvement in long term survival, notwithstanding the use of newer agents as is seen in other cancers, emphasizes the need for improved understanding of the processes that lead to chemo-resistant disease. AREAS COVERED: This review will cover the following topics: 1. Molecular and cellular mechanisms in platinum and paclitaxel resistance 2. Other molecular mediators of chemo-resistance 3. Expression of stem cell markers in ovarian cancer and relationship to chemo-resistance 4. MicroRNA and long non-coding RNA expression in chemo-resistant ovarian cancer 5. Determination of chromosomal aberrations as markers of chemo-resistance 6. Molecular profiling in chemo-resistant disease. A standard MEDLINE search was performed using the key words; ovarian cancer, chemo-resistant disease, molecular profiling, cancer stem cells and chemotherapy. Expert Commentary: Over the next few years the challenge remains to precisely determine the mechanisms responsible for the onset and maintenance of chemo-resistance and to effectively target these mechanisms.

Challenging Case of Postmenopausal Bleeding and Complete Urogenital Duplication.

BACKGROUND: Müllerian duct anomalies represent a wide spectrum of congenital abnormalities ranging from simple uterine anomalies to more complex multisystem derangements. Complete duplication of uterus, cervix, and vagina may be associated with urologic and caudal gastrointestinal malformations. CASE REPORT: We present a case report detailing the management of a morbidly obese patient with postmenopausal bleeding and thickened endometrial stripe who had a very rare condition of pelvic organ duplication, including 2 hemiuteri, 2 vaginas, 2 hemibladders, and 2 each of ovaries, fallopian tubes, kidneys, and ureters. Laparoscopic hysterectomy was complicated by difficulties understanding urinary system anatomy requiring intraoperative urology consultation and imaging. CONCLUSIONS: Management of patients with urogenital duplication and abnormal uterine bleeding requires a thorough understanding of possible associated malformations. Thorough preoperative evaluation, careful surgical exploration, and multidisciplinary approach may be necessary to avoid urologic injury in such patients.

An update on the current pharmacotherapy for endometrial cancer.

INTRODUCTION: Endometrial cancer (EC) is the most common gynecologic malignancy in the developed world and is increasing in incidence. While the mainstay of treatment for EC is surgery followed by chemotherapy and/or radiation therapy, the available pharmacotherapies are rapidly and constantly evolving. Understanding these new therapies is an important part of the research and clinical care of women with EC. A review of available literature from MEDLINE (1879-2015) was conducted for the historic treatments and current therapies available for endometrial tumors. AREAS COVERED: This article reviews the current conventional therapies and discusses novel therapeutic agents, some of which are available to clinicians while others are currently being investigated in the preclinical setting. EXPERT OPINION: Genomic and immunohistochemical characterization of endometrial cancer may soon be the best approach for the identification of aggressive forms of tumor. Targeted therapies will soon be standard in the management of endometrial cancer.

Solitomab, an EpCAM/CD3 bispecific antibody construct (BiTE), is highly active against primary uterine serous papillary carcinoma cell lines in vitro.

