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�Surviving, Previving, and Thriving:�Prioritizing Prevention for our Patients�

Andrea Hagemann, MD, MSCI

Associate Professor of Obstetrics and Gynecology

Division of Gynecologic Oncology, Washington University School of Medicine

February 2022

hagemanna@wustl.edu

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Disclosures

I have no financial disclosures
I will refer to genetic testing companies by name
I grew up in Minnesota

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Objectives

Describe current strategies for genetic counseling, testing and cancer risk management

From BRCA1 to keeping up with expanding guideline-based care!

Describe the preventive impact of cascade genetic testing, and better understand barriers and facilitators

Describe considerations in gynecologic cancer risk reduction for BRCA1/2 mutation carriers

How will you advocate for prevention and survivorship as an Ob/Gyn?

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Very excited to be here today, an honor to speak to you all about a topic—hereditary cancer risk assessment—that has expanded rapidly over the past few years. I want to stress that this is a topic too big for one person, or one division. But I think it’s a PERFECT topic for our Dept of Ob/Gyn, made up of amazing individuals advocating for improved healthcare at every step of the reproductive lifespan. So as you listen, think about opportunities for collaboration. Think about how we can prevent cancer and help each other survive and thrive longer.

Importance of collaboration among specialties so that our system grows stronger and our patients are healthier for it.

Very excited to update you on prevention research. Caveats to US and CA-125

Salpingectomy with delayed oophorectomy, Hormone replacement options

Combination Breast/Gyn surgeries

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Our discussion today is about the role we all can play in moving from precision oncology care to precision prevention.

Perhaps one of the biggest proponents for population-based testing for BRCA1/2 gene mutations is

Dr. Mary Claire King, the geneticist who discovered BRCA1 on chromosome 17 in the early 90s. won her greatest fame by working in Argentina with a human rights group, the Grandmothers of Plaza de Mayo, attempting to reunite, with their families, children who were kidnapped in the 1970's and early 1980's by the Argentinian military. By using mitochondrial DNA from the grandmas, she was able to match the missing daughters and infants—a true human rights activist. While she had studied math, it was the human stories found in genetics research that really kept her motivated.

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J Clin Invest. 2014 Oct 1; 124(10): 4148–4151.

Discovery & History of BRCA1/2

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The French physician Pierre Paul Broca was the first to describe inherited breast cancer in 1866 (3), but modern epidemiological techniques were first applied to the disease by Janet Lane-Claypon in 1926 (4). In 1988, Dr. King demonstrated that some forms of early-onset familial breast cancer are heritable (7); in 1990, she showed that some heritable breast cancers are linked to a gene found on chromosome 17q21 (9). BRCA1 was cloned and sequenced by a group lead by Mark Skolnick of Myriad Genetics in 1994 (15); since they were officially the first, Myriad was able to patent BRCA1/2. The first commercial test for mutations in BRCA1 and BRCA2 was brought to market in 1996. The test was very expensive—hard to market, since it only needed to be done once. BRCA1/2 were not the first genes to be patented, but stories of women who were diagnosed with later stage cancers and couldn’t access testing drove the ACLU to question this legal precedent. In 2013, the Supreme Court ruled that, as products of nature, genes could not be patented (18).

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BRCA1/2 and Homologous Recombination Deficiency in Ovarian Cancer

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Case Studies

Sunni, a 41 yo G1P0010, presents with a pelvic mass and elevated CA-125.

Sunni noted 3-4 weeks of increased abdominal pain and swelling. She did present to the urgent care a week prior and was given a script for Cipro for a UTI. When the pain kept increasing, she presented again to the ED where a CT showed a 10 cm pelvic mass, omental nodularity, and an elevated CA-125 of >5000.

Inguinal lymph nodes

12 x 14 cm pelvic mass, ascites

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Sunni’s family history and treatment course

She notes a family history of her mother with breast cancer at age 52, and her maternal grandmother with breast cancer, as well. Her mother is alive at age 78, s/p chemo/radiation and lumpectomy for her breast cancer at age 52. Her brother had prostate cancer and is doing well after treatment.

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Case Studies

Sandi, 54 yo G2P1013, presented with chest pain and shortness of breath.

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Case Studies

Sandi, 54 yo G2P1013, presented in July 2016 with chest pain and shortness of breath.

