Premenopausal Cancer Research Articles

High amount of fertility reducing tumors and procedures, but no evidence for premature ovarian failure in female Lynch syndrome patients

Lynch syndrome (LS; HNPCC) patients carry heterozygous pathogenic germline variants in mismatch repair (MMR) genes, which have also been shown to play an important role in meiosis. Therefore, it was hypothesized, that LS might be associated with a higher risk for premature ovarian failure (POF) or earlier menopause. Data on medical gynaecological history, cancer diagnoses and therapy were collected from 167 female LS patients and compared to a population-based control cohort. There was no difference between the age of menopause in patients compared to controls and no evidence for a higher risk of POF in LS patients. However, around one third (35%) of the probands have already had premenopausal cancer and mostly cancer-related treatment affecting fertility before the age of 45 years. Therefore, childbearing time might still be limited in these patients, especially due to the premenopausal cancer risk. LS patients should be informed in time about the elevated premenopausal cancer risks and the possible impact on family planning. This is particularly relevant since the average childbearing age has increased during the last decades.

Hyperglycemia and O-GlcNAc transferase activity drive a cancer stem cell pathway in triple-negative breast cancer

BackgroundEnhanced glucose metabolism is a feature of most tumors, but downstream functional effects of aberrant glucose flux are difficult to mechanistically determine. Metabolic diseases including obesity and diabetes have a hyperglycemia component and are correlated with elevated pre-menopausal cancer risk for triple-negative breast cancer (TNBC). However, determining pathways for hyperglycemic disease-coupled cancer risk remains a major unmet need. One aspect of cellular sugar utilization is the addition of the glucose-derived protein modification O-GlcNAc (O-linked N-acetylglucosamine) via the single human enzyme that catalyzes this process, O-GlcNAc transferase (OGT). The data in this report implicate roles of OGT and O-GlcNAc within a pathway leading to cancer stem-like cell (CSC) expansion. CSCs are the minor fraction of tumor cells recognized as a source of tumors as well as fueling metastatic recurrence. The objective of this study was to identify a novel pathway for glucose-driven expansion of CSC as a potential molecular link between hyperglycemic conditions and CSC tumor risk factors.MethodsWe used chemical biology tools to track how a metabolite of glucose, GlcNAc, became linked to the transcriptional regulatory protein tet-methylcytosine dioxygenase 1 (TET1) as an O-GlcNAc post-translational modification in three TNBC cell lines. Using biochemical approaches, genetic models, diet-induced obese animals, and chemical biology labeling, we evaluated the impact of hyperglycemia on CSC pathways driven by OGT in TNBC model systems.ResultsWe showed that OGT levels were higher in TNBC cell lines compared to non-tumor breast cells, matching patient data. Our data identified that hyperglycemia drove O-GlcNAcylation of the protein TET1 via OGT-catalyzed activity. Suppression of pathway proteins by inhibition, RNA silencing, and overexpression confirmed a mechanism for glucose-driven CSC expansion via TET1-O-GlcNAc. Furthermore, activation of the pathway led to higher levels of OGT production via feed-forward regulation in hyperglycemic conditions. We showed that diet-induced obesity led to elevated tumor OGT expression and O-GlcNAc levels in mice compared to lean littermates, suggesting relevance of this pathway in an animal model of the hyperglycemic TNBC microenvironment.ConclusionsTaken together, our data revealed a mechanism whereby hyperglycemic conditions activated a CSC pathway in TNBC models. This pathway can be potentially targeted to reduce hyperglycemia-driven breast cancer risk, for instance in metabolic diseases. Because pre-menopausal TNBC risk and mortality are correlated with metabolic diseases, our results could lead to new directions including OGT inhibition for mitigating hyperglycemia as a risk factor for TNBC tumorigenesis and progression.

Abstract P2-06-03: Dietary exposure to acrylamide and breast cancer risk: results from the NutriNet-Santé cohort

