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Cancers
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Sex Differences in Cancer
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Sex Differences in Cancer

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: 15 October 2024 | Viewed by 6376

Special Issue Editors

Dr. Jill S. Barnholtz-Sloan

grade E-Mail Website1 Website2
Guest Editor
1. Informatics and Data Science (IDS) Program, Center for Biomedical Informatics and Information Technology (CBIIT), National Cancer Institute (NCI), Bethesda, MD, USA
2. Trans-Divisional Research Program (TDRP), Division of Cancer Epidemiology and Genetics (DCEG), National Cancer Institute (NCI), Bethesda, MD, USA
Interests: cancer; epidemiology; biostatistics; informatics; bioinformatics; sex differences
Dr. Sarah S. Jackson

E-Mail Website
Guest Editor
Infections and Immunoepidemiology Branch (IIB), Division of Cancer Epidmiology and Genetics (DCEG), National Cancer Institute (NCI), Bethesda, MD, USA
Interests: epidemiology; sex differences; transgender and gender-diverse
Dr. Kristin A. Waite

E-Mail Website
Guest Editor
Trans-Divisional Research Program (TDRP), Division of Cancer Epidmiology and Genetics (DCEG), National Cancer Institute (NCI), Bethesda, MD, USA
Interests: brain tumors; sex differences; cancer genetics; signal transduction

Special Issue Information

Dear Colleagues,

The genetic, epigenetic, and hormone actions of sexual differentiation interact with a multitude of mechanisms, resulting in sex differences that can be observed in disease. In cancer, sexual differentiation interacts with both cancer protection and oncogenic mechanisms. Most non-reproductive cancers exhibit sex differences in incidence and clinical outcomes, with males being more prone to develop and die from cancer compared to females. Recent studies have demonstrated that these differences are not solely attributed to underlying risk behaviors in males, but instead due to underlying biological sex differences. Despite the well-known differences between males and females, most cancer patients still receive the same treatment. Historically, sex differences are often overlooked at all levels of research (design, analysis, and reporting); e.g., preclinical treatment studies performed exclusively in male animals and clinical trials enrolling more males than females. As we are now beginning to fully realize the impact of this bias, efforts by the National Institute of Health to increase consideration of sex differences have been implemented. Studies focused on sex differences in cancer will add to our body of knowledge, generate additional potential material for research investigations, drive hypotheses, and aid in the generation of personalized, sex-based medicine tailored to the unique vulnerabilities of male and female cancer patients.

Dr. Jill S. Barnholtz-Sloan
Dr. Sarah S. Jackson
Dr. Kristin A. Waite
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • cancer
  • sex differences
  • cancer biology
  • cancer epidemiology
  • sex-based medicine

Published Papers (6 papers)