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Sandi’s family history and clinical course

Her family history is notable for her mother and two sisters with breast cancer and another sister with melanoma. Her Sister age 56 at diagnosis has triple negative breast cancer and was recently diagnosed with a BRCA1 mutation.
Her other sister has had triple negative breast cancer also diagnosed around age 56. Her BRCA testing was inconclusive.
Mother had breast cancer at age 49-50.
Sister had melanoma on her labia at age 21.
Brother later diagnosed with prostate cancer.

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Strategies for Identification of Germline Mutations

Test everyone

Population-based screening for BRCA1/2
General population screening

Test if strong family history of cancer

Detailed, multi-generational family history

Test individuals with a cancer diagnosis

Germline testing
Somatic testing
Traceback testing

Test an enriched population

Cascade genetic testing

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So how do we find these mutations? Multiple strategies have been proposed to identify patients for germline genetic testing. As we talk through them, consider which strategy fits your clinic population. Population based genetic testing has been proposed. Such a strategy has become increasingly realistic with decreasing cost and increasing availability of genetic testing. However, it would require increased genetic counseling resources to feasibly and equitably reach the target population and to explain the results to that patient and their relatives.

More traditionally, patients can be identified based on a detailed multi-generational family history. This strategy requires clinicians or genetic counselors to take and update family histories, to recognize when a patient requires referral for testing, and for such testing to be completed. Even then the generation of a detailed pedigree is not very sensitive or specific.

As a gyn oncologist, I’ve come to this topic by this third approach—the explosion of precision therapeutics in cancer care—we can start by testing the tumor, sometimes germline, sometimes both. Guidelines are rapidly changing and we’re doing our best to keep up as precision treatment options such as PARP inhibitors or immunotherapy options expand cancer care.

A related testing model is traceback testing where genetic testing is performed on pathology or tumor registry specimens from deceased patients with cancer [7]. This genetic testing information is then provided to the family. Traceback models of genetic testing are an active area of research, but can introduce ethical dilemmas.

Finally—and here’s where we need to work together as a department—we can test the enriched population of family members of a patient with cancer who has been found to carry a pathogenic variant in a clinically relevant cancer susceptibility gene. This type of testing is termed cascade genetic testing. Cascade testing in first-degree family members carries a 50% probability of detecting the same pathogenic mutation.

As an oncologist, diagnosing a BRCA-related ovarian cancer in a 60 year old feels like a missed opportunity for prevention.

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Palag Hasson et al. Pharmacogenomics and Personalized Medicine 2020:13

Breast Cancer

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Ovarian Cancer

Kathryn P. Pennington et al. Clin Cancer Res 2014;20:764-775

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Kastrinos et al, 2020, Gastroenterology Vol 158, No 2

Colon Cancer

Endometrial Cancer—Somatic

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Point-of-Care Testing in CAM13C Gyn Onc Clinics

All epithelial ovarian cancer patients, MMR-d endometrial cancers, others
Expanding to generalist Ob/Gyn clinics

Similar process to prenatal genetic testing

New! COH3 testing now available! Workflow and educational materials
Next up—COH7

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Barriers to Cascade Genetic Testing

HIPAA
Proband shoulders most of the burden—how can we help them?
Testing options vary everywhere
Access to testing, follow up
Worry

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Barriers-Provider Factors

Interpretation of genetic testing results
Whose job is it?

Generalist Ob/Gyn
Primary care physician
Medical oncologist
Gynecologic oncologist
Breast surgeon
Genetic counselor
Gastroenterologist
Urologist

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Provider Factors

Provider factors that affect cascade genetic testing include awareness of testing guidelines, interpretation of genetic testing results and education and knowledge of specific mutations. For instance, providers must recognize that cascade testing is not appropriate for variants of uncertain significance (VUS). This can lead to unnecessary surveillance testing and prophylactic surgeries. Providers, however, must continue to follow patients and periodically update testing results as variants may be reclassified over time. Additionally, providers must be knowledgeable about the complex and nuanced nature of the screening guidelines for each mutation. The National Comprehensive Cancer Network provides detailed recommendations by mutation (NCCN guidelines). Patients may benefit from care with cancer specialists who are aware of the guidelines, particularly for moderate-penetrance genes like BRIP1 and PALB2, as discussions about the timing of risk-reducing surgery are more nuanced in this population. Finally, which providers are responsible for facilitating cascade testing may be unclear; oncologists and genetic counselors not primarily treating probands’ relatives may assume the proper information has been passed along to family members without a practical means to follow up, and primary care providers may assume it is being taken care of by the oncology provider.