Abstract Background: Acrylamide is classified as a probable human carcinogen by the IARC but epidemiological evidence on the carcinogenicity of acrylamide from dietary sources is limited. This study aimed to investigate the associations between dietary acrylamide and breast cancer risk in the NutriNet-Santé cohort. Methods: This prospective cohort study included 80,597 French women (mean [SD] age at baseline: 40.8 [14] years) during a mean (SD) follow-up of 8.8 (2.3) years. Acrylamide intake was evaluated using repeated 24h dietary records (n= 5.5 [SD 3.0]), linked to a comprehensive food composition database. Associations between acrylamide intake and breast cancer risk (overall, premenopausal and post-menopausal) were assessed by Cox hazard models adjusted for known risk factors. Results: The mean (SD) dietary acrylamide intake was 30.1 (21.9) µg/d (main contributors: coffee, potato fries and chips, pastries and cakes, and bread). During follow-up, 1016 first incident breast cancer cases were diagnosed (431 premenopausal, 585 postmenopausal). A borderline significant positive association was observed between acrylamide intake and breast cancer risk overall (HRQ4 vs Q1= 1.21 [95% CI: 1.00-1.47]) and a positive association was observed with premenopausal cancer (HRQ4 vs Q1= 1.40 [95% CI: 1.04-1.88]). Restricted cubic spline analyses suggested evidence for non-linearity of these associations, with higher HR for intermediate (Q2) and high (Q4) exposures. Receptor-specific analyses revealed a positive association with estrogen receptor-positive breast cancer, which represented 86% of total cancer cases. Acrylamide intake was not associated with post-menopausal breast cancer. Conclusions: Results from this large prospective cohort study suggest the potential deleterious role of dietary acrylamide in breast cancer etiology, especially in premenopausal women, and provide new insights that should encourage further mitigation strategies to reduce the content of acrylamide in food. Citation Format: Alice Bellicha, Gaëlle Wendeu-Foyet, Xavier Coumoul, Meriem Koual, Fabrice Pierre, Françoise Guéraud, Laurent Zelek, Charlotte Debras, Bernard Srour, Laury Sellem, Emmanuelle Kesse-Guyot, Chantal Julia, Pilar Galan, Serge Hercberg, Mélanie Deschasaux-Tanguy, Mathilde Touvier. Dietary exposure to acrylamide and breast cancer risk: results from the NutriNet-Santé cohort [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-06-03.

Melatonin Mitigates Cisplatin-Induced Ovarian Dysfunction via Altering Steroidogenesis, Inflammation, Apoptosis, Oxidative Stress, and PTEN/PI3K/Akt/mTOR/AMPK Signaling Pathway in Female Rats.

Ovarian damage and fertility impairment are major side effects of chemotherapy in pre-menopausal cancer patients. Cisplatin is a widely used chemotherapeutic drug. The present study was designed to assess the ameliorative effects of melatonin as an adjuvant for fertility preservation. Thirty-two adult female Wistar rats were divided randomly into four equal groups: Control, Melatonin, Cisplatin (CP) treated, and CP + Melatonin treated. The cisplatin-treated group showed decreased body and ovarian weights, decreased serum E2 and AMH, increased serum LH and FSH, reduced ovarian levels of SOD, CAT, GSH, and TAC, and increased ovarian MDA. The histopathological examination of the cisplatin-treated group showed deleterious changes within ovarian tissue in the form of damaged follicles and corpus luteum, hemorrhage, and inflammatory infiltrates with faint PAS reaction in zona pellucida, increased ovarian collagen deposition, and marked expression of caspase-3 immune reaction in granulosa and theca cells, stroma, and oocytes. Alongside, there was a significant downregulation in the mRNA expression of steroidogenic enzymes, IL10, AMPK, PI3K, AKT, mTOR, and PTEN, while TGF-β1, IL1β, IL6, TNF-α, NF-Kβ, P53, p38-MAPK, JNK, and FOXO3 mRNA expressions were upregulated in cisplatin-treated rats' ovarian tissue. Coadministration of cisplatin-treated rats with melatonin reversed these changes significantly. In conclusion, melatonin's antioxidant, anti-inflammatory, and anti-apoptotic activities could modulate ovarian disturbances induced by cisplatin and preserve fertility.

Dietary exposure to acrylamide and breast cancer risk: results from the NutriNet-Santé cohort

Abstract Background Acrylamide is classified as a probable human carcinogen by the IARC but epidemiological evidence on the carcinogenicity of acrylamide from dietary sources is limited. This study aimed to investigate the associations between dietary acrylamide and breast cancer risk in the NutriNet-Santé cohort. Methods This prospective cohort study included 80,597 French women (mean [SD] age at baseline: 40.8 [14] years) during a mean (SD) follow-up of 8.8 (2.3) years. Acrylamide intake was evaluated using repeated 24h dietary records (n = 5.5 [SD 3.0]), linked to a comprehensive food composition database. Associations between acrylamide intake and breast cancer risk (overall, premenopausal and post-menopausal) were assessed by Cox hazard models adjusted for known risk factors. Results The mean (SD) dietary acrylamide intake was 30.1 (21.9) µg/d (main contributors: coffee, potato fries and chips, pastries and cakes, and bread). During follow-up, 1016 first incident breast cancer cases were diagnosed (431 premenopausal, 585 postmenopausal). A borderline significant positive association was observed between acrylamide intake and breast cancer risk overall (HRQ4 vs Q1= 1.21 [95% CI: 1.00-1.47]) and a positive association was observed with premenopausal cancer (HRQ4 vs Q1= 1.40 [95% CI: 1.04-1.88]). Restricted cubic spline analyses suggested evidence for non-linearity of these associations, with higher HR for intermediate (Q2) and high (Q4) exposures. Receptor-specific analyses revealed a positive association with estrogen receptor-positive breast cancer, which represented 86% of total cancer cases. Acrylamide intake was not associated with post-menopausal breast cancer. Conclusions Results from this large prospective cohort study suggest the potential deleterious role of dietary acrylamide in breast cancer etiology, especially in premenopausal women, and provide new insights that should encourage further mitigation strategies to reduce the content of acrylamide in food. Key messages

