[Show abstract][Hide abstract] ABSTRACT: Adjuvant therapy increases disease-free survival in endometrial cancer (EC), but has no impact on overall survival and negatively influences the quality of life. We investigated the discriminatory power of classical and immunological predictors of recurrence in a cohort of EC patients and confirmed the findings in an independent validation cohort.
We reanalysed the data from 355 EC patients and tested our findings in an independent validation cohort of 72 patients with EC. Predictors were selected and Harrell's C-index for concordance was used to determine discriminatory power for disease-free survival in the total group and stratified for histological subtype.
Predictors for recurrence were FIGO stage, lymphovascular space invasion and numbers of cytotoxic and memory T-cells. For high risk cancer, cytotoxic or memory T-cells predicted recurrence as well as a combination of FIGO stage and lymphovascular space invasion (C-index 0.67 and 0.71 vs 0.70). Recurrence was best predicted when FIGO stage, lymphovascular space invasion and numbers of cytotoxic cells were used in combination (C-index 0.82). Findings were confirmed in the validation cohort.
In high-risk EC, clinicopathological or immunological variables can predict regional or distant recurrence with equal accuracy, but the use of these variables in combination is more powerful.British Journal of Cancer advance online publication, 28 July 2015; doi:10.1038/bjc.2015.268 www.bjcancer.com.
British Journal of Cancer 07/2015; DOI:10.1038/bjc.2015.268 · 4.82 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Polymorphisms in the VEGF/angiogenesis pathway have been previously implicated in cancer risk, prognosis, and response to therapy including in esophageal adenocarcinoma. Prior esophageal adenocarcinoma studies focused on using candidate polymorphisms, limiting the discovery of novel polymorphisms. Here, we applied the tagSNP approach to identify new VEGF-pathway polymorphisms associated with esophageal adenocarcinoma prognosis and validated them in an independent cohort of esophageal adenocarcinoma patients. In 231 esophageal adenocarcinoma patients of all stages/treatment plans, 58 genetic polymorphisms (18 KDR, 7 VEGFA, 33 FLT1), selected through tagging and assessment of predicted function were genotyped. Cox-proportional hazard models adjusted for important socio-demographic and clinico-pathological factors were applied to assess the association of genetic polymorphisms with overall survival (OS) and progression-free survival (PFS). Significantly associated polymorphisms were then validated in an independent cohort of 137 esophageal adenocarcinoma patients. Among the 231 discovery cohort patients, 86% were male, median diagnosis age was 64 years, 34% were metastatic at diagnosis, and median OS and PFS were 20 and 12 months respectively. KDR rs17709898 was found significantly associated with PFS (adjusted hazard ratio,aHR=0.69, 95%CI:0.53-0.90;P=5.2E-3). FLT1 rs3794405 and rs678714 were significantly associated with OS (aHR=1.44, 95%CI:1.04-1.99;P=0.03 and aHR=1.50, 95%CI:1.01- 2.24;P=0.04, respectively). No VEGFA polymorphisms were found significantly associated with either outcome. Upon validation, FLT1 rs3794405 remained strongly associated with OS (aHR=1.59, 95%CI:1.04-2.44;P=0.03). FLT1 rs3794405 is significantly associated with OS in esophageal adenocarcinoma; whereby each variant allele confers a 45-60% increased risk in mortality. Validation and evaluation of this association in other cancer sites is warranted.
