The goals of research conducted within the Women's Cancer Program are to advance understanding about breast cancer and gynecologic cancers and to improve treatment strategies for these cancers.
To help meet these goals, the Women's Cancer Program collaborates with numerous Mayo Clinic faculty researchers across many disciplines on four main focus areas related to women's cancers.
Identifying key genetic alterations underlying women's cancers
Among their achievements, our investigators reclassified variants of undetermined significance in BRCA2 as pathogenic or benign through the use of cell-based functional assays that measure the DNA repair activity of BRCA2. These assays have demonstrated high sensitivity and specificity for detection of pathogenic mutations.
This information has been distributed globally to providers, genetic counselors and patients, and is being incorporated into the clinical classification models of commercial testing laboratories.
In this key research area, our investigators also have:
- Demonstrated that patients with triple-negative breast cancer should be offered genetic testing for BRCA1 and BRCA2 mutations.
- Demonstrated that tumor subtype impacts prognosis in patients with high-grade serous ovarian cancer.
- Contributed to a study linking clinical response to bevacizumab to ovarian cancer molecular subtypes. Among those treated with bevacizumab, the proliferative and mesenchymal subtypes had better outcomes than in those with immunoreactive subtypes, suggesting that molecular subtype may be a predictive marker of response.
Defining key mediators and pathways in the biology of women's cancers
In this focus area, our investigators contributed substantially to the clinical development of PARP inhibitors (PARPi) for homologous recombination-deficient cancers. They discovered that iniparib, a drug that failed in phase III breast cancer trials, was not a PARPi. They also discovered novel mechanisms of PARPi action and resistance pathways.
These discoveries led to ARIEL2, a multi-institutional phase II trial for women with platinum-sensitive relapsed ovarian cancers treated with rucaparib, which later resulted in U.S. Food and Drug Administration approval of rucaparib and the extended use of PARPi beyond high-grade serous ovarian cancers with germline BRCA1 or BRCA2 mutations.
Our researchers also:
- Demonstrated that ERβ is expressed in about 30% of patients with triple-negative breast cancer, and that ligand-mediated activation of ERβ in triple-negative breast cancer elicits potent anti-cancer effects
- Identified that constitutive activation of Raf-1 oncogenic signaling induces stabilization and accumulation of Aurora-A mitotic kinase, driving the epithelial-to-mesenchymal transition in ERα+ breast cancer cells
- Mapped the gynecologic tract microbiome in the setting of endometrial hyperplasia and endometrial cancer, and identified Atopobium vaginae and a previously uncultured representative of porphyromonas species, especially in the setting of a high pH, as being associated with endometrial hyperplasia and endometrial cancer
- Demonstrated that the breast tissue microbiota of women with invasive breast cancer had increased abundance of fusobacterium, atopobium, hydrogenophaga, gluconacetobacter and lactobacillus relative to the microbiota of women with benign disease
- Showed that high levels of CD8+ tumor infiltrating lymphocytes in high-grade serous, mucinous and endometrioid ovarian cancers correlated with improved overall survival
- Demonstrated that low-stage and late-stage high-grade serous ovarian cancers have similar mutation and copy number profiles, with deleterious TP53 mutations as some of the earliest events, followed by deletions or loss of heterozygosity of chromosomes carrying TP53, BRCA1 or BRCA2
- Demonstrated a strong correlation between mutation burden and expression of APOBEC3B, a mutagenic member of the cytidine deaminase enzyme family, which suggests that ectopic expression of APOBECs might contribute to ongoing mutagenesis in ovarian cancer
- Identified that the drug 5-aza-2'-deoxycytidine (decitabine), which is FDA approved for the treatment of certain hematological cancers, could significantly inhibit the growth of triple-negative breast cancer, an effect also seen in tumors resistant to chemotherapy (a response dependent on the presence of certain critical proteins called DNA methyltransferase proteins that are present in only a subset of triple-negative breast cancers, providing a way to identify which patients could benefit from this therapy)
Improving identification of women at increased risk
In this research focus area, our researchers:
- Developed a new breast cancer risk prediction model that more accurately classifies breast cancer risk than does the previous screening standard
- Demonstrated that molecular breast imaging is a valuable supplemental screening study in women with dense breasts, increasing detection of cancers threefold and improving sensitivity and specificity
- Reported that the background uptake of sestamibi on molecular breast imaging stratifies future cancer risk, with a 3.5-fold increase in risk among women with moderate or marked uptake compared with lesser uptake, suggesting that molecular breast imaging may refine risk prediction among women with dense breasts
- Showed that tampons can be used to detect endometrial cancer by collecting vaginal secretions that can then be examined for the presence of methylation
Developing and testing innovative treatment strategies for women's cancers
Our investigators have made a number of key advances in this research area, including:
- Studying the pharmacogenetics of tamoxifen in secondary analyses of prospective trials and leading the Clinical Pharmacogenetics Implementation Consortium (CPIC) practice guidelines about the use of CYP2D6 genotype to guide tamoxifen treatment
- In collaboration with the National Cancer Institute, developing and completing a phase I study of Z-endoxifen, the active metabolite of tamoxifen
- Demonstrating that extending treatment for hormone receptor positive early breast cancer in postmenopausal women with an adjuvant aromatase inhibitor to 10 years resulted in significantly higher rates of disease-free survival and a lower incidence of contralateral breast cancer compared with a placebo
- Demonstrating that abemaciclib plus a nonsteroidal aromatase inhibitor was effective as initial therapy, significantly improving progression-free survival and objective response rate and demonstrating a tolerable safety profile in women with HR positive, HER2-negative advanced breast cancer
- Demonstrating that MV-NIS, an Edmonston-lineage measles virus strain that expresses the human sodium iodide symporter, offers a promising new modality for the targeted infection and destruction of ovarian cancer
- Showing that different oncolytic platforms, including measles virus, vesicular stomatitis virus and vaccinia, have significant activity in vivo and in vitro against endometrial cancer