Dietary exposure to acrylamide and breast cancer risk: results from the NutriNet-Santé cohort

Acrylamide is classified as a probable human carcinogen by the International Agency for Research on Cancer but epidemiologic evidence on the carcinogenicity of acrylamide from dietary sources is limited. This study aimed to investigate the associations between dietary acrylamide and breast cancer risk in the NutriNet-Santé cohort, accounting for menopausal and hormone receptor status. This prospective cohort study included 80,597 French females (mean±SD age at baseline: 40.8±14 y) during a mean±SD follow-up of 8.8±2.3 y. Acrylamide intake was evaluated using repeated 24-h dietary records (n±SD=5.5±3.0), linked to a comprehensive food composition database. Associations between acrylamide intake and breast cancer risk (overall, premenopausal, and postmenopausal) were assessed by Cox hazard models adjusted for known risk factors (sociodemographic, anthropometric, lifestyle, medical history, and nutritional factors). The mean±SD dietary acrylamide intake was 30.1±21.9 µg/d (main contributors: coffee, potato fries and chips, pastries, cakes, bread). During follow-up, 1016 first incident breast cancer cases were diagnosed (431 premenopausal, 585 postmenopausal). A borderline significant positive association was observed between dietary acrylamide exposure and breast cancer risk overall (HR for quartile 4 compared with 1: 1.21; 95% CI: 1.00, 1.47) and a positive association was observed with premenopausal cancer (HRQ4vs.Q1: 1.40; 95% CI: 1.04, 1.88). Restricted cubic spline analyses suggested evidence for nonlinearity of these associations, with higher HRs for intermediate (quartile 2) and high (quartile 4) exposures. Receptor-specific analyses revealed positive associations with estrogen receptor-positive breast cancer (total and premenopausal). Acrylamide intake was not associated with postmenopausal breast cancer. Results from this large prospective cohort study suggest a positive association between dietary acrylamide and breast cancer risk, especially in premenopausal females, and provide new insights that support continued mitigation strategies to reduce the content of acrylamide in food.This trial was registered at clinicaltrials.gov as NCT03335644.

The Clinical and Pathological Profile of BRCA1 Gene Methylated Breast Cancer Women: A Meta-Analysis.

Simple SummaryThe aim of the present meta-analysis was to analyze all available studies reporting clinical characteristics of breast cancer gene 1 (BRCA1) gene hypermethylated breast cancer in women, and to pool the results in order to provide a unique clinical profile of this cancer setting population. Identifying the clinical profile of breast cancer in women harboring BRCA1 gene hypermethylation may help oncologists select a subgroup of patients who may be candidates for BRCA1 methylation assessment, thus, possibly enlarging the cancer population who may benefit from new target-therapy agents. Results showed that BRCA1 gene hypermethylation should be suspected in all breast cancer patients with advanced disease stages, positive lymph nodes, and premenopausal age at diagnosis. Multidisciplinary groups treating women with breast cancer should take into account the possibility of addressing patients with these characteristics with a BRCA1 gene methylation status analysis.Background: DNA aberrant hypermethylation is the major cause of transcriptional silencing of the breast cancer gene 1 (BRCA1) gene in sporadic breast cancer patients. The aim of the present meta-analysis was to analyze all available studies reporting clinical characteristics of BRCA1 gene hypermethylated breast cancer in women, and to pool the results to provide a unique clinical profile of this cancer population. Methods: On September 2020, a systematic literature search was performed. Data were retrieved from PubMed, MEDLINE, and Scopus by searching the terms: “BRCA*” AND “methyl*” AND “breast”. All studies evaluating the association between BRCA1 methylation status and breast cancer patients’ clinicopathological features were considered for inclusion. Results: 465 studies were retrieved. Thirty (6.4%) studies including 3985 patients met all selection criteria. The pooled analysis data revealed a significant correlation between BRCA1 gene hypermethylation and advanced breast cancer disease stage (OR = 0.75: 95% CI: 0.58–0.97; p = 0.03, fixed effects model), lymph nodes involvement (OR = 1.22: 95% CI: 1.01–1.48; p = 0.04, fixed effects model), and pre-menopausal status (OR = 1.34: 95% CI: 1.08–1.66; p = 0.008, fixed effects model). No association could be found between BRCA1 hypermethylation and tumor histology (OR = 0.78: 95% CI: 0.59–1.03; p = 0.08, fixed effects model), tumor grading (OR = 0.78: 95% CI :0.46–1.32; p = 0.36, fixed effects model), and breast cancer molecular classification (OR = 1.59: 95% CI: 0.68–3.72; p = 0.29, random effects model). Conclusions: hypermethylation of the BRCA1 gene significantly correlates with advanced breast cancer disease, lymph nodes involvement, and pre-menopausal cancer onset.