[Show abstract][Hide abstract] ABSTRACT: This study aimed to investigate whether molecular analysis can be used to refine risk assessment, direct adjuvant therapy, and identify actionable alterations in high-risk endometrial cancer. TransPORTEC, an international consortium related to the PORTEC3 trial, was established for translational research in high-risk endometrial cancer. In this explorative study, routine molecular analyses were used to detect prognostic subgroups: p53 immunohistochemistry, microsatellite instability and POLE proofreading mutation. Furthermore, DNA was analyzed for hotspot mutations in 13 additional genes (BRAF, CDKNA2, CTNNB1, FBXW7, FGFR2, FGFR3, FOXL2, HRAS, KRAS, NRAS, PIK3CA, PPP2R1A, and PTEN) and protein expression of ER, PR, PTEN, and ARID1a was analyzed. Rates of distant metastasis, recurrence-free, and overall survival were calculated using the Kaplan-Meier method and log-rank test. In total, samples of 116 high-risk endometrial cancer patients were included: 86 endometrioid; 12 serous; and 18 clear cell. For endometrioid, serous, and clear cell cancers, 5-year recurrence-free survival rates were 68%, 27%, and 50% (P=0.014) and distant metastasis rates 23%, 64%, and 50% (P=0.001), respectively. Four prognostic subgroups were identified: (1) a group of p53-mutant tumors; (2) microsatellite instable tumors; (3) POLE proofreading-mutant tumors; and (4) a group with no specific molecular profile (NSMP). In group 3 (POLE-mutant; n=14) and group 2 (microsatellite instable; n=19) patients, no distant metastasis occurred, compared with 50% distant metastasis rate in group 1 (p53-mutant; n=36) and 39% in group 4 (NSMP; P<0.001). Five-year recurrence-free survival was 93% and 95% for group 3 (POLE-mutant) and group 2 (microsatellite instable) vs 42% (group 1, p53-mutant) and 52% (group 4, NSMP; P<0.001). Targetable FBXW7 and FGFR2 mutations (6%), alterations in the PI3K-AKT pathway (60%) and hormone receptor positivity (45%) were frequently found. In conclusion, molecular analysis of high-risk endometrial cancer identifies four distinct prognostic subgroups, with potential therapeutic implications. High frequencies of targetable alterations were identified and may serve as targets for individualized treatment.Modern Pathology advance online publication, 27 February 2015; doi:10.1038/modpathol.2015.43.
Modern Pathology 02/2015; 28(6). DOI:10.1038/modpathol.2015.43 · 6.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Despite the declining incidence of cervical cancer as a result of the introduction of screening programs, globally it remains a leading cause of cancer-related death in women. Outcomes for patients who are diagnosed with anything but early-stage disease remain poor. Here we examine emerging strategies to improve the treatment of locally advanced disease. We discuss emerging biologic data, which are informing our investigation of new therapeutic interventions in persistent, recurrent, and metastatic cervical cancer. We recognize the importance of interventions to improve quality of life and to prevent long-term sequelae in women undergoing treatment. Finally, and perhaps most importantly, we recognize the need for global collaboration and advocacy to improve the outcome for all women at risk of and diagnosed with this disease.
[Show abstract][Hide abstract] ABSTRACT: Ovarian low-grade serous carcinoma (LGSC) has fewer mutations than ovarian high-grade serous carcinoma (HGSC) and a less aggressive clinical course. However, an overwhelming majority of LGSC patients do not respond to conventional chemotherapy resulting in a poor long-term prognosis comparable to women diagnosed with HGSC. KRAS and BRAF mutations are common in LGSC, leading to clinical trials targeting the MAPK pathway. We assessed the stability of targetable somatic mutations over space and/or time in LGSC, with a view to inform stratified treatment strategies and clinical trial design.
Eleven LGSC cases with primary and recurrent paired samples were identified (stage IIB-IV). Tumor DNA was isolated from 1-4 formalin-fixed paraffin-embedded tumor blocks from both the primary and recurrence (n = 37 tumor and n = 7 normal samples). Mutational analysis was performed using the Ion Torrent AmpliSeqTM Cancer Panel, with targeted validation using Fluidigm-MiSeq, Sanger sequencing and/or Raindance Raindrop digital PCR.
