Gender-Based Differences in Chemotherapy: Efficacy and Safety

Ideally, a health care provider would be able to pick a chemotherapeutic agent that has the best efficacy and fewest number of side effects for each individual patient. These types of decisions are often guided by clinical trials and developing data on biomarkers and genetics. One part of the patient’s history that can be easily overlooked when considering different treatment options is the patient’s gender. The role of gender in the epidemiology of cancer is well known; it is well established that men have higher overall rates of cancer than women in North America.^1,2 However, the impact of gender on specific outcomes, including efficacy and safety, is less recognized and understood, despite growing research.

One recent example was published in the Annals of Oncology by Davison and colleagues.³ This study evaluated the interpatient variability of chemotherapy metabolism and dose-response based on gender in patients with esophagogastric (EG) cancer. A pooled analysis of 4 randomized clinical trials was performed in patients receiving a triple chemotherapy regimen including a platinum, anthracycline, and fluoropyrimidine. These 4 studies were all multicentered and took place in the United Kingdom. The studies included 1654 patients; approximately 80% were male and 20% were female.

There were no significant differences in all-grade toxicities between men and women, however, women did have statistically significant higher rates of certain toxicities, especially those within the gastrointestinal (GI) tract. These included all-grade stomatitis (49.5% vs 40.7%, P = .004), all-grade nausea and vomiting (89.3% vs 78.3%, P < .001) and all-grade diarrhea (53.8% vs 46.9%, P = .027). In addition to these GI toxicities, women also experienced more all-grade alopecia (81.4% vs 74.3%, P = .009). On the contrary, men had significantly higher rates of peripheral neuropathy compared with women (49.3% vs 42.6%, P = .03). There were no statistically significant differences in outcomes between men and women, including in the rates seen for progression free survival (PFS), overall survival (OS), and objective response rate (ORR).

The more prominent GI toxicity profile among women was an interesting finding, although the exact reason for this phenomenon is unclear. It would be interesting to stratify gut microbiome profiles by gender to see if that played a role in GI toxicity differences. Also, whether the location of the malignancy within the GI tract played a prominent role in these toxicities compared with similar chemotherapy regimens in non-GI malignancies could be an area of future research.  Regardless, this type of information could prove valuable when constructing treatment protocols and clinical trials for specific patients. It may allow for earlier identification of toxicities within women.

The exact pathophysiology behind these gender-based differences is not entirely understood. The obvious factors that could play a role in all malignancies include lifestyle, different levels of gene expression, and varying levels of hormones. There can also be factors within specific types of cancer yet to be identified. A recent study conducted by Li and colleagues evaluated the differences in genetic mutations between men and women within several cancers.⁴ In all cancer types, malignancies found in men had higher levels of single nucleotide variants (SNVs) compared with women (difference in means 0.17, 95% confidence interval [CI], 0.14-0.20). When evaluating specific types of cancer, these imbalances in SNVs were most prominent across 5 types of cancer within men: urothelial cancer, melanoma, renal papillary cell cancer, lung adenocarcinoma, and hepatocellular cancer. Glioblastoma was the only cancer that had a higher SNV rate in women compared with men.

These elevated numbers of SNVs could correlate with defects in DNA mismatch repair (MMR) which can be measured via microsatellite instability (MSI). The authors were able to review MSI data within EG, pancreatic cancer, and colorectal cancer. There was an increased association of MSI in females compared with males in EG cancer (40% vs 25%, P < .001) and colorectal cancer (33% vs 25%, P = .025), but not pancreatic cancer.

Chemotherapy outcomes and how they vary between genders is an intriguing topic that still requires further research. However, there is enough evidence at this point to suggest that gender could play a more significant role in clinical trial development in the future to make more personalized treatment plans a reality.

References

1. Cook MB, Dawsey SM, Freedman ND, et al. Sex disparities in cancer incidence by period and age. Cancer Epidemiol Biomarkers Prev. 2009;18(4):1174-1182.
2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7-30.
3. Davidson M, Wagner AD, Kouvelakis K, et al. Influence of sex on chemotherapy efficacy and toxicity in oesophagogastric (OG) cancer: a pooled analysis of four randomised trials [published online October 23, 2018]. Ann Oncol. 2018;29(suppl_8). doi: 10.1093/annonc/mdy424.032
4. Li CH, Haider S, Shiah YJ, Thai K, Boutros PC. Sex differences in cancer driver genes and biomarkers. Cancer Res. 2018;78(19):5527-5537.