Clinicopathological characteristics and prognosis analysis of ovarian metastases in colorectal cancer: a single-center experience.

This study aimed to improve the management of ovarian metastases (OM) in colorectal cancer (CRC) by evaluating the clinicopathological characteristics, therapeutic strategies, and prognostic factors associated with OM originating from CRC. Medical records of patients who were histopathologically diagnosed with OM of CRC origin were reviewed from January 2011 to December 2018 in our medical center. Data related to clinicopathological characteristics, therapeutic strategies, and survival time were recorded and analyzed. Survival and prognosis analyses were carried out to identify variables significantly associated with the outcomes. Forty-six patients were included in the study with a median follow-up of 14months. Premenopausal (< 50years) and colon cancer patients were more likely to develop OM. Synchronous OM was found in 34 patients and elevated carbohydrate antigen 125 value could be seen in 67.4% of patients. Bilateral ovarian involvement (27/46, 58.8%) and combined extra-ovarian metastases (32/46, 69.6%) were common in included patients. Complete cytoreduction surgery (R0 resection) was finally achieved in 19 of included patients and 41 patients received postoperative chemotherapy. However, the overall prognosis remains poor, with a median survival time of only 12months. In univariate analysis, histological types (P = 0.002), peritoneal metastasis (P < 0.0001), the extent of metastatic lesions (P = 0.0001), and completeness of cytoreduction surgery (P < 0.0001) were found to be closely related to prognosis. Finally, completeness of cytoreduction surgery was considered to be the independent determinant of patients' outcome (HR 0.186, 95% CI 0.047-0.727, P = 0.016) by multivariate analysis. In multitudinous factors, complete cytoreduction surgery (R0 resection) may provide survival benefits in patients with OM of CRC origin. Thus, it is reasonable to recommend aggressive surgery with curative intent even if extra-ovarian metastases are present. Furthermore, postoperative chemotherapy may exert a positive effect on the treatment, but needs to be confirmed by large-scale trials with more participants in the future.

Potential Mechanisms of Ovarian Protection with Gonadotropin-Releasing Hormone Agonist in Breast Cancer Patients: A Review.

The use of chemotherapy in premenopausal cancer patients may lead to chemotherapy-induced premature ovarian failure. Pharmacological temporary ovarian suppression obtained with the gonadotropin-releasing hormone agonist (GnRHa) administered concomitantly with chemotherapy has been investigated as a technique capable to reduce the gonadotoxicity, reducing the risk of developing premature menopause. In recent years, important evidence has become available on the efficacy and safety of this strategy that should now be considered a standard option for ovarian function preservation in premenopausal breast cancer patients. However, in women interested in fertility preservation, this is not an alternative to cryopreservation strategies, which remains the first option to be proposed. The purpose of this review is to summarize the mechanisms of GnRHa in the preservation of fertility in premenopausal cancer patient candidates to receive chemotherapy, highlighting the areas of doubt that require further investigation.

About time: how time influences and facilitates patient autonomy in the clinical encounter

In this article I discuss the little examined relationship between time and patient autonomy. Using the findings from a study on the experience of premenopausal cancer patients making fertility preservation decisions during their treatment, I focus on how the patients in the study understood time, and how this understanding interacted with and influenced their decision-making. I then analyse in more depth the importance of time in patient decision-making, and the relationship of time to concepts of patient autonomy and decision-making in the field of bioethics more generally. Focusing on the relational conception of autonomy, I conclude that time is an integral part of patient autonomy which warrants further research, such that it can be better integrated into concepts of patient autonomy, and the policy and guidelines that they inform and influence.