KRAS (3/11), BRAF (2/11) and/or NRAS (1/11) mutations were identified in five unique cases. A novel, non-synonymous mutation in SMAD4 was observed in one case. No somatic mutations were detected in the remaining six cases. In two cases with a single matched primary and recurrent sample, two KRAS hotspot mutations (G12V, G12R) were both stable over time. In three cases with multiple samplings from both the primary and recurrent surgery some mutations (NRAS Q61R, BRAF V600E, SMAD4 R361G) were stable across all samples, while others (KRAS G12V, BRAF G469V) were unstable.
Overall, the majority of cases with detectable somatic mutations showed mutational stability over space and time while one of five cases showed both temporal and spatial mutational instability in presumed drivers of disease. Investigation of additional cases is required to confirm whether mutational heterogeneity in a minority of LGSC is a general phenomenon that should be factored into the design of clinical trials and stratified treatment for this patient population.
BMC Cancer 12/2014; 14(1):982. DOI:10.1186/1471-2407-14-982 · 3.32 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective
The phosphatidylinositol-3 kinase/serine-threonine kinase PI3K/AKT pathway is postulated to be central to cancer cell development. Activation of this pathway is believed to promote angiogenesis, protein translation and cell cycle progression. A large percentage of endometrial carcinomas have demonstrated mutations within this regulation pathway which result in constitutional activation. The downstream effector protein mammalian target of rapamycin (mTOR) acts as a critical checkpoint in cancer cell cycling and is a logical target for drug development. The efficacy and tolerability of the oral mTOR inhibitor Ridaforolimus was evaluated in this study.
This phase II study evaluated the single agent tolerability and activity of oral ridaforolimus administered at a dose of 40 mg for 5 consecutive days followed by a 2 day break, in women with recurrent or metastatic endometrial carcinoma who had received no chemotherapy in the metastatic setting.
31 of 34 patients were evaluable. Three partial responses (8.8%) were observed with response duration ranging between 7.9-26.5 months. An additional 18 patients showed disease stabilisation (52.9%) for a median duration of 6.6 months. Response rates were not affected by previous chemotherapy exposure. No correlation was found between response and mutation status.
Oral Ridaforolimus was reasonably tolerated and demonstrated modest activity in women with recurrent or metastatic endometrial cancers. Potential synergy between mTOR inhibition, angiogenesis and hormonal pathways warrants ongoing evaluation.
[Show abstract][Hide abstract] ABSTRACT: Background:Folate receptor 1 (FOLR1) is expressed in the majority of ovarian carcinomas (OvCa), making it an attractive target for therapy. However, clinical trials testing anti-FOLR1 therapies in OvCa show mixed results and require better understanding of the prognostic relevance of FOLR1 expression. We conducted a large study evaluating FOLR1 expression with survival in different histological types of OvCa.Methods:Tissue microarrays composed of tumour samples from 2801 patients in the Ovarian Tumour Tissue Analysis (OTTA) consortium were assessed for FOLR1 expression by centralised immunohistochemistry. We estimated associations for overall (OS) and progression-free (PFS) survival using adjusted Cox regression models. High-grade serous ovarian carcinomas (HGSC) from The Cancer Genome Atlas (TCGA) were evaluated independently for association between FOLR1 mRNA upregulation and survival.Results:FOLR1 expression ranged from 76% in HGSC to 11% in mucinous carcinomas in OTTA. For HGSC, the association between FOLR1 expression and OS changed significantly during the years following diagnosis in OTTA (Pinteraction=0.01, N=1422) and TCGA (Pinteraction=0.01, N=485). In OTTA, particularly for FIGO stage I/II tumours, patients with FOLR1-positive HGSC showed increased OS during the first 2 years only (hazard ratio=0.44, 95% confidence interval=0.20-0.96) and patients with FOLR1-positive clear cell carcinomas (CCC) showed decreased PFS independent of follow-up time (HR=1.89, 95% CI=1.10-3.25, N=259). In TCGA, FOLR1 mRNA upregulation in HGSC was also associated with increased OS during the first 2 years following diagnosis irrespective of tumour stage (HR: 0.48, 95% CI: 0.25-0.94).Conclusions:FOLR1-positive HGSC tumours were associated with an increased OS in the first 2 years following diagnosis. Patients with FOLR1-negative, poor prognosis HGSC would be unlikely to benefit from anti-FOLR1 therapies. In contrast, a decreased PFS interval was observed for FOLR1-positive CCC. The clinical efficacy of FOLR1-targeted interventions should therefore be evaluated according to histology, stage and time following diagnosis.British Journal of Cancer advance online publication, 30 October 2014; doi:10.1038/bjc.2014.567 www.bjcancer.com.