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Research

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24 pages, 22183 KiB  
Article
Sex Matters–Insights from Testing Drug Efficacy in an Animal Model of Pancreatic Cancer
by Benjamin Schulz, Emily Leitner, Tim Schreiber, Tobias Lindner, Rico Schwarz, Nadine Aboutara, Yixuan Ma, Hugo Murua Escobar, Rupert Palme, Burkhard Hinz, Brigitte Vollmar and Dietmar Zechner
Cancers 2024, 16(10), 1901; https://doi.org/10.3390/cancers16101901 - 16 May 2024
Viewed by 490
Abstract
Preclinical studies rarely test the efficacy of therapies in both sexes. The field of oncology is no exception in this regard. In a model of syngeneic, orthotopic, metastasized pancreatic ductal adenocarcinoma we evaluated the impact of sex on pathological features of this disease [...] Read more.
Preclinical studies rarely test the efficacy of therapies in both sexes. The field of oncology is no exception in this regard. In a model of syngeneic, orthotopic, metastasized pancreatic ductal adenocarcinoma we evaluated the impact of sex on pathological features of this disease as well as on the efficacy and possible adverse side effects of a novel, small molecule-based therapy inhibiting KRAS:SOS1, MEK1/2 and PI3K signaling in male and female C57BL/6J mice. Male mice had less tumor infiltration of CD8-positive cells, developed bigger tumors, had more lung metastasis and a lower probability of survival compared to female mice. These more severe pathological features in male animals were accompanied by higher distress at the end of the experiment. The evaluated inhibitors BI-3406, trametinib and BKM120 showed synergistic effects in vitro. This combinatorial therapy reduced tumor weight more efficiently in male animals, although the drug concentrations were similar in the tumors of both sexes. These results underline the importance of sex-specific preclinical research and at the same time provide a solid basis for future studies with the tested compounds. Full article
(This article belongs to the Special Issue Sex Differences in Cancer)
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13 pages, 2644 KiB  
Article
MGMT Methylation and Differential Survival Impact by Sex in Glioblastoma
by Addison E. Barnett, Ahmad Ozair, Anas S. Bamashmos, Hong Li, David S. Bosler, Gabrielle Yeaney, Assad Ali, David M. Peereboom, Justin D. Lathia and Manmeet S. Ahluwalia
Cancers 2024, 16(7), 1374; https://doi.org/10.3390/cancers16071374 - 31 Mar 2024
Viewed by 982
Abstract
Introduction: Sex differences in glioblastoma (GBM) have been observed in incidence, genetic and epigenetic alterations, and immune response. These differences have extended to the methylation of the MGMT promoter, which critically impacts temozolomide resistance. However, the association between sex, MGMT methylation, and [...] Read more.
Introduction: Sex differences in glioblastoma (GBM) have been observed in incidence, genetic and epigenetic alterations, and immune response. These differences have extended to the methylation of the MGMT promoter, which critically impacts temozolomide resistance. However, the association between sex, MGMT methylation, and survival is poorly understood, which this study sought to evaluate. Methods: A retrospective cohort study was conducted and reported following STROBE guidelines, based on adults with newly diagnosed GBM who received their first surgical intervention at Cleveland Clinic (Ohio, USA) between 2012 and 2018. Kaplan–Meier and multivariable Cox proportional hazards models were used to analyze the association between sex and MGMT promoter methylation status on overall survival (OS). MGMT was defined as methylated if the mean of CpG 1-5 ≥ 12. Propensity score matching was performed on a subset of patients to evaluate the effect of individual CpG site methylation. Results: A total of 464 patients had documented MGMT methylation status with a mean age of 63.4 (range 19–93) years. A total of 170 (36.6%) were female, and 133 (28.7%) received gross total resection as a first intervention. A total of 42.5% were MGMT methylated, with females more often having MGMT methylation than males (52.1% vs. 37.4%, p = 0.004). In univariable analysis, OS was significantly longer for MGMT promoter methylated than un-methylated groups for females (2 yr: 36.8% vs. 11.1%; median: 18.7 vs. 9.5 months; p = 0.001) but not for males (2 yr: 24.3% vs. 12.2%; median: 12.4 vs. 11.3 months; p = 0.22, p for MGMT–sex interaction = 0.02). In multivariable analysis, MGMT un-methylated versus methylated promoter females (2.07; 95% CI, 1.45–2.95; p < 0.0001) and males (1.51; 95% CI, 1.14–2.00; p = 0.004) had worse OS. Within the MGMT promoter methylated group, males had significantly worse OS than females (1.42; 95% CI: 1.01–1.99; p = 0.04). Amongst patients with data on MGMT CpG promoter site methylation values (n = 304), the median (IQR) of CpG mean methylation was 3.0% (2.0, 30.5). Females had greater mean CpG methylation than males (11.0 vs. 3.0, p < 0.002) and higher per-site CpG methylation with a significant difference at CPG 1, 2, and 4 (p < 0.008). After propensity score matching, females maintained a significant survival benefit (18.7 vs. 10.0 months, p = 0.004) compared to males (13.0 vs. 13.6 months, p = 0.76), and the pattern of difference was significant (P for CpG–sex interaction = 0.03). Conclusions: In this study, females had higher mean and individual CpG site methylation and received a greater PFS and OS benefit by MGMT methylation that was not seen in males despite equal degrees of CpG methylation. Full article
(This article belongs to the Special Issue Sex Differences in Cancer)
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10 pages, 425 KiB  
Article
Sex Differences in Cancer Incidence Rates by Race and Ethnicity: Results from the Surveillance, Epidemiology, and End Results (SEER) Registry (2000–2019)
by Sararat Tosakoon, Wayne R. Lawrence, Meredith S. Shiels and Sarah S. Jackson
Cancers 2024, 16(5), 989; https://doi.org/10.3390/cancers16050989 - 29 Feb 2024
Cited by 1 | Viewed by 790
Abstract
Men have 2–3 times the rate of most non-sex-specific cancers compared to women, but whether this is due to differences in biological or environmental factors remains poorly understood. This study investigated sex differences in cancer incidence by race and ethnicity. Cancer incidence data [...] Read more.
Men have 2–3 times the rate of most non-sex-specific cancers compared to women, but whether this is due to differences in biological or environmental factors remains poorly understood. This study investigated sex differences in cancer incidence by race and ethnicity. Cancer incidence data from the Surveillance, Epidemiology, and End Result (SEER) program (2000–2019) were used to calculate male-to-female incidence rate ratios (MF IRRs) for each cancer site, stratified by race and ethnicity, and age-standardized to the 2000 U.S. population for individuals ages ≥ 20 years. Among 49 cancer sites, 44 showed male predominance (MF IRR > 1), with seven inconsistencies across race and ethnicity, including cancers of the lip, tongue, hypopharynx, retroperitoneum, larynx, pleura cancers, and Kaposi sarcoma. Four cancers exhibited a female predominance (MF IRR < 1), with only gallbladder and anus cancers varying by race and ethnicity. The MF IRRs for cancer of the cranial nerves and other nervous system malignancies showed no sex differences and were consistent (MF IRR = 1) across race and ethnicity. The MF IRRs for most cancers were consistent across race and ethnicity, implying that biological etiologies are driving the observed sex difference. The lack of MF IRR variability by race and ethnicity suggests a minimal impact of environmental exposure on sex differences in cancer incidence. Further research is needed to identify biological drivers of sex differences in cancer etiology. Full article
(This article belongs to the Special Issue Sex Differences in Cancer)
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13 pages, 1413 KiB  
Communication
The Disproportionate Rise in Pancreatic Cancer in Younger Women Is Due to a Rise in Adenocarcinoma and Not Neuroendocrine Tumors: A Nationwide Time-Trend Analysis Using 2001–2018 United States Cancer Statistics Databases
by Yi Jiang, Yazan Abboud, Jeff Liang, Brent Larson, Arsen Osipov, Jun Gong, Andrew E. Hendifar, Katelyn Atkins, Quin Liu, Nicholas N. Nissen, Debiao Li, Stephen J. Pandol, Simon K. Lo and Srinivas Gaddam
Cancers 2024, 16(5), 971; https://doi.org/10.3390/cancers16050971 - 28 Feb 2024
Viewed by 915
Abstract
In previous studies, a significant increase in the incidence of pancreatic cancer among younger women compared to men in the United States was noted. However, the specific histopathologic characteristics were not delineated. This population-based study aimed to assess whether this disproportionate rise in [...] Read more.
In previous studies, a significant increase in the incidence of pancreatic cancer among younger women compared to men in the United States was noted. However, the specific histopathologic characteristics were not delineated. This population-based study aimed to assess whether this disproportionate rise in pancreatic cancer in younger women was contributed by pancreatic ductal adenocarcinoma (PDAC) or pancreatic neuroendocrine tumors (PanNET). The United States Cancer Statistics (USCS) database was used to identify patients with pancreatic cancer between 2001 and 2018. The results showed that, in younger adults, the incidence of PDAC has increased in women [average annual percentage change (AAPC) = 0.62%], while it has remained stable in men (AAPC = −0.09%). The PDAC incidence rate among women increased at a greater rate compared to men with a statistically significant difference in AAPC (p < 0.001), with neither identical nor parallel trends. In contrast, cases of PanNET did not demonstrate a statistically significant sex-specific AAPC difference. In conclusion, this study demonstrated that the dramatic increase in the incidence rate of PDAC explains the disproportionate rise in pancreatic cancer incidence in younger women. This prompts further prospective studies to investigate the underlying reasons for these sex-specific disparities in PDAC. Full article
(This article belongs to the Special Issue Sex Differences in Cancer)
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Review