Diagnostic value of serum human epididymis protein 4 and carbohydrate antigen 125 combined with risk of ovarian malignancy algorithm index for ovarian cancer

Objective To investigate the clinical value of serum human epididymis protein 4 (HE4), carbohydrate antigen 125 (CA125) combined with risk of ovarian malignancy algorithm (ROMA) index in the diagnosis of ovarian cancer. Methods A total of 541 patients in the Department of Gynaecology in Baoji Central Hospital from August 2016 to February 2018 were collected. The serum HE4 and CA125 levels were measured by using electrochemiluminescence immunoassay in 226 cases of ovarian cancer (ovarian cancer group), 315 cases of ovarian benign disease (ovarian benign disease group) and 100 female healthy people (the control group). ROMA index was calculated according to ROMA model and the results were analyzed statistically. Results The levels of serum HE4, CA125 and ROMA index were significantly different in premenopausal and postmenopausal ovarian cancer group, ovarian benign disease group and the control group (all P < 0.05). The sensitivity and Yonden's index of the three combined diagnosis of serum HE4, CA125 and ROMA for premenopausal ovarian cancer were 97.01% and 77.01% respectively, which were higher than those of a single detection (HE4: 79.37%, 69.11%; CA125: 76.06%, 66.38%; ROMA index: 89.55%, 72.41%; χ2sensitivity=12.35, P=0.000; χ2Yonden's index=6.460, P=0.013. The sensitivity and Yonden's index of the three combined diagnosis of serum HE4, CA125 and ROMA for postmenopausal ovarian cancer were 98.99% and 82.99% respectively, which were higher than those of a single detection (HE4: 86.90%, 79.40%; CA125: 82.98%, 76.31%; ROMA index: 93.54%, 80.64%; χ2sensitivity=14.25, P=0.000; χ2Yonden's index=4.822, P=0.031). The area under the curve of the combined detection of three indicators was higher than that of a single detection (premenopausal group: 0.871 vs. 0.682, 0.626, 0.708; postmenopausal group: 0.981 vs. 0.724, 0.705, 0.833), and there were significant differences (premenopausal group: χ2= 11.24, P= 0.000; postmenopausal group: χ2= 16.38, P= 0.000). Conclusion The combined detection of serum HE4, CA125 and ROMA index can increase the sensitivity and accuracy for diagnosing ovarian cancer, which can provide a more reliable basis for diagnosis and screening of ovarian cancer. Key words: Ovarian neoplasms; Human epididymis protein 4; Carbohydrate antigen 125; Risk of ovarian malignancy algorithm; Diagnosis

Abstract IA20: A coding region variant in the TP53 tumor-suppressor gene may underlie cancer disparities in African Americans

Abstract In addition to being frequently mutated in sporadic cancer, the p53 tumor suppressor also contains several coding region variants that alter function and can contribute to increased cancer risk. We previously published that the Pro47Ser variant of p53 exists in approximately 1-2% of individuals of African descent, and that this variation prevents a key phosphorylation event on p53, and reduces the ability of this protein to induce cell death (1). We recently published a mouse model for this variant, and show that this mouse develops a striking incidence of sporadic cancer, predominantly hepatocellular cancer but also including cancers of the pancreas, stomach, and intestine. In a cohort of African American women with breast cancer, we found evidence for an association of Pro47Ser with pre-menopausal cancer incidence (HR 1.7, p&amp;lt;0.025) (2). Mechanistically, we find that the Pro47Ser variant displays a very selective transcriptional defect compared to wild-type p53, for a subset of target genes involved in ferroptosis and metabolism (3). Metabolic studies on mouse and human cells, as well as our Pro47Ser mouse, indicate that there is a profound difference in metabolism, with cells and mice containing Pro47Ser showing a significant predilection for aerobic glycolysis instead of oxidative phosphorylation. Interestingly, this defect actually leads to an apparent increase in fitness in these mice. We recently conducted a drug screen to search for compounds that may be selectively efficacious in tumors containing the Pro47Ser variant; this analysis revealed several compounds with increased efficacy against Pro47Ser tumors, compared to identical tumors with wild-type p53 (4). Our combined data suggest that the Pro47Ser variant may underlie increased cancer risk in African Americans, and that we may be able to personalize therapy for individuals containing this variant. 1. Li X, Dumont P, Della Pietra A, Shetler C, Murphy ME. The codon 47 polymorphism in p53 is functionally significant. J Biol Chem 2005;280(25):24245-51. PubMed PMID: 15851479. 2. Murphy ME, Liu S, Yao S, et al. A functionally significant SNP in TP53 and breast cancer risk in African-American women. NPJ Breast Cancer 2017;3:5. PubMed Central PMCID: PMC5445618. 3. Jennis M, Kung CP, Basu S, et al. An African-specific polymorphism in the TP53 gene impairs p53 tumor suppressor function in a mouse model. Genes Dev 2016;30(8):918-30. PubMed Central PMCID: PMC4840298. 4. Basu S, Barnoud T, Kung CP, Reiss M, Murphy ME. The African-specific S47 polymorphism of p53 alters chemosensitivity. Cell Cycle 2016;15(19):2557-60. PubMed Central PMCID: PMC5053554. Citation Format: Maureen E. Murphy. A coding region variant in the TP53 tumor-suppressor gene may underlie cancer disparities in African Americans [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr IA20.