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Can a toolkit introduced to oncology providers and cancer patients improve the rates of cascade genetic testing?

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Mixed Methods Study with Introduction of a Toolkit

Provider Interviews
Proband Surveys
Invitation to Family Members for Surveys

Primary outcome: Rates of cascade genetic testing in first degree relatives after the introduction of the Families Accelerating Cascade Testing Toolkit

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Provider Interviews: Siteman Cancer Center

Semi-structured interview guide included questions about:

processes for genetic testing
barriers and facilitators to cascade genetic testing
resources for cascade testing

Conducted interviews with 28 providers across 7 specialties
Audio recorded and transcribed interviews
Utilized a thematic analysis approach that involved 3 phases: Immersion, Reduction, and Interpretation

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How is testing currently being performed across Siteman?

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Facilitators

Theme	Exemplar quote
No or low-cost testing helps overcome barriers to testing	“... the lab that we work with… will do free family testing for 150 days. That's Invitae. We also will often work with Ambry, and they are doing free family testing for 90 days, which is the more standard. Invitae expanded theirs because of COVID. That also helps overcome a potential barrier of cost.”
Telehealth helps facilitate genetic counseling for family members	“...telemedicine… has made a huge difference in getting people testing that they wouldn’t otherwise have access...”
Screening guidelines help providers determine appropriate action	“…if they [patients] don’t meet strict NCCN criteria but they have a family history, I’ll refer them to genetic counseling. If they meet the criteria based on NCCN, I typically will send off panel testing for them.”
Department prioritization, when present, increases the frequency of testing	“We feel strongly about having it done… Actually, there’s… very few times, that I have had to do testing on someone who meets criteria because their surgeon, a lot of times, has already done it. I definitely think that comes down from just all our physicians being very good at what they do. Then I’m thinking the leadership probably has been very good at that as well.”

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Theme	Exemplar quote
Cost, insurance coverage and insurance changes are key concerns for patients & families	“A lot of patients don't know what the cost will be for their family members. I know a lot of the testing centers will allow a family member to get abbreviated costs and stuff, but… a cost that's abbreviated may be okay for me, but not for you. Financial burdens are really real.” “...fear of persecution, or not being a candidate for life insurance policies, or affecting future healthcare coverage, and all of the things that we have to try to do to educate people about.”
Health literacy and education are key determinants to family testing	“Some of these people are more plugged in and have an easier time navigating the health care system. Probably health care literacy. I would say that's probably the… biggest one [barrier].”
Family dynamics influence communication and follow through for cascade testing	“…we will fairly often see disrupted family. If the patient doesn't communicate about other things, she's not going to talk to people about a sensitive topic like genetic test results.”
Some patients and families feel fear around genetic testing	“I say “fear” because a lot of family members, they don’t wanna know, or they’re scared.”

What are barriers to testing: Patient Level

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What are barriers to testing: Provider & system

Theme	Exemplar quote
Dissatisfaction with EHR documentation systems for tracking genetic testing	“I'm not satisfied with how genetic testing results coming from companies is reported in Epic… what ends up happening is it gets into some random tab in media, or you get it set in some random genetic counsellors note, or your note or My Note has like an iPhone picture of something that doesn't fit into things.”
Lack of systematic workflows for discussion & referral for cascade testing	“We don't have a really good systematic approach to it [cascade testing] because even if they do have an interest in it, then we gotta get them referred and make sure to follow up that they actually saw the counselors and got follow-up.”
Lack of tools and resources makes it difficult to have conversations about cascade testing	“I just don’t have the language on the tip of my tongue. I don’t have like a package of resources, so that the patient could simply provide it to their family members, or have that conversation itself. I don’t think I empower my patients to go out and talk to their family and their relatives about it.”
Difficult to contact family members for testing	“... there's the HIPAA aspects to it as well. Obviously we can't just cold call people and reach out and say, ‘Hey, we know you're at risk.’ I think that that always creates a barrier, being able to work with a family member to be able to get notice out and information out to them.”

