FOUR MOLECULAR VARIANTS EXPLAINED
Hearing your doctor utter the words HER2-positive, HR-positive, triple-negative, or BRCA mutation can be devastating — even for the most resilient person. Simply put, breast cancer is a complex disease. A diagnosis can be derived from any combination of the factors listed above — or none at all.
The National Cancer Institute (Bethesda, MD) has outlined four molecular subtypes of the disease. Each subtype is categorized by cancer’s hormone receptor (HR) status and the level of expression from the HER2 gene. These cellular distinctions lead patients on different treatment journeys because the cancer subtype determines the drugs used in a treatment plan.
This article presents a quick primer on the science behind HER2-positive, HR-positive, triple-negative, and the BRCA gene.
HER2-positive (HER2+) breast cancer patients — about 20% of all breast cancer cases — have the most highly effective therapies available on the market. HER2+ cancer cells produce, and therefore present, larger than normal numbers of the HER2 receptors on their cell surface. These HER2 receptors capture growth factors, which trigger the cell to grow and reproduce more rapidly than normal. Mutations are more likely with rapid reproduction; thus, a tumor is born.
The overexpression of the HER2 receptor results from having extra copies of the HER2 gene — known in the world of genomics as gene amplification. Gene amplification events are thought to be caused by mutations that occur after a person is born — it is not an inherited form of cancer.
Genentech’s (South San Francisco, CA) Herceptin is a monoclonal antibody that binds to and blocks the activity of the HER2 receptor on cancer cells. When the HER2 receptor is blocked, the HER2 growth factor can no longer bind and send a growth signal to the cell, so the cancer cells stop dividing. The presence of an antibody on the surface of HER2+ breast cancer cells also signals the patient’s immune system to attack that cell.
Kadcyla, also made by Genentech, is an antibody-drug conjugate — a monoclonal antibody that delivers a highly toxic drug directly to HER2+ breast cancer cells. Kadcyla binds the HER2 receptor-like Herceptin but also delivers a toxic payload (which is actually attached to the monoclonal antibody). As a normal part of the cell’s lifecycle, cell-surface receptors get internalized or “taken up” by the cell on a regular basis. When Kadcyla is attached to a receptor that gets internalized, the toxic payload is released from the antibody and kills the cancer cell internally.
About 70% of breast cancer diagnoses involve a significant number of receptors for either estrogen or progesterone, making them hormone receptor-positive (HR+). HR+ cancers may respond positively to treatments that block either the action or the production of estrogen. In some cases, these treatments may continue to be used for up to five years after initial treatment in order to prevent a recurrence.
Two common types of medication for HR-positive breast cancers are Tamoxifen and aromatase inhibitors. Both types of drugs may also be prescribed as a preventive treatment in women who are at high risk for breast cancer. In fact, Tamoxifen is named on the World Health Organization’s List of Essential Medicines, a list of the most important medications needed in a basic healthcare system.
Tamoxifen works by inhibiting the estrogen receptor and was originally discovered by AstraZeneca (London, U.K.). On the other hand, aromatase inhibitors block the production of estrogen by inhibiting an enzyme whose activity is required for estrogen production. The different aromatase inhibitors on the market include Arimidex (AstraZeneca), Femara (Novartis; Basel, Switzerland, and Aromasin (Pfizer; New York, NY).
Selective estrogen receptor degraders (SERDs) are drugs that bind to estrogen receptors and cause them to be degraded. Fewer estrogen receptors mean that the cells receive growth signals from estrogen. Currently, there is only one selective estrogen receptor degrader approved — Faslodex, marketed by AstraZeneca. On January 30, 2023, the U.S. FDA approved ORSERDU™ (elacestrant) by Radius Health (Waltham, MA) for the treatment of postmenopausal women or adult men with ER+, HER2-, ESR1-mutated advanced or metastatic breast cancer that has progressed after at least one line of endocrine therapy.
Another new class of therapies for estrogen-receptor-positive breast cancer are small molecule inhibitors of cellular enzymes known as cyclin-dependent kinases (CDKs). CDKs promote the development and division of cancer cells, and inhibiting CDKs help to arrest cancer growth.
The first CDK inhibitor, Ibrance (Pfizer), was approved in 2015. Kisqali (Novartis) was approved in March of 2017, and Eli Lilly’s (Indianapolis, Indiana) Abemaciclib (Verzenio) was approved by FDA On March 3, 2023.
Triple-negative breast cancers lack receptors — they are estrogen-receptor-negative, progesterone-receptor-negative, and HER2-negative. Since there are no receptor drug targets, this subtype is challenging to treat, and there are no targeted therapeutics to date. If detected early enough, triple-negative breast cancer may respond well to chemotherapy.
THE BRCA GENE
BRCA stands for “BReast CAncer susceptibility gene,” and everyone has the BRCA 1 and BRCA 2 genes. The job of BRCA is to scan cellular DNA for damage and trigger DNA repair processes when mutations are found. BRCA genes are passed down from one generation to the next — a good thing, unless the version passed down is a mutated variation.
Mutated BRCA1/2 genes are non-functioning, so they cannot locate DNA damage, nor can they enlist DNA repair. Testing positive for BRCA1/2 mutations may indicate there is an accumulation of DNA damage, which may eventually lead to cancer. BRCA is normally active in breast and ovarian cells, which is why certain mutations in BRCA1/2 are associated with a significantly increased risk of developing breast or ovarian cancer. It must be stressed that BRCA1/2 mutations in and of themselves do not cause cancer; they simply make it more likely to occur.
A new class of drugs known as PARP1 inhibitors gives hope to women whose breast cancer is associated with non-functioning BRCA genes. PARP1 is a second type of DNA repair protein. By inhibiting this pathway, DNA damage becomes so extensive that the cancer cells commit “cell suicide” (or apoptosis.) When the cell in question is a cancerous cell, apoptosis is a very good outcome.
The first FDA-approved PARP1 inhibitor drug, Lynparza (AstraZeneca), was approved for BRCA-associated ovarian cancer in December 2014. Clovis Oncology (Boulder, CO) achieved the second FDA approval of a PARP1 inhibitor, Rubraca, in December 2016, and Tesaro (Waltham, MA) garnered the most recent approval in March 2017.
Not all triple-negative breast cancers are BRCA-associated, but many BRCA-associated cancers are triple-negative. For this reason, triple-negative breast cancer patients may find hope in PARP1 inhibitor drugs.
Breast cancer is a complex disease, and a better understanding of its molecular causes has enabled researchers to develop more effective therapies. As our understanding of the disease continues, we can expect to see additional novel therapeutics.