Ovulation Induction for Infertility the Risk of Breast Cancer: A Population-Based Case-Control Study [11B

INTRODUCTION: There is a well-established interplay between reproductive hormone levels and breast cancer. Questions remain in regards to the potential ovulation-inducing fertility treatments, which elevate serum estrogen and progesterone to supraphysiologic levels the treatment period, to affect breast tumorigenesis. METHODS: A population-based case-control study using the Clinical Practice Research Datalink (CPRD) was performed. All cases of breast cancer occurring between 1995-2013 were matched with 10 age-matched controls. Cases and controls were assessed for exposure to clomiphene or in-vitro fertilization (IVF) via their clinical records. Odds ratios and 95% confidence intervals for each exposure were computed using multivariate logistic regression, adjusted for smoking, alcohol use, BMI, oral contraceptive use, hormone replacement therapy and oophorectomy. RESULTS: The study population consisted of 27,026 cases of breast cancer and their matched controls, with 1,717 subjects having a history of clomiphene exposure and 1,137 subjects having a history of IVF. Ever-exposure to clomiphene was significantly associated with breast cancer, OR 1.34 95% CI [1.26-1.44]. IVF-exposure was similarly associated with breast cancer, OR 1.52 95% CI [1.40-1.65]. The stratified analysis indicated clomiphene was associated with pre-menopausal cancers (OR 1.59 95% CI [1.47-1.73]) but not post-menopausal malignancies (OR 0.94 95% CI [0.83-1.06]). IVF was associated with both pre- and post-menopausal cancers. CONCLUSION: Ovulation induction with clomiphene citrate and gonadotropins increases the risk of breast cancer. Women should be advised of this elevated risk understanding the associated implications.

Melatonin and Fertoprotective Adjuvants: Prevention against Premature Ovarian Failure during Chemotherapy.

Premature ovarian failure is one of the side effects of chemotherapy in pre-menopausal cancer patients. Preservation of fertility has become increasingly important in improving the quality of life of completely recovered cancer patients. Among the possible strategies for preserving fertility such as ovarian tissue cryopreservation, co-treatment with a pharmacological adjuvant is highly effective and poses less of a burden on the human body. Melatonin is generally produced in various tissues and acts as a universally acting antioxidant in cells. Melatonin is now more widely used in various biological processes including treating insomnia and an adjuvant during chemotherapy. In this review, we summarize the information indicating that melatonin may be useful for reducing and preventing premature ovarian failure in chemotherapy-treated female patients. We also mention that many adjuvants other than melatonin are developed and used to inhibit chemotherapy-induced infertility. This information will give us novel insights on the clinical use of melatonin and other agents as fertoprotective adjuvants for female cancer patients.

Prevalence of germline TP53 p.R337H mutation in Brazilian young breast cancer patients.

e13101 Background: Germline TP53 mutations are associated with Li-Fraumeni syndrome (LFS), a disease that predisposes carriers to a wide variety of early onset tumors. Pre-menopausal breast cancer is the most frequent tumor found in carriers. In Southern and Southeastern Brazil, a germline TP53 mutation in exon 10, p.R337H, was diagnosed in 0,3% of the population due to a founder effect, a prevalence that is substantially higher than other LFS mutations. Methods: In this study we investigated the prevalence of the p.R337H TP53 germline mutation in 287 young female breast cancer patients (diagnosed before the age of 40) at A. C. Camargo Cancer Center, Sao Paulo, Brazil. DNA was extracted from saliva and Sanger sequencing of exon 10 was performed. All patients were consented. Results: The p.R337H TP53 mutation was present in 1.74% (5/287). Family history of cancer was present in three cases although it did not fulfill LFS clinical criteria. Conclusions: The identification of germline p.R337H mutation in this cohort strengthen the role of TP53 mutations in the early onset of breast cancer in pre-menopausal cancer in Brazil.