British Journal of Cancer 10/2014; 111(12). DOI:10.1038/bjc.2014.567 · 4.82 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose/Objective(s): Angiogenesis is up-regulated in many solid tumors including cervical cancer and may contribute to radioresistance. Pre-clinical studies have shown that sorafenib, an oral multi-targeted kinase inhibitor with antiangiogenic effects, can improve response to radiation therapy (RT). The purpose of this study was to examine the efficacy and toxicity of sorafenib in patients with cervix cancer receiving RT and cisplatin chemotherapy (RTCT).
Materials/Methods: This was a prospective phase 1/2 study of sorafenib in patients with locally advanced cervix cancer receiving standard RTCT. There were 6 FIGO IB/IIA, 3 IIB/IIIA and 4 IIIB tumors. Sorafenib 400 mg or 800 mg was administered daily for 1 week prior to the start of RTCT in all patients, as well as during RTCT in 3 patients with high-risk disease. Needle-based measurements of hypoxia and interstitial fluid pressure (IFP), DCEMR and tumor biopsies were obtained before treatment and after 1 week of sorafenib. Biopsy-based markers of proliferation, vascularity, and hypoxia were evaluated by IHC separately in tumor and stroma excluding necrosis. Median follow-up was 4.1 years.
Results: At last follow-up, 1 patient had died without achieving disease control and 4 recurred after an initial complete response 2 in pelvis and 2 at distant metastatic sites. Acute toxicity was similar to RTCT alone. Grade 3-4 late toxicity was identified in 5 patients, 1 with pelvic fistulae, 3 with rectal bleeding and 1 with an anal fissure.MR tumor volume increased during treatment with sorafenib alone (mean 78 to 86 cm3, p < 0.01). The ktrans from DCE MR decreased (mean 0.016 to 0.008s-1, p = 0.02) in keeping with a reduction in tumor perfusion and/or vascular permeability. The tumors also became more hypoxic (mean pO2 14 to 3 mm Hg, p = 0.01; and mean hypoxic proportion 51 to 67%, p = 0.06). At baseline, the mean tumor, stromal, and necrotic percentages were 23%, 29%, and 48%, respectively, and remained unchanged after 1 week of sorafenib. Tumor expression of the HIF-dependent genes GLUT1 (p < 0.04) and CXCR4 (p < 0.03) increased with sorafenib, consistent with increased hypoxia. There was a reduction in stromal infiltration by CD11b+ (p = 0.001) and CD66b+ (p = 0.01) myeloid cells, implicated in pre-clinical studies as contributing to disease progression following antiangiogenic treatment or RT.
Conclusions: Sorafenib reduces tumor perfusion/permeability and increases hypoxia in cervical cancer suggesting that it is unlikely to improve clinical outcomes when used prior to RT. However, sorafenib also reduces tumor infiltration by myeloid cells that can contribute to vascular persistence and new vessel formation during RT. Further study of the interaction between the angiogenic and chemokine pathways involved in vascular response to RT is warranted, particularly in relation to the potential for combined inhibition during and after treatment.