BACKGROUND: Uterine serous carcinoma is an aggressive form of endometrial cancer that carries an extremely poor prognosis. Solitomab is a novel bispecific single-chain antibody construct that targets epithelial cell adhesion molecule on tumor cells and also contains a CD3 binding region. We evaluated the expression levels of epithelial cell adhesion molecule and the in vitro activity of solitomab against primary uterine serous carcinoma cell lines in vitro and ex-vivo in the ascites of patients with uterine serous carcinoma. OBJECTIVE: The purpose of this study was to determine the frequency of expression of epithelial cell adhesion molecule on uterine serous carcinoma cell lines and the ability of solitomab to modulate immune responses (T-cell proliferation, activation, cytokine production, and tumor killing) to tumor cells when it is combined with lymphocytes and epithelial cell adhesion molecule-positive cell lines or epithelial cell adhesion molecule-positive ascitic fluid in vitro. STUDY DESIGN: Epithelial cell adhesion molecule expression was evaluated by flow cytometry in a total of 14 primary uterine serous carcinoma cell lines. Sensitivity to solitomab-dependent cellular-cytotoxicity was tested against a panel of primary uterine serous carcinoma cell lines that express different levels of epithelial cell adhesion molecule in standard 4-hour chromium release assays. The proliferative activity, activation, cytokine secretion (ie, type I vs type II), and cytotoxicity of solitomab in autologous tumor-associated T cells in the ascitic fluid of patients with uterine serous carcinoma was also evaluated by carboxyfluorescein succinimidyl ester and flow-cytometry assays. Differences in epithelial cell adhesion molecule expression, solitomab-dependent cellular-cytotoxicity levels were analyzed with the use of an unpaired t test. T-cell activation marker increase and cytokine release were analyzed by a paired t test. RESULTS: Surface expression of epithelial cell adhesion molecule was found in 85.7% (12 of 14) of the uterine serous carcinoma cell lines that were tested by flow cytometry. Epithelial cell adhesion molecule-positive cell lines were found resistant to natural killer cells or T-cell-mediated killing after exposure to peripheral blood lymphocytes in 4-hour chromium-release assays (mean killing ± standard of the mean, 2.7% ± 3.1% after incubation of epithelial cell adhesion molecule-positive cell lines with control bispecific antibody construct). In contrast, after incubation with solitomab, epithelial cell adhesion molecule-positive uterine serous carcinoma cells became highly sensitive to T-cell cytotoxicity (mean killing, 25.7% ± 4.5%; P < .0001) by peripheral blood lymphocytes. Ex vivo incubation of autologous tumor-associated lymphocytes with epithelial cell adhesion molecule that expressed malignant cells in ascites with solitomab resulted in a significant increase in T-cell proliferation in both CD4+ and CD8+ T cells, increase in T-cell activation markers (ie, CD25 and HLA-DR), and a reduction in number of viable uterine serous carcinoma cells in ascites (P < .001). CONCLUSION: Solitomab induces robust immunologic responses in vitro that result in increased T-cell activation, proliferation, production of cytokines, and direct killing of tumor cells. These findings suggest that solitomab may represent a novel, potentially effective agent for the treatment of recurrent/metastatic and/or chemo-resistant uterine serous carcinoma-overexpressing epithelial cell adhesion molecule.

Dual HER2/PIK3CA Targeting Overcomes Single-Agent Acquired Resistance in HER2-Amplified Uterine Serous Carcinoma Cell Lines In Vitro and In Vivo.

HER2/neu gene amplification and PIK3CA driver mutations are common in uterine serous carcinoma (USC) and may represent ideal therapeutic targets against this aggressive variant of endometrial cancer. We examined the sensitivity to neratinib, taselisib, and the combination of the two compounds in in vitro and in vivo experiments using PIK3CA-mutated and PIK3CA wild-type HER2/neu-amplified USC cell lines. Cell viability and cell-cycle distribution were assessed using flow-cytometry assays. Downstream signaling was assessed by immunoblotting. Preclinical efficacy of single versus dual inhibition was evaluated in vivo using two USC xenografts. We found both single-agent neratinib and taselisib to be active but only transiently effective in controlling the in vivo growth of USC xenografts harboring HER2/neu gene amplification with or without oncogenic PIK3CA mutations. In contrast, the combination of the two inhibitors caused a stronger and long-lasting growth inhibition in both USC xenografts when compared with single-agent therapy. Combined targeting of HER2 and PIK3CA was associated with a significant and dose-dependent increase in the percentage of cells in the G0-G1 phase of the cell cycle and a dose-dependent decline in the phosphorylation of S6. Importantly, dual inhibition therapy initiated after tumor progression in single-agent-treated mice was still remarkably effective at inducing tumor regression in both large PIK3CA and pan-ErbB inhibitor-resistant USC xenografts. Dual HER2/PIK3CA blockade may represent a novel therapeutic option for USC patients harboring tumors with HER2/neu gene amplification and mutated or wild-type PIK3CA resistant to chemotherapy.

