British Journal of Haematology | 2021
Gender effects in cancer treatment and outcome
Abstract
In this issue of the Journal, Wiernik et al. present an analysis of gender effect in a large cohort of patients with acute myeloid leukaemia (AML), including a substantive number with acute promyelocytic leukaemia (APL) (total 3546 AML, including 548 APL), enrolled in 10 multi-institutional trials utilising modern treatment approaches and modern era cytogenetic and molecular characterisation. They demonstrate an overall significant advantage for the female gender in terms of survival, and show gender as an independent prognostic variable, irrespective of patient age, initial white blood cell count, or initial blood or marrow blast count. Also of interest, the survival benefit for the female gender was significant at all dose levels of daunorubicin, and was even more striking in female APL patients who received all-trans-retinoic acid (ATRA) compared with males, suggesting that gender-specific pharmacological evaluations may be an important aspect of determining treatment outcome. The authors also point out that gender-specific smoking patterns have been linked to leukaemia outcome, as have reports of a higher incidence of deleterious genetic mutations and chromosomal deletions among males with AML. These all suggest important areas for further biological investigation of gender differences in treatment results and potentially in treatment guidance. Additionally, Wiernik et al. cite a multi-factorial analysis of sex differences among patients with glioblastoma multiforme (GBM). That report describes complex sex-specific interactions, both in the setting of neurofibromatosis, as well as pointing out that the incidence of low grade glioma is equivalent in males and females, but that there is a higher incidence of malignant brain tumours in males. Similar to the findings in patients with AML, the female sex was a favourable survival predictor following chemotherapy treatment for GBM. This group presents ongoing work to elucidate sex-specific molecular subtypes of GBM based on cell cycle and integrin-signalling pathways, and presents correlations between gene expression and in vitro chemosensitivity. Aside from cancers arising in gender-specific organs, many reported sex differences in the incidence of certain other cancers, or differences in the outcome of treatment results, remain poorly explained. Examples of considerable differences in incidence include the preponderance of papillary thyroid cancer in females, and of kidney cancer in males. Whereas environmental factors, such as cigarette smoking, or toxin exposure, have been postulated to have gender preponderance, thus leading to differences in incidence in some cancers, this does not always explain such differences. Gender differences are also noted in other illnesses, such as asthma, in terms of incidence and/or severity, and sex-specific genetic variants are being elucidated. Gender differences in treatment outcome are even more complex to explain and elucidate mechanism. Concepts under investigation include environmental exposures, hormonal fluctuations, gender-specific drug metabolism, as well as sex-specific differences in genetics and molecular pathways involved in drug-tumour interactions. A recent evaluation of gender-specific and possibly therapeutic agent-specific outcome was reported by Mamtani et al. among patients with resected renal cell cancer (RCC) in a randomised clinical trial (Eastern Cooperative Oncology trial, E2805), who received adjuvant anti-vascular endothelial growth factor receptor tyrosine kinase inhibitors (TKI), sunitinib or sorafenib versus placebo. Patients were analysed for mortality by age category (≤ 56 years and > 56 years) and by gender. Those of an older age and the female sex were previously associated with more severe toxicity from sunitinib in patients with advanced RCC. In Mamtani’s analysis, among patients > 56 years old and treated with sunitinib, mortality was twice as high for women as compared to men in this adjuvant study, and the five-year survival was 20% lower for older women who received sunitinib compared with those receiving placebo. There was no such finding with sorafenib. The major limitation was that this was a post hoc analysis with no data regarding actual subsequent cause of death or follow-on treatment patterns. Correspondence: Janice P. Dutcher, St. Luke’s Roosevelt Medical Center, New York, NY, USA. Email: [email protected] commentary