International Journal of Radiation OncologyBiologyPhysics 09/2014; 90(1):S187–S188. DOI:10.1016/j.ijrobp.2014.05.717 · 4.18 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Immunohistochemistry (IHC) for mismatch repair protein expression, microsatellite instability (MSI) testing, tumor morphology, and family history were compared to determine which screening strategy is superior in identifying Lynch syndrome (LS) in unselected women with newly diagnosed endometrial cancer (EC) who have undergone universal germline mutation testing. A prospective cohort study was performed that recruited women with newly diagnosed EC. Participants completed a family history assessment with molecular characterization of EC with IHC and MSI testing and EC assessment for LS-associated morphologic features and underwent universal germline mutation testing for mutations in the mismatch repair pathway. The sensitivity, specificity, and positive and negative predictive values were compared between the screening strategies. A total of 118 (65%) of 182 consecutive women with EC participated. Of these, 34 women (29%) had tumors that were IHC deficient and 27 women (23%; N = 117) had tumors that were positive for MSI. Twenty women (17%) met IHC criteria and 16 women (15.2%, N = 105) met family history criteria based on Ontario Ministry of Health Criteria for the genetic assessment for LS. Seven women (5.9%) had a germline mutation: 4 had MLH1 (mutL homolog 1), 2 had MSH6 (mutS homolog 6), and 1 had MSH2 (mutS homolog 2). IHC in women aged <60 years had the best performance characteristics, with a sensitivity of 100%, a specificity of 86.1%, a positive predictive value of 58.3%, and a negative predictive value of 100%. Family history and tumor morphology both had the lowest sensitivity at 71.4%. Overall tumor morphology had the poorest performance, with a specificity of 42.1%. The mutation rate of 5.9% was higher than expected in this unselected cohort of women with EC. The superior screening strategy to identify women presenting with EC is universal IHC screening in women aged <60 years. Cancer 2014;;120:3932–3939.
Cancer 07/2014; 120(24). DOI:10.1002/cncr.28933 · 4.90 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective. Treatment options remain limited for women with relapsed/metastatic endometrial cancer (EC). Angiogenesis is one of the major components of tumor progression and thus an attractive target. The aim of this phase II trial was to assess the efficacy and tolerability of sunitinib, an oral multitargeted receptor tyrosine-kinase inhibitor with antiangiogenic and antitumor activity in the treatment of recurrent EC. Methods. We performed a multicenter, single arm, two-stage phase II study of sunitinib, 50 mg daily administered on a 4 weeks on-2 weeks off schedule. Eligibility criteria included recurrent/metastatic EC or carcinosarcoma with no more than one prior line of chemotherapy. The primary endpoint was objective response rate. Results. 34 women were enrolled; 33 received at least one dose of sunitinib and were included in the analyses. Six women (18.1%) had a partial response and six additional women (18.1%) stable disease. In total, ten patients (303%) had disease control for at least 6 months and of these, seven were controlled for more than one year. Median progression free and overall survival times were 3 months and 19.4 months, respectively. Adverse events related to treatment were frequent At least one grade 3 toxicity occurred in 30 patients and dose reductions were required in 17 patients (52%). The most common grade 3 toxicities were fatigue, hypertension, palmar-plantar erythrodysesthesia, diarrhea and hematologic. Conclusion. Sunitinib therapy showed promising activity in women with recurrent EC. Toxicity was seen frequently but was manageable. Anti-angiogenic agents warrant further investigation in EC to define which patients will derive the greatest benefit.
[Show abstract][Hide abstract] ABSTRACT: Introduction: Endometrial cancer (EC) is the most common gynecological cancer in the developed world. For women with advanced or high-risk disease, survival has remained unchanged over the last 20 years highlighting the need for better therapies. Phase II trials are critical to ascertain an estimate of benefit and determine which new agents undergo further development. Areas covered: Based on a literature search of MEDLINE and ASCO over the last 5 years, the authors present Phase II clinical trial data in the context of EC management. They highlight ongoing clinical trials from the National Cancer Institute website and suggest future directions to address ongoing questions. Expert opinion: A better understanding of EC biology and high-quality preclinical studies will inform the future design of EC Phase II studies. Inclusion of correlative studies and continued longitudinal profiling in future trials is essential to elucidate mechanisms of drug resistance and response. Targeting the phosphoinisotol-3-kinase, angiogenesis, DNA repair and metabolic pathways appear promising strategies for subsets of patients with recurrent or advanced disease. Further, investigation of maintenance strategies and radio-sensitizing agents in the frontline setting should be explored. Given the patient demographic, and frequency of co-morbidities, tolerability and quality of life are key be considerations when designing future studies.
