Ovarian Cancer Risk Influenced by Vaginal Microbiome?

Pam Harrison

July 24, 2019

Women under the age of 50 who have been diagnosed with ovarian cancer or carry the BRCA1 mutation that increases ovarian cancer risk were found to have lower levels of protective bacteria in their cervicovaginal microbiota when compared with healthy controls and nonmutation carriers.

The finding comes from a case-control study published online July 9 in the Lancet Oncology.

The fact that the microbiota was deficient in protective lactobacilli species in women with or at risk for ovarian cancer suggests the reduced prevalence might be causal, researchers speculate.

However, they add it is too early to say if restoring the cervicovaginal microbiota with a probiotic suppository might lower the risk.

In an accompanying commentary, editorialist Hans Verstraelen, MD, PhD, Ghent University, Belgium, is a little more skeptical.

In most populations, the vaginal microbiota of younger women is largely dominated by lactobacilli, and adverse reproductive health outcomes have been observed among women who deviate from the normal vaginal microbiota state, he explains.

"However, the vagina is also a highly dynamic ecosystem," Verstraelen points out, "and by assessing the microbiota on only one occasion, there is a risk of misclassification bias in the authors' findings," he notes.

The more important question to answer is how the vaginal microbiota could promote ovarian cancer, as Verstraelen suggests.

It could be that the vaginal microbiota simply reflects some constellation of extrinsic factors that could be involved in ovarian carcinogenesis.

Smoking, for example, is thought to negatively affect lactobacillus dominance, whereas as oral contraceptives and hormone replacement therapy are thought to promote it, he points out.

"Some researchers have suggested that the vaginal microbiota acts as a so-called microbial seed bank for the upper genital tract," Verstraelen adds, suggesting a role of the extra-ovarian origins in ovarian cancers.

"Overall, there is no direct evidence that the human microbiota has a key role in cancer causation," Verstraelen emphasizes.

"But the microbiota needs to be taken into account in future research," he said, concurring with the study authors.

First Study of Its Kind

"To our knowledge, this study is the first case-control analysis of the cervicovaginal microbiome in women with ovarian cancer and in women at high risk for ovarian cancer," lead researcher Nuno Nene, PhD, University College London, United Kingdom, and colleagues comment.  

"Once the functional relevance of community type O cervicovaginal microbiota [ie, lactobacilli < 50% of species present] in ovarian cancer development has been established, vaginal lactobacilli transplantation in young carriers of germline BRCA1 mutations could become available as a risk reduction measure," they suggest.

In healthy women, the cervicovaginal microbiota is predominantly populated by four different species of Lactobacillus. The authors explain that Lactobacillus prevents urogenital disease by lowering the vaginal pH through the production of lactic acid, among other mechanisms.

A lower vaginal pH could potentially decrease the risk of ascending infection, they also suggest.

The FORECEE Program

The vaginal microbiota study was part of the multicenter FORECEE (4C) program conducted in Europe, which involved women aged 18-87 years.

One cohort was made up of 360 individuals, of whom 176 had epithelial ovarian cancer (largely serous, high-grade disease), 115 were healthy controls, and 69 were controls with benign gynecological conditions.

The BRCA group was made up of 220 women, 109 of whom had BRCA1 mutations, 97 were healthy controls, and 14 were controls with benign gynecological conditions.

Cervicovaginal smear samples were collected from all participants using the ThinPrep system (Hologic, Marlborough, Massachusetts) and underwent genetic sequencing.

"For each sample, we calculated the proportion of lactobacilli species (ie, Lactobacillus crispatus, Lactobacillus iners, Lactobacillus gasseri, and Lactobacillus jensenii), which are essential for the generation of a protective low vaginal pH in the cervicovaginal microbiota," the authors note.

Samples were then grouped into those in which lactobacilli accounted for at least 50% of the species present (community type I) and those in which lactobacilli accounted for less than 50% of the species present (community type O).

Younger vs Older Patients

Results showed that women under the age of 50 who had ovarian cancer were almost three times more likely to carry levels of lactobacilli of less than 50% in their cervicovaginal samples relative to those who had no history of ovarian cancer (odds ratio [OR], 2.8; P = .20).

Similarly, women under the age of 50 who carried a BRCA1 mutation were almost three times more likely to have lower levels of lactobacilli in their vaginal microbiota than women who did not carry the mutation (OR, 2.79; P = .012).     

"This risk was increased further if more than one first-degree family member was affected by any cancer," study authors note. This subgroup of patients had a risk that was increased by more than fivefold (OR, 5.26; P = .0022).

In both the ovarian cancer and BRCA1 cohorts, investigators observed that the younger the woman, the stronger the association was between having low levels of lactobacilli and ovarian cancer risk.

For example, women under the age of 40 who had lower levels of lactobacilli in their vaginal microbiota were seven times more likely to have ovarian cancer compared to women with higher levels of lactobacilli (OR, 7.00; P = .025).

Women who were under the age of 35 in the BRCA group were also more than four times as likely to develop ovarian cancer if levels of lactobacilli species were low, at an OR of 4.40 (P = .031) compared to women with higher lactobacilli levels.

In contrast, "there was a tendency towards a higher prevalence of type O communities than type 1 communities in the cervicovaginal samples for women 50 years of age and older in the ovarian cancer cohort," Nene and colleagues note. However, the difference between the two groups was not significant.

Nor was the difference significant between older women who had greater than 50% lactobacilli present in their vaginal microbiome compared with those with less than 50% lactobacilli, they add.

"In this study, we showed that the prevalence of women with nonlactobacilli-dominated cervicovaginal microbiomes was higher both in patients with ovarian cancer and in women with BRCA1 mutations who had yet to develop cancer compared with age-matched, healthy women and women without BRCA1 or BRCA2 mutations, respectively," Nene points out.

"The finding that the prevalence of community type I microbiota was lower in patients with ovarian cancer than in healthy controls, irrespective of disease stage, suggests that this reduced prevalence of type I microbiota could be causal rather than consequential," they speculate.

Nene and Verstraelen have reported no relevant financial relationships. Disclosures for the other authors are listed in the article.

Lancet Oncol. Published online July 9, 2019. Abstract, Editorial

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