CE / CME
Pharmacists: 0.75 contact hour (0.075 CEUs)
Nurses: 0.75 Nursing contact hour
Physicians: Maximum of 0.75 AMA PRA Category 1 Credit™
Released: August 09, 2023
Expiration: August 08, 2024
Screening and Molecular Testing in Gynecologic Cancers
Maria Avila-Wallace, NP:
In my experience at the Massachusetts General Hospital Department of Surgery, all patients identified to have malignant disease are approached by the gynecologic oncologists in the same manner, regardless of race or background. The differences in modalities initially pursued depend on the stage of disease at presentation, symptoms, comorbidities, and Eastern Cooperative Oncology Group performance status. Any presurgical procedures also are taken into consideration, including paracentesis or thoracentesis and pelvic biopsy, as applicable.
We explain and discuss with patients the process of obtaining tumor samples for molecular testing, which can offer guidance for additional or targeted therapies. Tumor sampling can be obtained at the time of cytoreductive surgery or before beginning neoadjuvant chemotherapy, considering the possibility of not enough tumor sample remaining with dramatic treatment responses.
Endometrial Cancer
There is no standard or routine screening test for endometrial cancer in the United States for asymptomatic patients. In my current practice, I see symptomatic patients for evaluation and diagnosis of endometrial cancer, and I initiate a dialogue regarding management of disease and the use and clinical implications of molecular testing. Through early detection, I address increasing mortality rates from endometrial cancer by identifying asymptomatic patients at higher risk for the disease, such as patients with abnormal glandular Pap smears suggestive of endometrial pathology, patients with Lynch syndrome, and/or patients taking tamoxifen.
In patients with a confirmed diagnosis of endometrial cancer, current guidelines recommend genomic profiling at initial evaluation using a validated and/or FDA-approved assay.1 Testing for mismatch repair (MMR) protein loss by immunohistochemistry (MLH1, MSH2, MSH6, and PMS2)—particularly MLH1 and MSH6 if there is suspected Lynch syndrome—also is recommended. Genomic profiling and immunohistochemistry testing can determine eligibility for the combination of standard-of-care platinum-based chemotherapy plus immunotherapy agents (either dostarlimab or pembrolizumab) in microsatellite instability (MSI)‒high or MMR-deficient advanced/recurrent endometrial cancer, or pembrolizumab in combination with the antiangiogenic agent lenvatinib in MSI-stable/MMR-proficient disease.1-4 For our patients with advanced stage at presentation or recurrent, metastatic serous uterine cancer, in our institution estrogen receptor and HER2 immunohistochemistry testing is performed to identify those who can benefit from the addition of trastuzumab.
Ovarian Cancer
Early-stage ovarian cancer remains mostly an incidental finding in patients undergoing abdominal surgery. Ovarian cancer screening with a transvaginal ultrasound and CA-125 tumor marker test is offered to identified patients with higher risk due to hereditary cancer syndromes: those with family history of ovarian cancer, those with personal or family history of BRCA1/2 mutations, and those with Lynch syndrome. Therefore, of utmost importance is assessing risk in all patients we see—regardless of race, culture, or socioeconomic background—and providing assistance with the use of all available resources.
In patients with a confirmed diagnosis of ovarian cancer, guidelines recommend genetic risk assessment screening to identify any family history that may be associated with an increased risk of potentially harmful mutations in BRCA1/2 genes, followed by genetic counseling and, often, genetic testing.1 For those with high-risk factors (eg, BRCA mutations or family history of breast and/or ovarian cancer), guidelines recommend risk-reducing salpingo-oophorectomy (surgical removal of ovaries and fallopian tubes); in those declining/deferring this surgery, CA-125 monitoring and endovaginal ultrasound are also an option. Germline testing is recommended at the time of diagnosis, and somatic tumor testing should be done just before initiating therapy using an FDA-approved companion diagnostic test.5 Moreover, evaluation of homologous recombination deficiency also may be considered. Patients with primary refractory or recurrent disease also may consider testing for other predictive markers of benefit with novel treatments, for example, folate receptor α, RET, or NTRK gene fusions.1
Eva Y. Pan, PharmD, BCOP:
Also important to note that approximately 50% of ovarian cancers have alterations in the homologous recombination repair genes, which are involved in repair of double-strand DNA breaks.6 For example, these genes can have mutations, deletions, amplifications, or promoter methylation. The major pathogenic mutations in homologous recombination repair genes include the germline (~14%) and somatic (6%) BRCA1/2 mutations that can render cells sensitive to PARP inhibition. Ovarian cancer cells in patients with homologous recombination deficiency are more susceptible to PARP inhibition than normal noncancerous cells, as well.7
Cervical Cancer
Maria Avila-Wallace, NP:
The National Comprehensive Cancer Network guidelines recommend testing for molecular biomarkers found to be associated with response to novel treatments in patients with recurrent, progressive, or metastatic disease.1 These biomarkers include PD-L1 combined positive score, MMR/MSI and tumor mutational burden status by an FDA-approved assay, HPV testing, and NTRK and RET gene fusion testing.
Resources are available to patients requiring financial assistance with HPV screening, molecular testing, or affording the available treatment options. A compilation of patient-oriented resources, including links to financial assistance programs, can be downloaded here.
Guidelines for Screening and Histologic/Cytologic Assessment and HPV Vaccination in Cervical Cancer
Maria Avila-Wallace, NP:
HPV is responsible for approximately 99% of cervical cancers.8-10 HPV vaccination and HPV and Pap smear screening are our most effective ways to prevent disease, whereas colposcopy and treatment after early diagnosis can contribute to a decrease in incidence and mortality observed for Black and Hispanic patients compared with White patients.1,11 Colposcopy is used for the evaluation of premalignant disease of the genital tract (cervix, vagina, vulva) but not endometrial cancer.
