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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 has outlined four molecular subtypes of the disease. Each subtype is categorized by the 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.

In this WEEKLY, we present a quick primer on the science behind HER2-positive, HR-positive, triple-negative, and the BRCA gene.

HER2-POSITIVE

HER2-positive (HER2+) breast cancer patients—about 20 percent of all breast cancer cases—have the most highly effective therapies available on the market. HER2+ cancer cells present greater than normal numbers of the HER2 receptors on their cell surface. These HER2 receptors bind growth factors, which trigger the cell to grow and reproduce more rapidly than normal. Mutations are more likely with rapid reproduction and thus, a tumor is born.

Overexpression of the HER2 receptor is the result of 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 life cycle, 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.

HR-POSITIVE

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 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.

Both drugs work by blocking estrogen’s growth-stimulating effects on HR-positive breast cancer cells. Tamoxifen is a small molecule that was originally discovered by scientists at AstraZeneca (Cambridge, England) in the 1960s. Tamoxifen binds estrogen receptors and prevents them from transmitting growth signals to the cell.  Aromatase inhibitors block the production of estrogen by inhibiting an enzyme whose activity is required for estrogen production. No estrogen, no estrogen signaling. 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 means that the cells receive fewer growth signals from estrogen. Currently, there is only one selective estrogen receptor degrader approved – Faslodex, marketed by Astra Zeneca (Cambridge, England). Other SERDs in clinical development include Elacestrant (Phase 2; Radius Health (Waltham, MA)); AZD9496 (Phase 1; AstraZeneca), and SAR439859 (Phase 1; Sanofi (Paris, France)).

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 helps to arrest cancer growth.

The first CDK inhibitor, Ibrance (Pfizer) was approved in 2015. Kisqali (Novartis) was approved in March of 2017, and Eil Lilly’s (Indianapolis, Verzenio was approved in September of 2017.

TRIPLE-NEGATIVE

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 to date, there are no targeted therapeutics. 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 small molecule 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.

Several PARP1 inhibitors are already on the market, including Lynparza (AstraZeneca), Clovis Oncology’s (Boulder, CO) Rubaca, Zejula (Tesaro Pharmaceuticals; Waltham, MA), and Pfizer’s Talzenna.

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.

The WEEKLY will be taking a hiatus for the next two Thursdays to enjoy the Winter holidays. See you in 2019!

Co Authors :

Sarah Van Tiem

Editor

Sarah Van Tiem began her career with Detroit Legal News, gaining unparalleled experience in public communication. Subsequent stints at Earthwatch Radio and Wisconsin Department of Natural Resources established Sarah as a respected writer/editor. Currently working as Editor for the Biotech Primer WEEKLY newsletter, Sarah is widely known for her expertise in science communication.

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