[Show abstract][Hide abstract] ABSTRACT: Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is the most common undifferentiated ovarian malignancy in women under 40 years of age. We sequenced the exomes of six individuals from three families with SCCOHT. After discovering segregating deleterious germline mutations in SMARCA4 in all three families, we tested DNA from a fourth affected family, which also carried a segregating SMARCA4 germline mutation. All the familial tumors sequenced harbored either a somatic mutation or loss of the wild-type allele. Immunohistochemical analysis of these cases and additional familial and non-familial cases showed loss of SMARCA4 (BRG1) protein in 38 of 40 tumors overall. Sequencing of cases with available DNA identified at least one germline or somatic deleterious SMARCA4 mutation in 30 of 32 cases. Additionally, the SCCOHT cell line BIN-67 had biallelic deleterious mutations in SMARCA4. Our findings identify alterations in SMARCA4 as the major cause of SCCOHT, which could lead to improvements in genetic counseling and new treatment approaches.
[Show abstract][Hide abstract] ABSTRACT: In the era of targeted therapies, patients with gynecologic malignancies have not yet been major beneficiaries of this new class of agents. This may reflect the fact that the main tumor types-ovarian, uterine, and cervical-are a highly heterogeneous group of cancers with variable response to standard chemotherapies and the lack of models in which to study the diversity of these cancers. Cancer-derived cell lines fail to adequately recapitulate molecular hallmarks of specific cancer subsets and complex microenvironments, which may be critical for sensitivity to targeted therapies. Patient-derived xenografts (PDX) generated from fresh human tumor without prior in vitro culture, combined with whole genome expression, gene copy number, and sequencing analyses, could dramatically aid the development of novel therapies for gynecologic malignancies. Gynecologic tumors can be engrafted in immunodeficient mice with a high rate of success and within a reasonable time frame. The resulting PDX accurately recapitulates the patient's tumor with respect to histologic, molecular, and in vivo treatment response characteristics. Orthotopic PDX develop complications relevant to the clinic, such as ascites and bowel obstruction, providing opportunities to understand the biology of these clinical problems. Thus, PDX have great promise for improved understanding of gynecologic malignancies, serve as better models for designing novel therapies and clinical trials, and could underpin individualized, directed therapy for patients from whom such models have been established.
[Show abstract][Hide abstract] ABSTRACT: The advances achieved in the surgical management of vulvar squamous cell carcinoma (SCC) have not been mirrored in systemic therapy options. The objective of this paper is to summarize current evidence regarding systemic therapy in vulvar cancer, review the latest research on the biology of this disease, and identify future strategies to improve patient management.
MEDLINE and EMBASE were searched for all relevant English-language articles from inception to December 10, 2012. Existing evidence regarding systemic therapy in vulvar SCC was synthesized descriptively, with an emphasis on prospective studies when available. Single-patient case-reports were excluded.
We identified 12 studies of neoadjuvant chemoradiation, 8 studies of neoadjuvant chemotherapy alone, 18 studies of chemoradiation as primary therapy, 4 studies of chemotherapy in the adjuvant setting, and 8 studies of chemotherapy for recurrent or metastatic disease. Review of the biology of vulvar cancer was performed, and promising targets for the future were identified based on the two biologic pathways of disease development. New therapeutic strategies such as immune-therapy and targeted agents hold promise for the future.
Advances in systemic therapy for vulvar SCC are urgently needed, especially in the setting of recurrent and metastatic disease. A focus on the investigation of new targeted agents is encouraged and consideration of quality of life and sexual health issues is essential. International cooperation and adaptive trial designs are required to improve outcomes for this group of traditionally under-served women.