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19 pages, 2740 KiB  
Review
Studies in Cancer Epigenetics through a Sex and Gendered Lens: A Comprehensive Scoping Review
by Katherine Huerne, Sarah S. Jackson, Rina Lall, Nicole Palmour, Alison May Berner, Charles Dupras and Yann Joly
Cancers 2023, 15(17), 4207; https://doi.org/10.3390/cancers15174207 - 22 Aug 2023
Viewed by 1163
Abstract
Background: Sex and gender are vitally important in the study of epigenetic mechanisms for various types of cancer. However, little has been done to assess the state of sex and gender-based analyses (SGBA) in this field. The aim was to undertake a [...] Read more.
Background: Sex and gender are vitally important in the study of epigenetic mechanisms for various types of cancer. However, little has been done to assess the state of sex and gender-based analyses (SGBA) in this field. The aim was to undertake a critical evaluation of sex and gender representation, discussion, and data analysis within the cancer epigenetics field since 2010. Methods: A PRISMA-ScR scoping review was conducted with 111 peer-reviewed studies comprising of colorectal, gastric, head and neck, hepatocellular carcinoma, and lung cancers. Data extraction and a quality appraisal were performed by a team of epidemiologists and bioethicists. Results: Of the 111 included studies, only 17 studies (15.3%) explicitly stated sex and gender analysis to be their primary aim. A total of 103 studies (92.8%) provided a detailed analysis of sex/gender as a biological or social variable, while the remaining 8 studies (7.2%) only stratified results by sex/gender. Although sex and gender were a key facet in all the eligible studies, only 7 studies (6.3%) provided an explicit definition of the terms “sex” or “gender”, while the remaining 104 studies (93.7%) used the words “sex” or “gender” without providing a definition. A total of 84 studies (75.7%) conflated the concepts of “sex” and “gender”, while 44 studies (39.6%) were inconsistent with their usage of the “sex” and “gender” terms. Conclusions: Very few studies offered a robust analysis of sex/gender data according to SAGER guidelines. We call for clear and directed guidelines regarding the use of sex/gender as a variable in epigenetics research. Full article
(This article belongs to the Special Issue Sex Differences in Cancer)
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Other

