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FAQ: Precision Med in GYN Cancers
Frequently Asked Questions: Precision Medicine in Gynecologic Cancers

Released: June 30, 2023

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Key Takeaways
  • Current shortages of platinum-based therapies (carboplatin and cisplatin) are challenging healthcare professionals to be more thoughtful about their use for gynecologic cancers and to consider other viable alternatives (eg, clinical trials).
  • Mirvetuximab has been established as the standard of care in patients with platinum-resistant or platinum-refractory ovarian cancer with high expression of folate receptor α, but gaining access to local or in-house testing remains a challenge.
  • Precision treatment for endometrial cancer is now a reality with the incorporation of immunotherapies into the treatment paradigm of primary advanced stage III/IV disease that is mismatch repair deficient/microsatellite instability‒high.

The management of patients with gynecologic cancer has become personalized with the introduction of biomarker-driven therapy, making precision medicine approaches a reality. The most promising targeted agents in gynecologic cancers now include PARP inhibitors, antibody‒drug conjugates, and immune checkpoint inhibitors. These advances are challenging healthcare professionals (HCPs) to select the optimal treatment for their patients. In this commentary, experts answer frequently asked questions on how to manage patients with gynecologic cancer in a rapidly evolving therapeutic landscape that were submitted by an audience of HCPs during an educational webinar on this topic. 

What are your thoughts on innovations to overcome the platinum chemotherapy shortage in the United States?

David Scott Miller, MD, FACOG, FACS:
The Society of Gynecologic Oncology already has provided guidance recommendations on how to conserve and allocate the available limited supply of carboplatin and cisplatin to help HCPs during the platinum shortage. An approach we are contemplating at our institution was published in 2013 by Dr Thomas Herzog and colleagues. They explored the role of oxaliplatin, docetaxel, and bevacizumab in 132 patients with previously untreated advanced peritoneal, fallopian tube, and ovarian cancers after initial debulking surgery. That approach yielded an overall response rate of 58.6%. Moreover, the 12-month progression-free survival (PFS) rate for the subgroup with measurable disease was 65.7%, median PFS was 16.3 months, and median overall survival (OS) was 47.3 months. The most common grade 3/4 adverse events were neutropenia (42.4%), leukopenia (13.6%), hypertension (8.3%), fatigue (6.1%), and nausea (6.1%); 1 patient (0.8%) had a fatal gastrointestinal perforation. Results from that trial are encouraging and potentially could be an alternative. The current shortage also represents an opportunity for industry to explore experimental approaches that can be tested in a clinical trial setting. 

What is your experience in ordering testing for folate receptor α (FRα) in your patients with platinum-resistant or platinum-refractory ovarian cancer? Any issues in obtaining insurance to cover FRα testing?

David Scott Miller, MD, FACOG, FACS:
Data from the confirmatory phase III MIRASOL trial—which investigated mirvetuximab soravtansine, an antibody‒drug conjugate against FRα, compared with investigator’s choice of chemotherapy in patients with platinum-resistant epithelial ovarian, primary peritoneal, or fallopian tube cancers with high expression of FRα and 1-3 previous lines of chemotherapy—demonstrated impressive OS improvement in a very difficult-to-treat patient population. However, this treatment necessitates evaluating FRα in our patients whose disease is platinum resistant. At our institution, we encouraged integration of FRα into the College of American Pathologists template as part of the standard of care. We have no issues in getting this testing.

Domenica Lorusso, MD, PhD:
FRα testing is a challenge for us in Europe because the test itself needs to be In Vitro Diagnostic Regulation validated. This means we cannot perform the FRα testing ourselves. In trials evaluating mirvetuximab soravtansine, FRα testing was performed centrally. We are working on figuring out what will happen with FRα testing for us in Italy, but most likely it will become centralized in each European country in the near future.

Hye Sook Chon, MD:
At our institution, we are “sending out” our FRα testing, and we have been doing it for a long time because we are participating in those clinical trials for ovarian cancer. I also agree with Dr Lorusso that local testing has to be validated.  

Domenica Lorusso, MD, PhD:
If I may add, FRα testing is critical to identify the patients who are more likely to benefit from mirvetuximab soravtansine therapy. In our experience, approximately 53% to 80% of patients with high-grade serous ovarian cancer test positive for FRα. After FRα testing becomes more standardized, we might be able to assess for this biomarker longitudinally and whether it changes with therapy.

In patients receiving PARP inhibitors who experience hematologic toxicity, have you looked at total hematopoiesis and in the setting of drug tolerance? 

David Scott Miller, MD, FACOG, FACS:
I personally have not performed these analyses. Have any of my cofaculty?

Domenica Lorusso, MD, PhD:
Published data suggest that PARP inhibitor use in patients with high-grade serous ovarian cancer may preselect certain hematopoietic clones with a survival advantage. In turn, this can lead to a small number of patients, unfortunately, developing myelodysplastic syndromes and/or acute myeloid leukemia (1.2%-8.0%). Again, this is in a minority of patients, but it is something we need to be aware of and talk to patients about. We published our results in the Journal of the American Medical Association looking at preexisting TP53-variant clonal hematopoiesis and risk of secondary myeloid neoplasm in patients with high-grade ovarian cancer as predictors of hematologic toxicity with PARP inhibitors.

Are you routinely performing molecular testing for your patients with endometrial or cervical cancers?  

Domenica Lorusso, MD, PhD:
Yes. We have implemented the molecular classification of endometrial cancer in the pathologic report at diagnosis based on European guidelines. This approach is further validated by the very positive results from both the phase III RUBY trial of dostarlimab and the phase III NRG GY018 trial of pembrolizumab where adding immunotherapy to the standard of care yielded a significant PFS and OS benefit in patients with mismatch repair deficient (dMMR) disease. 

Hye Sook Chon, MD:
We have not yet started testing for microsatellite instability/dMMR in cervical cancer, but we are doing this for endometrial cancer. Presently, we are trying to do next-generation sequencing in the first-line setting as opposed to the recurrent setting. Next-generation sequencing can help us identify the group classified as POLE, and this is of interest because of the good prognosis of this group and the potential for de-escalation of therapy.

David Scott Miller, MD, FACOG, FACS:
Thanks to both of my colleagues for the great discussion. I want to encourage our readers to go onto the program page to browse more educational content on precision medicine for the care of your patients with ovarian, endometrial, and cervical cancers.

Your Thoughts?
What are your thoughts and questions on the management of patients with gynecologic cancers in the rapidly evolving therapeutic landscape? Please answer the polling question and join the conversation by posting a comment in the discussion section.


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