Assessment of TP53 Polymorphisms and MDM2 SNP309 in Premenopausal Breast Cancer Risk.

Germline polymorphic variants in cancer predisposition genes such as TP53 have been shown to impact the risk of premenopausal cancer. Accordingly, the aim of this study was to assess the spectrum of polymorphisms in TP53 and its negative regulatory gene, MDM2 (SNP309:T>G) in patients with premenopausal breast cancer. Our findings in a cohort of 40 female patients demonstrate no significant correlation between the studied polymorphisms and risk of premenopausal breast cancer. Although one polymorphism is found in high frequency in this cohort (rs1800372:A>G, 9.0%), it was not associated with the risk of developing cancer before the age of 35 years in an extended cohort of 1,420 breast cancer cases. Functional studies of the rs1800372:A>G polymorphic allele reveal that it does not affect p53 transactivation function. Further study of variants or mutations in other cancer susceptibility genes is warranted to refine our understanding of the germline contribution to premenopausal breast cancer susceptibility.

Chemotherapy Use Is a Significant Predictor for Sexual Dysfunction in Women with Gynecologic Cancer

Objectives: Sexual dysfunction is a significant survivorship issue in women with gynecologic cancer. We examined the association between chemotherapy and impaired sexual functioning. Methods: A cross sectional study of women with gynecologic cancer was conducted with a 181-item survey of validated instruments. A sub-analysis of women with chemotherapy treatment was performed to examine factors associated with sexual function including age, menopause status, BMI, diagnosis, stage, surgery/radiation use, active disease status, number of regimens, and number of cycles. Sexual dysfunction was measured by change in the Female Sexual Function Index (FSFI) score from pre-treatment with a significant decline in sexual function determined to be a 5.6 point decrease using a Reliable Change Index Statistic (RCIS). Standard statistical tools were employed. Results: A total of 107 (63%) of the women in the larger study had received chemotherapy as part of their treatment and were included in the sub-study. Women undergoing chemotherapy were more likely to experience sexual dysfunction post-treatment (51% vs. 26%; OR 2.9, 95% CI 1.5 - 5.7). In bivariate analyses, sexual dysfunction following chemotherapy was associated with age < 50 (80% vs. 42%; OR 5.6, 95% CI 1.9 - 16.6), premenopausal (30.8% vs. 12.7%, OR 3.1, 95% CI 1.1 - 8.2) cervical cancer (25.5% vs. 10.0%, OR 3.1, 95% CI 1.0 - 9.4), and low (I/II) stage (51.1% vs. 24.5%; OR 3.2, 95% CI 1.4 - 7.7). Conclusions: Women treated with chemotherapy for gynecologic cancer are at a significant risk of impaired sexual function. Women with cervical cancer, early stage disease, those who are premenopausal, and those younger than age 50 are at the highest risk.

Prevalence of Triple-Negative Breast Cancer in India: Systematic Review and Meta-Analysis.

PurposeThere is considerable variation in prevalence rates of triple-negative breast cancer (TNBC) reported by various studies from India. We performed a systematic review and literature-based meta-analysis of these studies.MethodsWe searched databases of Medline, Scopus, EMBASE, and Web of Science for studies that reported on the prevalence of TNBC in India that were published between January 1, 1999, and December 31, 2015. We extracted relevant information from each study by using a standardized form. We pooled study-specific estimates by using random-effects meta-analysis to provide summary estimates. We explored sources of heterogeneity by using subgroup analyses and metaregression.ResultsData were obtained from 17 studies that involved 7,237 patients with breast cancer. Overall combined prevalence of TNBC was 31% (95% CI, 27% to 35%). There was substantial heterogeneity across the studies (I2 of 91% [95% CI, 88% to 94%]; P < .001) that was not explained by available study level characteristics, including study location, definition of human epidermal growth factor receptor 2 or estrogen receptor, mean age of participants, proportion of patients with premenopausal cancer, grade 3 disease, or tumor size > 5 cm. Overall combined prevalence of hormone receptor–positive and human epidermal growth factor receptor 2–positive breast cancer was 48% (95% CI, 42% to 54%) and 27% (95% CI, 24% to 31%), respectively. There was no evidence of publication bias.ConclusionPrevalence of TNBC in India is considerably higher compared with that seen in Western populations. As many as as one in three women with breast cancer could have triple-negative disease. This finding has significant clinical relevance as it may contribute to poor outcomes in patients with breast cancer in India. Additional research is needed to understand the determinants of TNBC in India.