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At the provider and system level a common theme was dissatisfaction with the electronic health record for tracking genetic testing, with providers frustrated with how difficult genetic testing results are to find. Providers also identified lack of systematic workflows for cascade genetic testing and lack of tools and resources for having conversations about cascade genetic testing. One provider stated I just don’t have the language on the tip of my tongue. I don’t have like a package of resources, so that the patient could simply provide it to their family members or have that conversation themselves. I don’t think it empowers my patients to go out and talk to their family and relatives about it. Another common barrier was providers felt they couldn’t test family members because that person was not their patient.

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Can a toolkit introduced to oncology providers and cancer patients improve the rates of cascade genetic testing?

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Risk Management—What’s next after a positive test?

Guideline-based care discussions
Caveats to US and CA-125
Risk-reducing BSO?
Hysterectomy?
Salpingectomy with delayed oophorectomy
Preimplantation genetic testing?
Hormone replacement options
Combination Breast/Gyn surgeries
Colon screening or surgery
Pancreatic screening?

This Photo by Unknown Author is licensed under CC BY-ND

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‘Precision Prevention’ is a prevention strategy which incorporates individual variability in non-genetic (e.g. environment, epidemiologic, hormonal, lifestyle, behavioural), as well as genetic and even epigenetic risk-factors. This comprises both primary prevention (disease prevention) and secondary prevention (screening/early-detection).

Crucially, early recognition enables women to proactively participate in high-risk screening programs, chemoprevention and risk-reducing surgery. These clinically effective preventative strategies have a substantial impact on reducing the morbidity and mortality of women's cancers [[8], [9], [10], [11]]. Furthermore, knowledge of carrier status provides opportunity for making lifestyle and reproductive choices, preimplantation genetic diagnosis during family planning, as well as cascade testing in other unaffected relatives.

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Gyn Onc

Ob/Gyn

Breast Surgeon

Plastic Surgeon

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BRCA-associated breast and ovarian cancer risks

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Women choosIng Surgical Prevention

https://clinicaltrials.gov/show/NCT02760849

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Importance: Risk reducing salpingo-oophorectomy (RRSO) is an effective option to prevent ovarian cancer in high-risk women, but side effects related to premature menopause remain a barrier to uptake.

400 patients from 9 sites were enrolled.

Objective: To determine change in sexual function and other menopause-related symptoms in women self-selecting ISDO versus RRSO with and without post-operative hormone replacement therapy.

Design: Prospective, multi-center, non-randomized trial

Setting: Nine U.S. academic cancer centers.

Intervention: Interval salpingectomy and delayed oophorectomy versus risk-reducing salpingo-oophorectomy.

Main Outcomes and Measures: Baseline, 6 and 12 month questionnaires regarding sexual function (primary outcome), menopausal symptoms, and other outcomes were collected. A safety stopping rule was employed to prevent an unacceptable rate of invasive cancers in the ISDO arm.

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Manuscript submitted

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SO-ROCk Trial here at Missouri Baptist

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Discussion topics

How does/should management of ovarian/fallopian tube health differ for patients who have had

breast cancer versus not?

ER/PR+ versus -

RRM versus breast surveillance?

Hormone replacement options in surgical considerations -- making sure our patients are hearing consistent messages about what is safe for both breast and gynecologic health

How do these trials fit in with combination breast/gyn surgeries?

How to best educate the community about these expanding options?

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Gynecologic Oncology Genetics Clinic

CAM13C
Started out of an urgent need to test our ovarian cancer patients, and a research interest
Multidisciplinary Dream
Current Team

1 Gyn Onc MD with City of Hope training
Coordinator Chelsea Walker
Genetic counselors

Susan Jones and Rachita Nikam

Gyn Onc nursing and MA support
Every other Wednesday afternoon

Changing patient makeup
Epic: Ambulatory Referral to Gyn Onc

Genetics Clinic/Hagemann in comments

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Cancer Genetic Counseling Referrals�

In Epic: Ambulatory Referral to Pediatric Genetics

If you don’t have Epic: fax a referral to 844-965-9624

Dr. Patricia Dickson Rachita Nikam, CGC Susan Jones, CGC

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Cancer Genetic Counseling Clinic Locations

New North County location

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High Risk and Hereditary Breast Cancer Clinic�Amy Cyr, MD, FACS, Department of Medicine

