By Krystal Redman (KR), DrPH, MHA, (they/she), Executive Director
The most common cause of hereditary breast cancer is an inherited mutation in the BRCA1 or BRCA2 gene. BRCA1 (BReast CAncer gene 1) and BRCA2 (BReast CAncer gene 2) are genes that produce proteins that help repair damaged DNA. Everyone has two copies of each of these genes—one copy is inherited from each parent. In normal cells, these genes help make proteins that repair damaged DNA but mutated versions of the genes can lead to abnormal cell growth, which can lead to cancer (cancer.gov, Dec 2022). Approximately 5% to 10% of breast cancers are hereditary. Hereditary cancer essentially means that cancer runs in your family, and could be caused by a change in genes that you inherit from biological parents (cancer.gov, Dec 2022).
When one thinks of genes, cancer does not usually come immediately to mind. We usually think about whether we inherited our eye color, dimples, handedness, hair texture, height, or maybe even blood type. You typically do not consider hereditary breast cancer. And certainly most people do not imagine a lifelong schedule of recurring MRIs and/or mammograms starting in their adolescent years. Although you cannot change your genetics or family history of breast cancer, being aware that you are at higher risk can help with acquiring more knowledge about your body, decision making, and creating an early detection plan to detect breast cancer in its earliest stages.
Some people with a family history of breast cancer may choose to participate in genetic counseling and genetic testing to see if they have inherited the genes that increase the risk of the disease. Family history is one of the unavoidable genetic risk factors for developing breast cancer but the genetic landscape of inherited breast cancer is broad, ranging from high and moderate penetrance pathogenic variants [how likely it is that a person who has a certain disease-causing mutation (change) in a gene will show signs and symptoms of the disease] in breast cancer susceptibility genes, to polygenic risk [a measure of your disease risk due to your genes] associated with the cumulative impact of single nucleotide polymorphisms (SNPs) [biological markers that aid scientists in locating genes that are associated with disease].
In the session titled Cancer Risks in Patients with Moderate Penetrance Gene Mutations and led by Dr. Payal D. Shah, MD, there was a heavy focus on reviewing the landscape of inherited breast cancer. The discussion focused on breast cancer susceptibility genes associated with moderately elevated risks of breast cancer including Partner and Localizer of BRCA2 (PALB2), Ataxia-Telangiesctasia Mutated (ATM), Checkpoint kinase 2 (CHEK2) and others. Within the presentation of recent data informing quantitative and qualitative cancer risk estimates, “management and treatment strategies” were briefly discussed. The study postulated that multiple germline genetic variants [a gene change in a reproductive cell (egg or sperm) that becomes incorporated into the DNA of every cell in the body of the offspring that can be passed from parent to offspring, and is, therefore, hereditary. This is also called a germline mutation.] increase the risk of breast cancer.
Further, the study looked at how a polygenic risk score (PRS) might impact management of cancer risk in carriers of moderate risk pathogenic variants (PVs). Dr. Shah stated that PRS provides a more precise estimate of lifetime risk allowing for reclassification of some individuals as having low or population-level risk. This allows for more precise age-specific estimates of cancer risk, thereby impacting the age at which high-risk screening begins.
It was found that the treatment of breast cancer associated with moderate penetrance genes is largely similar to that of breast cancer without a PV. Importantly, Dr. Shah noted that there is a scientific need for additional studies, particularly those including women of diverse ancestry, before PRS is incorporated into practice. And, that “forthcoming data on contralateral breast cancer risk will likely inform discussions with patients.”
In a linked presentation entitled Screening for high risk patients: Does everyone need annual MRI with mammogram? led by Dr. Madeleine M.A. Tilanus-Linthorst, MD, PhD, it was noted that, to reduce mortality, all guidelines advise women with very high breast cancer risk, due to a PV in genes like BRCA 1 and 2 or receiving chest wall irradiation between age 10-30 years of age, to undergo annual screening with magnetic resonance imaging (MRI) and 2D or 3D mammography (Mm). For MRI, the starting age for this group is usually 25 years. However, for Mm, some guidelines advise annual screening, starting from age 30 years of age. US and Canadian, but not European, guidelines advise MRI screening also for women with a ≥ 20% lifetime breast cancer risk, while the European guideline, unlike the US and Canadian, now advises women with extremely dense breasts to screen with MRI, although not annually.
One of the many concerns to note is that there are a multitude of indicators that influence dense breast tissue in patients. For instance, it is a known fact that Black women and patients younger in age are more prone to having dense breast tissue. So what guideline is used to determine frequency of MRI or Mm in these patients?
Another concern is the high false positive rate and possible overdiagnosis and unnecessary costs that are inevitably associated with screening. Dr. Tilanus-Linthorst states that “we need to balance the possible benefits with the disadvantages of screening…” [with MRI and Mm]. She suggests, based on the study, that screening for women at high risk can be better tailored to the age and risk group. For instance, it was noted that MRI detects significantly more cancers at an earlier stage but also yields more false positive results. For moderate breast cancer risk, annual screening with MRI is recommended for ages 35-60 years and Mm for ages > 60 years. Within the US, the threshold ages of 35-60 years should be screened with only MRI every 18 months while ages > 60 years should have biennial mammography.
Neither study highlighted the importance of patients’ demographics. They did not explore if demographics might modify the association between genetic risk factors and breast cancer. How about the environment? Or what about the association between the density of breast tissue and demographic groups?
Overall, Dr. Shah noted that mastectomy can be an option but should be considered through “shared decision-making” but what about cost, recovery, barriers to aftercare, etc.? Patients have full autonomy on the choice of screening modality, whether it be mammography, MRI, self-exam, mastectomy, or a combination of any or all of these options OR to do nothing at all. So many questions come to mind — starting with, risk does not mean diagnosis, so does “relative risk” justify the great push for MRI and mammograms? How can one study or paper change screening recommendations for patients at large? And, what are the potential implications of this on under-resourced, under-insured, and marginalized groups? The pressure from practitioners toward MRIs and mammograms is exhausting. Where is the push for patient education, autonomy, and power over our bodies?
The “management and treatment strategies” offered by scientists and practitioners are annual MRIs and Mms. This is not a patient-centered comprehensive strategy. The shift in guidelines and clinical recommendations based on a few ungeneralizable studies can potentially have severe unintended outcomes and impact. As I noted above, there is bound to be a grave increase in rates of false positive tests and misdiagnosis. Have the psychosocial and emotional or financial impacts been considered here? Not to mention, the studies did not look at the association between other (less invasive and harmful) screening tools such as self-examinations and if there was any correlation to an increase or decrease in mortality rate. So, without clear evidence regarding the impact (or lack thereof) of less invasive and cost efficient strategies on the rates of breast cancer, why aren’t less costly, less harmful approaches being recommended to all patient groups?