Do obesity and age effect the clinicopathological features and survival outcomes in premenopausal women with endometrial cancer?

The purpose of this study was to review the effect of age and body mass index (BMI) on the prognosis, demographic characteristics, and pathological features of patients diagnosed with endometrial cancer, specifically before menopause. Patients that were diagnosed with endometrial cancer before menopause, were screened retrospectively. Between 1999 and 2011, 163 patients were identified while 40 were excluded. Patients were classified into three groups according to age (under 40 years, between 40-45 years, more than 45 years) and BMI (normal weight group, overweight group, and obese weight group). Demographical characteristics, histopathological features (Stage, grade and histology of the tumor, the presence of myometrial and/or lymphovascular invasion, history of diabetes mellitus, history of hypertension, hormonal contraception method, smoking, parity, infertility, family history, and recurrences) and survival rates were compared among the groups. In total, 123 patients with a mean of 65.0 months follow up were enrolled into the study. The majority of the patients had endometrioid type in all age-related subgroups. Advanced stage endometrium cancer (Stage 2 and greater) was seen more commonly in the group of patient over 45 years of age against the other age-related subgroups (27.9% vs. 8% vs. 3.3%). Ratio of myometrial invasion more than 50% and occurrence of well-differentiated tumor were seen with a similar ratio among the age-related subgroups. Ratio of nulliparity and infertility were found statistically significant in the group of patients under 45 years of age against the group of patients over 45 years of age (p = 0.001, p = 0.03). The five-year estimated disease-free survival rates of women under 40 years of, women with an age between 40-45 years, and women over the age of 45 years were calculated as 73%, 95%, and 87%, respectively (p = 0.152). Concerning the histopathological features, there were no statistical differences between weight related subgroups. Comorbid conditions (hypertension and diabetes mellitus) were found as statistically high in the obese patients' group (43.5%-25.8%). In contrast to comorbid conditions, nulliparity and infertility histories were observed more often within the normal weight group (55.6%-38.5%). Mean disease-free survival time was calculated as 155.81 months in the normal weight group; 114.691 months in the overweight group, and 144.677 months in the obese group. Five-year disease-free survival rate was calculated as 91%, 81%, and 87%, respectively (p = 0.452). Women with premenopausal cancers generally exhibit early and favorable histopathological symptoms. Although advanced stage endometrium cancer incidence was detected to be higher in the premenopausal endometrium cancer patients aged above 45 years compared to other age subgroups. A significant difference in terms of survival rates between these groups was not reached. In the same manner, the authors did not find a significant difference in survival rates among different weight subgroups of premenopausal endometrium cancer patients. As a secondary result, the authors discovered that diabetes mellitus and hypertension play a key role in patients with a BMI above 30 kg/m2 and nulliparity and infertility play a key role in patients with a BMI below 25 kg/m2 in the development of premenopausal endometrial cancer.

Occurrence and recall rates of fertility discussions with young breast cancer patients.

Fertility preservation is an important issue for premenopausal cancer patients; however, not all patients receive counseling about chemotherapy-induced infertility and potential mitigation strategies. We aimed to identify characteristics of premenopausal breast cancer patients less likely to receive fertility counseling. We also investigated patient recall of chart-documented fertility discussions and patient attitudes toward fertility preservation. The study was approved by our institution's Institutional Review Board. All female patients with invasive primary breast cancer of any type, aged 40 or younger at the time of diagnosis, who were diagnosed during or up to 5 years prior to the study period were eligible. The study was conducted between February 2012 and October 2013. Enrolled patients completed an anonymous survey, and their medical charts were subsequently reviewed to identify provider documentation of fertility discussions, referral to fertility specialists, or implementation of fertility preservation. Patient comments regarding their fertility were solicited and examined thematically. Forty-nine patients consented to participate. Fertility discussions were documented by providers in 55% of patients. Patients aged over 35 and multiparous patients were significantly less likely than their counterparts (p < 0.01 in both cases) to have had chart-documented fertility discussions. Only 52% of patients with chart-documented discussions recalled having had such a conversation. Patient comments highlighted the difficulty of considering fertility at the time of diagnosis and also the risks and obstacles facing fertility preservation. Despite increasing awareness, fertility is not universally discussed with premenopausal breast cancer patients at the time of diagnosis; older and multiparous patients are at particular risk of not receiving fertility counseling. Even when such discussions are documented, only about half of patients recall the conversation. Patient-reported barriers to fertility preservation include lack of education combined with the stress of diagnosis, financial costs, and perceived treatment toxicities.