Gynecologic cancer treatment toxicities and relationships with the vaginal microbiome

Objectives: Gynecologic cancer survivors may live for decades with clinically significant, often persistent symptoms/toxicities including pain, dyspareunia, sexual dysfunction and fatigue. The vaginal microbiome (VM) plays a crucial role in women's health and has been previously associated with vaginal symptoms related to menopause (ie 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 of the vaginal microbiome with the persistence of vaginal toxicities, one year upon completion of cancer therapies while controlling for clinical and sociodemographic factors. Methods: We studied 20 women that received pelvic radiation therapy in parallel with a group of 27 age and race matched healthy women. We obtained VM data during 4 sampling times (pre-therapy, after 2, 6, and 12 months post-therapy) by amplicon 16S rRNA gene sequencing. For each sampling we recorded vaginal toxicities as measured by clinician/patient-reported validated instruments, including PRO-CTCAE, CTCAE, and FSFI, as well as lifestyle behaviors (use of estrogen, sexual activity, etc). Results: We observed differences among the VM profiles of cancer and healthy women at all time points assessed, but differences were further exacerbated with the progression of time. Cancer patients exhibit higher diversity VMs and a variety of vaginal community state types (CST) that are not dominated by Lactobacilli, with extensive VM variation -between individuals. Additionally, cancer patients exhibit highly unstable VMs (average Bray-Curtis distances) compared to healthy controls (Kruskal-Wallis, p=0.004). 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. However, among the symptomatic subjects, 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 and/or abnormally high pH have the most unstable microbiomes (Fisher's exact test, p=0.014 and 0.002). Associations were identified between vaginal symptoms and individual bacterial taxa, including Prevotella with vaginal dryness (p=0.0004), Delftia with pain following vaginal intercourse (p=0.0006), and Gemillaceaea with low levels of lubrication during intercourse (p=0.0002). Download : Download high-res image (337KB) Download : Download full-size image Conclusions: Differences in the VM among healthy and gynecologic cancer patients are more prominent a year after completion of cancer therapies, including enrichment of opportunistic bacterial pathogens. Highly unstable microbiomes are typical in cancer patients and were associated with symptom persistence which warrants further attention.