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25 pages, 4265 KiB  
Systematic Review
The Effect of Sex on the Therapeutic Efficiency of Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis Based on Randomized Controlled Trials
by Xingyu Zhong, Jianxuan Sun, Na Zeng, Yifan Xiong, Ye An, Shaogang Wang and Qidong Xia
Cancers 2024, 16(2), 382; https://doi.org/10.3390/cancers16020382 - 16 Jan 2024
Viewed by 1109
Abstract
Background: Sex is an important factor influencing the immune system, and the distribution of tumors, including their types and subtypes, is characterized by sexual dichotomy. The aim of this study was to investigate whether there is an association between sex and the treatment [...] Read more.
Background: Sex is an important factor influencing the immune system, and the distribution of tumors, including their types and subtypes, is characterized by sexual dichotomy. The aim of this study was to investigate whether there is an association between sex and the treatment effect of immune checkpoint inhibitors (ICI). Methods: Four bibliographic databases were searched. Studies of randomized controlled trials (RCTs) assessing the efficacy of ICI were identified and used, and the primary endpoint was the difference in efficacy of ICI between males and females, presented as overall survival (OS), progression-free survival (PFS) and recurrence-free survival (RFS). The study calculated the pooled HRs and 95% CIs for OS, PFS and RFS for males and females using a random effects model or a fixed effects model, and thereby assessed the effect of sex on the efficacy of ICI treatment. This study is registered with PROSPERO (CRD42022370939). Results: A total of 103 articles, including a total of 63,755 patients with cancer, were retrieved from the bibliographic database, of which approximately 70% were males. In studies with OS as the outcome, the combined hazard ratio (HR) was 0.77 (95% CI 0.74–0.79) for male patients treated with ICI and 0.81 (95% CI 0.78–0.85) for female patients compared to controls, respectively. The difference in efficacy between males and females was significant. Conclusions: ICI therapy, under suitable conditions for its use, has a positive impact on survival in various types of tumors, and male patients benefit more than females. It may be necessary to develop different tumor immunotherapy strategies for patients of different sexes. Full article
(This article belongs to the Special Issue Sex Differences in Cancer)
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: Sex differences in survival of neuroendocrine neoplasms (NENs): A comparative population based study of patients from National Cancer Registration and Analysis Service (NCRAS, UK) and Surveillance, Epidemiology, and End Results (SEER, US) databases
Authors: Mohamed Mortagy, Marie Line El Asmar, Chandrakumaran Kandiah, John Ramage
Affiliation: Hampshire Hospitals NHS Foundation Trus
Abstract: Introduction It has been reported that sex is an important predictor of survival of patients with neuroendocrine neoplasms (NENs) using data from the UK NCRAS database using Restricted mean survival time (RMST) analysis. The same statistical methods have not been applied to US SEER data as most SEER analyses are done using Cox regression which has been proven to be less accurate when compared to RMST. There are no studies directly comparing data from NCRAS and SEER regarding sex survival of patients of NENs Aims To compare and evaluate sex differences in survival of patients with NENs from NCRAS and SEER databases using the same statistical methods such as RMST. Materials and Methods 14,834 and 112,570 patients with NENs were extracted from NCRAS (2012 - 2018) and SEER (1975 – 2020) respectively. Included sites were appendix, cecum, colon, lung, pancreas, rectum, small intestine, and stomach. 60-month Restricted mean survival time (RMST), age-adjusted restricted mean time lost ratio (RMTL ratio), age-adjusted hazard ratio and Kaplan Meier curves were generated for males and females for all sites and for some subgroups (age, grade, and stage). Results 60-months RMST survival was highest in appendix NENs in both SEER and NCRAS data . It was lowest in NCRAS for colon NENs and in the SEER for lung NENs for males and for colon NENs for females . Females had better survival than males in both NCRAS and SEER for lung, pancreas, rectum, and stomach. Females had similar survival to males in both NCRAS and SEER for cecum, colon, and small intestine. Females have better survival than males for appendix NEN in SEER and similar survival in NCRAS. Subgroup analyses showed mixed results. Conclusion The finding from NCRAS that some NENs have better survival in females while others have similar survival to males is mainly corroborated by data from SEER, with some minor differences. These robust differences will need further investigations into causality which may have implications for the overall aetiogenesis of some NEN.

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