In an ABC News interview, actress Shannen Doherty told Amy Robach (herself a breast cancer survivor) that her breast cancer has returned and that it is now stage IV. The 48-year-old actress is best known for her roles in the original "Beverly Hills, 90210" and "Charmed."
Doherty was originally diagnosed in March 2015. At the time of diagnosis, she had "invasive breast cancer metastatic to at least one lymph node." She underwent mastectomy, chemotherapy, and radiation followed by reconstructive surgery. She shared a lot of her journey on social media and in 2017, was in remission. She reported that about a year ago, while filming a "90210" reboot, she was again diagnosed with breast cancer after experiencing some unusual pain. This time, she kept things quiet, filming 16 hours a day and telling only one castmate, Brian Austin Green, about her diagnosis.
Doherty is coming forward now because her diagnosis will be part of court documents, she said. She has filed against State Farm Insurance over claims the company denied when her home was damaged in the 2018 Woolsey fire in southern California. She preferred that "people hear it from me," she said. "I don't want it to be twisted. I don't want it to be a court document."
Robach asked Doherty how she is dealing with this second diagnosis: "I don't think that I've processed it," Doherty said. "It's a bitter pill to swallow in a lot of ways." She added: "I'm petrified; I'm pretty scared.... There are definitely days where I say, 'Why me?' And then I go, 'Why not me? Who else?' Who else besides me deserves this? None of us do."
Stage IV/Metastatic Breast Cancer
Stage IV breast cancer is another name for metastatic breast cancer (MBC). The most common distant sites for breast cancer are the brain, bones, lungs, and liver. Approximately 6% of female breast cancer patients are staged as having MBC at the time of their initial diagnosis ("de novo metastatic breast cancer"). In addition, nearly 30% of women initially diagnosed with early-stage breast cancer will develop MBC months to years after the initial diagnosis.
The symptoms of MBC vary according to the organ(s) affected. The most common symptoms include the following:
Bone
- Sudden onset of new pain
- Most common: ribs, spine, pelvis, long bones
Lungs
- Pain or discomfort in lungs
- Shortness of breath
- Persistent cough
Brain
- Headache
- Changes of speech or vision
- Memory problems
Liver
- Pain or discomfort in the midsection
- Fatigue and weakness
- Weight loss or poor appetite
Changing Prognosis
Although there is still no cure for MBC, recent treatments have prolonged the lives (and quality of life) of many people with stage IV breast cancer. Although median survival has been reported to be 18 to 24 months, some patients have long-term survival.
A 2017 study by researchers from the National Cancer Institute, Fred Hutchinson Cancer Research Center, and the Metastatic Breast Cancer Alliance found that the number of women in the U.S. living with MBC is growing. In addition, "the median and 5-year relative survival for women initially diagnosed with MBC is improving, especially among younger women."
The researchers estimated that between 1992-1994 and 2005-2012, the 5-year relative survival rate among women initially diagnosed with MBC at ages 15-49 doubled from 18% to 36%. Median relative survival time between 1992-1994 and 2005-2012 increased from 22.3 months to 38.7 months for women diagnosed between ages 15 and 49, and from 19.1 months to 29.7 months for women diagnosed between 50 and 64.
The analysis also found that a small but meaningful number of women live many years after an initial diagnosis of MBC. More than 11% of women diagnosed between 2000 and 2004 under the age of 64 survived 10 years or more.
Based on their calculations, the researchers estimated that the number of women living with MBC increased by 4% from 1990 to 2000 and by 17% from 2000 to 2010, and projected that the number will increase by 31% from 2010 to 2020.
Treatment of Metastatic Breast Cancer
As noted, the introduction of newer systemic treatments has led to meaningful improvements in survival for patients with MBC. As in all patients with breast cancer, tumor biology and clinical factors play an important role in determining a therapeutic strategy.
Biopsies of suspected lesions should be assessed for the molecular markers ER (estrogen receptor), PR (progesterone receptor), and HER2 overexpression. Mutations in tropomyosin receptor kinase and the presence of microsatellite-high/DNA mismatch-repair deficiency should also be evaluated. In addition, patients should undergo germline testing for BRCA1 and BRCA2 mutations.
Even if an original tumor was negative for the above mutations, conversion to positive is possible and could change therapy. A study by Aurilio et al. estimates that a discordance in ER, PR, and HER2 receptor mutations between a primary and recurrent breast cancer can occur in 5-30% of samples. This underscores the importance of rebiopsy.