We have observed that immigrant patients or those from underrepresented groups coming from countries where HPV vaccination is not offered or recommended require more education about the administration and benefits of HPV vaccination and screening compared with White patients. Information about the HPV vaccine and consistent patient education are key in achieving participation and increasing vaccination rates for vulnerable populations. Of importance, strategies should be sustainable according to the needs of targeted communities: availability of local vaccination clinics, aid in applying for eligible medical coverage, school vaccination programs, patient navigation and outreach programs, and engagement of local community leaders.
Eva Y. Pan, PharmD, BCOP:
At Yale, we offer HPV vaccination, and fortunately I have not noticed any disparities regarding who is receiving the vaccine. We do encourage patients to seek vaccination through retail pharmacies because it may be more affordable that way.
I also agree that patient education is an area where we still need to do better—particularly, asking patients with premalignant lesions or intraepithelial neoplasia about their vaccination status and whether they still need to complete the HPV vaccination series. Moreover, we should recommend clinical trial participation when appropriate. Ongoing clinical trials are evaluating multilevel intervention approaches for initiating HPV vaccination in children 11-12 years of age and assessing whether intervention also increases catch-up vaccination in patients 13-26 years of age (NCT05496231) and patients with HPV-associated premalignant lesions and cancers (NCT04131413, NCT04432597, NCT04580771). HCPs should encourage clinical trial participation as another avenue for educating about and encouraging HPV vaccination.
Maria Avila-Wallace, NP:
Many vaccination-eligible patients still are attending gynecology and colposcopy clinics. At my institution and associated satellites, I frequently encounter patients 35-45 years of age who present for evaluation of Pap smear abnormalities and HPV infections and who are interested in HPV vaccination. Most are hoping to clear the infection with such a strategy, but studies are limited regarding the efficacy of HPV vaccination after 30 years of age and suggest a lower or shorter-lasting immune response.12-14
For these patients, guideline-recommended screening and early detection remain the best strategies to prevent incidence and mortality from cervical cancer. Current guidelines recommend cervical cancer screening in patients 25-29 years of age every 5 years with cytology alone.15,16 Patients 30-65 years of age can undergo screening every 3 years with cytology alone or every 5 years with high-risk HPV testing alone (if 25 years of age) or in combination with cytology. Patients in whom we find more advanced precancerous lesions are those who have not been screened regularly in the previous 10 years. Unfortunately, that remains the reality of most cervical cancers we see.
Conversations About Treatments With Patients: Improving Equity in Delivery of Gynecologic Cancer Care
Maria Avila-Wallace, NP:
As molecular biomarker and genomic testing that directs treatment in gynecologic cancers becomes increasingly more prevalent for all patients in our institution, we are introducing these conversations earlier during phases of care. Telehealth offers additional time and opportunities for conversations and discussions, adding more convenient patient access to education, genetic counseling, and other clinical resources.
Some patients may respond differently to conversations about screening, molecular biomarkers, and treatments. Initially, a fundamental challenge can be if the patient is non‒English speaking. Long dialogues may ensue, including with interpreters and/or family members, which will require HCPs to provide additional resources and often personal time to deliver an equitable level of care. This clinical need has given rise to a growing bilingual workforce of HCPs to care for patients with gynecologic cancers—of which I am a strong supporter. Another challenge we often encounter is the high copay of cancer therapies, particularly for patients who are underinsured or have no insurance coverage at all.
At our institution, strategies to address inequality have led to novel initiatives and programs that include funding for individuals from high-risk communities with diverse cultural and ethnic backgrounds to help enrich the profession and offer high-quality cancer care that is both language appropriate and culturally appropriate.
Eva Y. Pan, PharmD, BCOP:
We have noticed some gaps with insurance coverage for certain groups. Where I practice, I have noticed a few insurance providers denying or delaying molecular or genetic testing coverage for patients with ovarian cancer. We also have had difficulty getting coverage with some state of Connecticut‒specific insurance providers and, to a lesser degree, private insurance. In my experience, patients with Medicare tend to be most vulnerable due to high copays but also may benefit from available financial assistance programs. In addition, some of the companies providing tumor profiling services may have financial assistance programs, and most of our patients can qualify for them with zero copays.
At Yale, we have a medication assistance program (MAP) that helps patients with copays and covers the cost of their medication. Our specialty pharmacy staff routinely reaches out to the MAP to refer patients who have high copays or may need additional financial assistance. Although we have seen improvement in access to PARP inhibitors over the years, a significant challenge for all patients with advanced epithelial ovarian cancer remains talking with HCPs about managing the costs of these treatments. Most patients pay thousands of dollars in monthly copays, which can be a significant financial burden, especially as they continue taking their medication for several years. On the other hand, we also may be able to get free/low-cost medication from the manufacturer via a clinical trial or use copay cards if/when available.
Pharmacists should inform all patients about ways they can empower themselves to lessen the impact of the costs of their cancer treatment—particularly those with Medicare/Medicaid insurance. These include:
I also agree with Maria that older, underinsured, and non‒English speaking patients are at a higher risk of not consistently filling their medications or following up with a treatment program. Oncology pharmacists should consider whether patients fall within these risk categories and facilitate access to resources as appropriate.
Maria Avila-Wallace, NP:
Financial toxicity is an enormous barrier in the delivery of equitable cancer care. At Massachusetts General Hospital, social workers are an integral part of the care team and a high-value resource in helping patients gain access to support programs, which may include transportation (ground and air), childcare, rent and utilities, and medication assistance, among others.
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