Tuesdays

Siteman North County
1255 Graham Road, Florissant

Wednesday afternoons

Siteman at Memorial Hospital East
1418 Cross Street, Shiloh, IL

Thursdays

Siteman South County
5225 Midamerica Plaza, Saint Louis

To place new patient referrals in Epic:
Ambulatory referral to oncology
Specify the location (currently there is no high risk breast provider at the CAM)
Add Dr. Amy Cyr as the provider to which you are referring

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Future Goals for Precision Cancer Prevention

Our Department of Ob/Gyn takes the lead in Precision Prevention

Hereditary Genetics
Weight management
HPV vaccination and cervical cancer prevention

Easy access to genetic testing and counseling for all
Improved electronic medical record and database management
Education

Continue outreach to promote awareness
Genetics cases at tumor board
Guideline-based checklists, more toolkits

Research

Grow clinical trials for prevention
Harness our strengths of busy clinical services and eager patient participation in clinical trials

Multidisciplinary Prevention Program—doesn’t have to/can’t be one clinic alone!

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Summary

Communication and collaboration between community practices and academic centers, and multidisciplinary collaboration for breast and gynecologic health, is of utmost importance to improve outcomes
NCCN guidelines are a starting point
Many options for hereditary cancer risk counseling and testing

Point of Care Testing in CAM and COH
Gyn Onc Genetics Clinic
Hereditary Breast Clinic with Dr. Cyr
Cancer Genetic Counseling through Department of Pediatrics

Growth opportunities for research, clinical training

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THANK YOU!

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Ovarian Cancer Screening Guidelines

Women with a risk near that of the general population (relative risk less than three times greater than that of the general public)

Ovarian cancer screening is not recommended. An annual gynecologic examination with pelvic examination is recommended for preventive healthcare.

Women with increased risk (relative risk of three to six times greater than that of the general public)

There is no clear evidence to suggest that ovarian cancer screening with currently available methods will result in a decrease in the number of deaths from ovarian cancer. If, after careful consideration of risks and benefits, ovarian cancer screening with serum markers such as CA-125 and/or transvaginal ultrasound is to be pursued, it is recommended that such screening be done within the framework of research studies to evaluate the efficacy of this approach.

Genetic counseling may also be helpful for women in this group to better clarify the risk of ovarian and related cancers.

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Who should have germline testing?

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Who should have germline testing?

Individuals meeting criteria but tested negative on previous limited testing

Prostate cancer histologies are expanded and include cribriform, high- and very-high-risk

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Who should have germline testing?

When testing is indicated because of family history of pancreatic or prostate cancer, it should only be offered to FDRs

Multiple cancers; don’t have to be bilateral

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New 2022 changes in germline testing eligibility

Testing criteria separated for breast, ovarian, pancreatic, and prostate cancer
TNBC at any age
Multiple (synchronous or metachronous)s breast cancers at any age

For women > age 50 with 2+ close relatives with breast or prostate cancer
To aid in surgical decision-making

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This most recent update separates testing criteria for breast, ovarian, pancreatic, and prostate cancer

Breast cancer testing eligibility changes include TNBC at ANY age—no longer under 60

The page detailing the recent updates states that testing can be considered for women with multiple primary breast cancers at any age, although I don’t actually see that guideline page updated so am going to reach out to NCCN about that inconsistency

Testing is also now indicated for older women with at least 2 relatives with breast or prostate cancer, any age, any grade

Potential impact on surgical decision-making is now included as an indication along with potential impact on systemic therapy decision-making.

Finally, NCCN notes that an individual does not need to meet testing criteria for every gene on a panel

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Caveats

Limited family structure
The possibility of more than 1 hereditary cancer syndrome
PRS are NOT yet appropriate for clinical decision-making
Autosomal recessive conditions and partner testing
Germline testing is needed to confirm actionable somatic testing findings

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NCCN guidelines have always included components of genetic counseling and have provided guidance on interpretation and implications of various results, but I want to call out a couple specific points

Some patients may not meet testing criteria but have a limited family structure—they may be adopted or have < 2 female first or second degree relatives living beyond age 45—this can itself be a criterion for genetic testing for women diagnosed at age 50 or younger

Polygenic risk scores, which are certainly promising and are now reported by various clinical labs—are not yet ready for prime-time when it comes to making clinical decisions. Stay tuned.