PIK3CA oncogenic mutations represent a major mechanism of resistance to trastuzumab in HER2/neu overexpressing uterine serous carcinomas.

OBJECTIVES: We evaluated the role of PIK3CA-mutations as mechanism of resistance to trastuzumab in primary HER2/neu-amplified uterine-serous-carcinoma (USC) cell lines. METHODS: Fifteen whole-exome-sequenced USC cell lines were tested for HER2/neu-amplification and PIK3CA-mutations. Four HER2/neu-amplified USC (2-harbouring wild-type-PIK3CA-genes and 2-harbouring oncogenic-PIK3CA-mutations) were evaluated in in vitro dose-titration-proliferation-assays, cell-viability and HER2 and S6-protein-phosphorylation after exposure to trastuzumab. USC harbouring wild-type-PIK3CA were transfected with plasmids encoding oncogenic PIK3CA-mutations (i.e., H1047R/R93Q) and exposed to trastuzumab. Finally, trastuzumab efficacy was tested by using two USC xenograft mouse models. RESULTS: Seven out of fifteen (46%) of the USC cell lines were HER2/neu-amplified by fluorescence in situ hybridisation. Within these tumours four out of seven (57%) were found to harbour oncogenic PIK3CA-mutations vs two out of eight (25%) of the HER2/neu not amplified cell lines (P=0.01). HER2/neu-amplified/PIK3CA-mutated USC were highly resistant to trastuzumab when compared with HER2/neu-amplified/wild-type-PIK3CA cell lines (P=0.02). HER2/neu-amplified/PIK3CA wild-type cell lines transfected with oncogenic PIK3CA-mutations increased their resistance to trastuzumab (P<0.0001). Trastuzumab was effective in reducing tumour growth (P=0.001) and improved survival (P=0.0001) in mouse xenografts harbouring HER2-amplified/PIK3CA wild-type USC but not in HER2-amplified/PIK3CA-mutated tumours. CONCLUSIONS: Oncogenic PIK3CA mutations are common in HER2/neu-amplified USC and may constitute a major mechanism of resistance to trastuzumab treatment.

Neratinib shows efficacy in the treatment of HER2 amplified carcinosarcoma in vitro and in vivo.

OBJECTIVE: Carcinosarcoma is a deadly gynecologic malignancy with few effective treatment options. The study of new therapies is difficult because of its rarity. The objective of this study was to determine the efficacy of neratinib in the treatment of HER2 amplified carcinosarcoma. METHODS: The efficacy of neratinib in the treatment of HER2 amplified carcinosarcoma was determined in vitro using seven primary carcinosarcoma cell lines with differential expression of HER2/neu. Data regarding IC50, cell cycle distribution, and cell signaling changes were assessed by flow cytometry. The efficacy of neratinib was determined in treating mice harboring HER2 amplified carcinosarcoma xenografts. RESULTS: Two of seven (28.5%) carcinosarcoma cell lines were HER2/neu amplified. HER2/neu amplified cell lines SARARK6 and SARARK9 were significantly more sensitive to neratinib than the five non-HER2/neu amplified carcinosarcoma cell lines (mean±SEM IC50:0.014µM±0.004vs.0.164µM±0.019 p=0.0003). Neratinib treatment caused a significant build up in G0/G1 phase of the cell cycle, arrest auto phosphorylation of HER2/neu and activation of S6. Neratinib inhibited tumor growth (p=0.012) and prolonged survival in mice harboring HER2 amplified carcinosarcoma xenografts (p=0.0039). CONCLUSIONS: Neratinib inhibits HER2 amplified carcinosarcoma proliferation, signaling, cell cycle progression and tumor growth in vitro. Neratinib inhibits HER2/neu amplified xenograft growth and improves overall survival. Clinical trials are warranted.