Changes in the Vaginal Microbiome and Associated Toxicities Following Radiation Therapy for Gynecologic Cancers

Abstract

Postmenopausal women often suffer from vaginal symptoms associated with atrophic vaginitis. Additionally, gynecologic cancer survivors may live for decades with additional, clinically significant, persistent vaginal toxicities caused by cancer therapies, including pain, dyspareunia, and sexual dysfunction. The vaginal microbiome (VM) has been previously linked with vaginal symptoms related to menopause (i.e. dryness). Our previous work showed that gynecologic cancer patients exhibit distinct VM profiles from healthy women, with low abundance of lactobacilli and prevalence of multiple opportunistic pathogenic bacteria. Here we explore the association between the dynamics and structure of the vaginal microbiome with the manifestation and persistence of vaginal symptoms, during one year after completion of cancer therapies, while controlling for clinical and sociodemographic factors. We compared cross-sectionally the vaginal microbiome in 134 women, 64 gynecologic patients treated with radiotherapy and 68 healthy controls, and we longitudinally followed a subset of 52 women quarterly (4 times in a year: pre-radiation therapy, 2, 6 and 12 months post-therapy). Differences among the VM profiles of cancer and healthy women were more pronounced with the progression of time. Cancer patients had higher diversity VMs and a variety of vaginal community types (CTs) that are not dominated by Lactobacilli, with extensive VM variation between individuals. Additionally, cancer patients exhibit highly unstable VMs (based on Bray-Curtis distances) compared to healthy controls. Vaginal symptoms prevalent in cancer patients included vaginal pain (40%), hemorrhage (35%), vaginismus (28%) and inflammation (20%), while symptoms such as dryness (45%), lack of lubrication (33%) and dyspareunia (32%) were equally or more prominent in healthy women at baseline. However, 24% of cancer patients experienced persistent symptoms at all time points, as opposed to 12% of healthy women. Symptom persistence was strongly inversely correlated with VM stability; for example, patients with persistent dryness or abnormally high pH have the most unstable microbiomes. Associations were identified between vaginal symptoms and individual bacterial taxa, including: Prevotella with vaginal dryness, Delftia with pain following vaginal intercourse, and Gemillaceaea with low levels of lubrication during intercourse. Taken together our results indicate that gynecologic cancer therapy is associated with reduced vaginal microbiome stability and vaginal symptom persistence.

Keywords: gynecologic cancer; longitudinal dynamics; postmenopausal women; radiation toxicities; vaginal microbial community; vaginal microbiome.

Figure 1

Prevalence of reported vaginal symptoms among gynecologic cancer and healthy postmenopausal women at the different time points of the study. (A) Prevalence of clinician-reported toxicities (B) Prevalence of patient-reported outcomes (PROs)/symptoms. T0=baseline (n=134); T1 = 2.5-3mos after completion of radiation therapy (n=52), T2 = 6mos (n=52), T3 = 12mos post baseline (n=52). Star symbols indicate statistical significance (p=<0.01, z-test with correction for multiple testing) of the different proportion between gynecologic cancer and healthy cohort. (C) Vaginal symptoms persistence in gynecologic cancer and healthy controls. Percentage of healthy and cancer participants which reported at least one of the four patient reported symptoms: Never, Occasionally (once or twice in the year), Persistently (three or four out of four times). (D) Correlation of PRO symptoms. The correlations were tested after transforming all data to categorical variables (presence or absence of symptom).

Figure 2

Comparison of α-diversity metrics among healthy and gynecologic cancer vaginal microbiome communities. Cancer patients exhibit higher α-diversity than healthy controls at baseline, which further increases at T1, upon completion of therapy. Star symbols indicate a p-value <0.01 in Kruskal-Wallis test between cancer and healthy.

Figure 3

Vaginal microbiome community state types (CST-A) identified in gynecologic cancer and healthy postmenopausal women. The dendrogram represents the hierarchical clustering of the VM communities based on Bray-Curtis dissimilarity distances. The taxonomic profiles for each VM are presented in stacked barplots for each subject, where only the most abundant 22 bacterial genera are shown (for aiding visualization). Certain CSTs are highly correlated with toxicities/symptoms, for example CST-E shows high correlation with persistent vaginal dryness (Fisher’s exact test and Bonferroni correction, p=0.001).

Figure 4

Comparison of vaginal microbiome stability in gynecologic cancer and healthy postmenopausal subjects throughout a year (on the left). (On the right), vaginal microbiomes from reproductive age women from published literature: eight healthy reproductive age women sampled over 3 months (R. J. Hickey et al., 2013); and 32 women sampled over four months (Gajer et al., 2012).