Finally, we need to do a better job of considering potential autosomal recessive conditions—several Fanconi Anemia pathway genes, for instance, are also breast cancer susceptibility genes. In these situations, partner testing needs to be discussed.

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We found a pathogenic variant. What’s next?�BRCA

Early detection: female

Age 18+ breast awareness

Age 25+ CBE Q 6-12 months

Age 25+ annual breast MRI

Age 30+ annual mammogram plus annual breast MRI

Age 30-35+ consider TVUS and CA-125

Age 75+ individualized

Surveillance is an acceptable option;

risk-reducing mastectomy is never mandatory, even for women with a breast cancer diagnosis

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We found a pathogenic variant. What’s next?�BRCA

Early detection: male

Age 35+ BSE

Age 35+ CBE Q 12 months

Age 40+ prostate cancer screening (recommended for BRCA2, consider for BRCA1)

Age 50+ (or 10 years prior to family male breast cancer) consider mammogram for men with gynecomastia

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ATM� BARD1 (TNBC)�BRIP1 downgraded for breast cancer management, but RRSO is an option�CHEK2 CRC risk downgraded�NBN downgraded for breast cancer risk�NF1 phenotype = increased risk, increased surveillance ages 30-50�PALB2 (TNBC)�RAD51C/D (TNBC)�TP53 (+/+/+)

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Autosomal recessive conditions

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What are our responsibilities?

First, do no harm
Counsel appropriately on the limits of germline testing (non-actionability of some variants or genes, changing recs on others, etc)
Offer germline testing for patients with these newer indications
We can use this info to improve their outcomes and those of their families
Don’t forget autosomal recessive conditions!

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Test Everyone?

Cost effectiveness

The incremental cost-effectiveness ratio was below the willingness to pay threshold of £30,000/QALY (ICER = £21,599.96/QALY) in the UK, as well as $100,000/QALY (ICER = $54,769.78) in the US.
This translates to potentially preventing an additional 17,505 ovarian cancer cases and 64,493 breast cancer cases in UK women, and 65,221 ovarian cancer and 237,610 breast cancer cases in US women.
Australia: BRCA1/2, MLH1, MSH2, cystic fibrosis, spinal muscular atrophy and Fragile X Syndrome extremely cost effective

Quality of life non-inferior
Abbreviated genetic counseling

DVD-assisted counselling for PGT is non-inferior to face-to-face counselling for increase in knowledge; counselling satisfaction; risk perception and is equivalent for uptake. 98% found DVD length/information satisfactory. 85–89% felt it improved understanding of risks/benefits/implications/purpose of PGT. 95% would recommend it to others.

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This question does keep coming up—should we just test everyone? Lizzo certainly has benefited and does not shy away from her results. But in all seriousness, Some research exists suggesting maybe.

The only caveat is making sure we have a system that can keep up with the testing, a landing place for people who test positive, and we ensure that results are interpreted and relayed in an effective way.

And herein lay the problem when we lost our genetic counselors in 2017.

More recently Manchanda et al. modelled the cost-effectiveness of PBGT for six high and moderate-risk OC and BC genes (BRCA1, BRCA2, RAD51C, RAD51D, BRIP1 and PALB2) [96]. In the UK & US modelling, multi-gene panel testing was more cost-effective than any FHM strategy (compared to FH-based BRCA testing alone or compared to FH-based panel testing). The incremental cost-effectiveness ratio was below the willingness to pay threshold of £30,000/QALY (ICER = £21,599.96/QALY) in the UK, as well as $100,000/QALY (ICER = $54,769.78) in the US. PBGT for this 6-gene panel on probabilistic sensitivity analysis was cost-effective in 83.7% and 92.7% simulations for UK and USA health systems respectively [96]. This panel-testing could prevent BC (2420/2386) and OC (657/655) in UK/US women per million [96]. This translates to potentially preventing an additional 17,505 ovarian cancer cases and 64,493 breast cancer cases in UK women, and 65,221 ovarian cancer and 237,610 breast cancer cases in US women. Of late, an Australian study showed that PBGT for BRCA1, BRCA2, MLH1, MSH2, cystic fibrosis (CF), spinal muscular atrophy (SMA) and fragile X syndrome (FXS) in an Australian population was extremely cost-effective (ICER = 7286 AUD/QALY) [97,98].