Treatment of metastatic disease is palliative in intent. Goals of treatment include prolonging life and improving quality of life. Treatment recommendations are usually grouped by the molecular markers present.
Hormone Receptor-Positive (HR+) Human Epidermal Growth Factor Receptor 2 (HER-2) Negative
Endocrine therapy is favored over chemotherapy as initial therapy in most patients with HR+, HER2-negative MBC. While tamoxifen has been used for many years in treating postmenopausal women with newly metastatic disease that is HR+, several randomized trials suggest equivalent or superior response rates and progression-free survival for aromatase inhibitors compared with tamoxifen.
In premenopausal women, several randomized, but underpowered, trials have tried to determine whether combined hormone therapy (luteinizing hormone-releasing hormone agonists plus tamoxifen) is superior to either approach alone. Unfortunately, the results have been inconsistent.
Although endocrine therapy is recommended for patients with metastatic HR+ disease, patients inevitably develop resistance to endocrine therapy. Preclinical models and clinical studies suggest that mammalian target of rapamycin inhibitors might enhance the efficacy of endocrine therapies.
Products of the genes CDK4 and CDK6 have been implicated in the continued proliferation of hormone receptor-positive breast cancer resistant to endocrine therapy. CDK inhibitors have been approved by the FDA in both first- and later-line treatment of advanced HR+, HER2-negative breast cancer. Three oral CDK4/6 inhibitors are currently available: palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio).
Activating mutations in PIK3CA are identified in approximately 40% of HR+ and HER2-negative breast cancers. Alpelisib (Piqray) is an alpha-specific PIK3 inhibitor.
HR Negative (HR-) HER2-Negative Breast Cancer (Triple Negative)
The treatment for hormone receptor-negative breast cancer is chemotherapy. Several chemotherapeutic agents have been used alone or in combination in the treatment of MBC. There are no data suggesting that combination therapy results in an overall survival benefit over single-agent therapy. Single agents include anthracyclines, taxanes, alkylating agents, fluoropyrimidines, antimetabolites, vinca alkaloids, and platinum. Combination chemotherapy is often given if there is evidence of rapidly progressive disease or visceral crisis.
Atezolizumab (Tecentriq), an anti-programmed death-ligand 1 (PD-L1) antibody, can be added to first-line taxane-based chemotherapy for patients with triple-negative advanced breast cancer.
HR- HER2+
Antibody therapy targeting the HER2 pathway has been used since the 1990s and has revolutionized the treatment of HER2-positive metastatic breast cancer. Several HER2-targeted agents (e.g., trastuzumab, pertuzumab, ado-trastuzumab emtansine, lapatinib) have been approved for treatment of this disease.
Germline BRCA Mutation
For patients with metastatic breast cancer who carry a germline BRCA mutation, the oral inhibitor of poly (adenosine diphosphate-ribose) polymerase (PARP) has shown activity. BRCA1 and BRCA2 are tumor-suppressor genes that encode proteins involved in DNA repair through the homologous recombination repair pathway. PARP plays a critical role in DNA repair and has been studied as therapy for patients with breast cancer who harbor a germline BRCA mutation. FDA approved drugs include olaparib (Lynparza) and talazoparib (Talzenna).
Bone-Modifying Therapy
The use of bone-modifying therapy to reduce skeletal morbidity in patients with bone metastases should be considered. Results of randomized trials of pamidronate (Aredia) and clodronate (Bonefos) in patients with bony metastatic disease show decreased skeletal morbidity. In addition, zoledronate (Zometa) has been at least as effective as pamidronate.
Another monoclonal antibody, denosumab (Xgeva), inhibits the receptor activator of nuclear factor kappa beta ligand. A meta-analysis of three phase III trials (NCT00321464, NCT00321620, and NCT00330759) comparing zoledronate versus denosumab for management of bone metastases suggests that denosumab is similar to zoledronate in reducing the risk of a first skeletal-related event.
An advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients is available. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria.
Michele R. Berman, MD, and Mark S. Boguski, MD, PhD, are a wife and husband team of physicians who have trained and taught at some of the top medical schools in the country, including Harvard, Johns Hopkins, and Washington University in St. Louis. Their mission is both a journalistic and educational one: to report on common diseases affecting uncommon people and summarize the evidence-based medicine behind the headlines.