The 5-year survival estimates for women with metastatic breast cancer (MBC) hover around 28%, according to the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) data from 2010 to 2016. But closer scrutiny of the evolution of MBC care reveals a more promising outlook, according to Adam Brufsky, MD, PhD, associate chief of the Division of Hematology/Oncology and co-director of the Comprehensive Breast Cancer Center at the University of Pittsburgh School of Medicine.
A 2017 analysis found that between 1992-1994 and 2005-2012, the 5-year relative survival doubled from 18% to 36% for younger women. And some patients with MBC live 10 years or more with the condition. "No one will deny that MBC is serious and ultimately fatal, but today, oncologists have so many more tools at our disposal to extend a patient's life 5, 10 years and hopefully longer," Brufsky said.
Despite this progress, Lisa A. Carey, MD, noted that there's still a long road ahead to understanding how the disease progresses and why some patients respond well to treatment while others do not.
"We've come far in terms of survival, but some subgroups of patients benefit more than others," said Carey, the Richardson and Marilyn Jacobs Preyer Distinguished Professor in Breast Cancer Research, chief of the Division of Hematology/Oncology, and deputy director of clinical sciences at University of North Carolina-Chapel Hill. "We still need a better understanding of what resistance is, what causes it, and how we can better predict treatment response."
Here are five things to know about monitoring treatment response in MBC.
1. MBC is moving towards chronic condition status.
Targeted agents and immunotherapy drugs emerging on the treatment landscape for three major types of MBC — estrogen (ER)-positive, human epidermal growth factor receptor 2 (HER2)-positive, and triple-negative tumors — have continued to move the needle on survival.
In April, the US Food and Drug Administration (FDA) approved the tyrosine kinase inhibitor (TKI) tucatinib to treat HER2-positve MBC in combination with trastuzumab and capecitabine. The approval was based on safety and efficacy data from a phase 3 trial which revealed a 1-year progression-free survival (PFS) of 33.1% in the tucatinib-combination group and 12.3% in the placebo-combination group. Perhaps most notable was the secondary outcome among patients with brain metastases, a notoriously challenging group to treat. The authors reported a 1-year PFS of 25% in the combination group compared with 0% in the placebo-combination group.
Last year, the FDA gave the PI3KCA inhibitor alpelisib the green light to treat men and postmenopausal women with hormone receptor (HR)-positive, HER2-negative, PIK3CA-mutated MBC. The approval was based on a phase 3 trial which found that patients with PIK3CA-mutated cancer who had already received endocrine therapy saw more benefit with alpelisib and fulvestrant than with placebo–fulvestrant. At a 20-month follow-up, PFS in the alpelisib combination group was 11 months vs 5.7 months in the placebo-drug group.
Regarding treatment of metastatic triple-negative tumors, a phase 3 trial published in 2018 found that the monoclonal antibody atezolizumab (which inhibits PD-L1) plus nab-paclitaxel extended PFS in patients with untreated MBC by 1.7 months compared with nab-paclitaxel and placebo (7.2 months vs 5.5 months, respectively). The PFS benefit widened slightly when patients with PD-L1–positive tumors received the targeted agent compared with the chemotherapy-placebo combination (7.5 months vs 5.0 months, respectively).
"Although we can't classify MBC as a chronic condition yet, we've been chipping away at the disease for decades, and I feel hopeful that we're getting closer to that vision," Brufsky said.
2. Molecular testing is shifting MBC care closer to personalized medicine.
Over the past few years, the FDA has approved a number of drugs alongside companion diagnostic tests. By identifying salient genetic mutations, receptors, or proteins — estrogen and progesterone receptors, HER2, PD-L1, BRCA1, BRCA2, and PIK3CA — molecular tests can help guide treatment choice.
When the FDA gave alpelisib the green light, the agency also approved the companion diagnostic test, therascreen PIK3CA RGQ PCR KIT, which detects the PIK3CA mutation in tissue or liquid biopsy samples.
Although personalizing treatment to a patient's actionable biomarkers can predict better outcomes and fewer deaths, questions remain about how best to use the information gleaned from these tests. First, Carey said, how do oncologists choose the optimal therapy when a patient with MBC has several actionable abnormalities? One example Carey gave is of a patient with metastatic HR-positive, HER2-negative disease whose next-generation sequencing reveals high tumor mutational burden (an indication for immunotherapy) and a PIK3CA E545K hotspot mutation (an indication for adding alpelisib to endocrine therapy). Second, according to Carey, should an oncologist change patients' treatment regimens if their abnormalities change over time?
"We are still learning how cancers evolve under selective pressures of time and drugs," Carey said. "Multiple studies have shown shifts in the tumor phenotypes between primary breast cancer and metastases, but these changes might not 'stick' and the cancer could revert to the initial phenotype. Plus, how those changes should affect treatment decisions and how often we need to monitor molecular signatures are less clear."
3. Knowing when it's time to switch to palliative care.
Providing palliative care early in patients with MBC can improve quality of life and symptoms, as well as avoid unnecessary care and reduce medical costs. Despite these benefits, palliative care services are often underused.
Although analyses on the use of palliative care in MBC tend to be limited to single-institution experiences, these studies suggest delays or poor uptake of these services. A 2018 study, for instance, found that just under 45% of patients with MBC (105/234) at a safety net hospital in Texas received referrals to palliative care. Another analysis, which retrospectively reviewed the use of palliative and hospice care in hospitalized patients with MBC at a tertiary care center in Boston, found that only 17% (16/94) went to an outpatient palliative care appointment, even though 57% received an evaluation from an inpatient palliative care team. A third study, out of the University of California, San Francisco, found that breast cancer oncologists referred about 20% of patients with MBC to palliative care, and just over half (11.5%) saw a palliative care doctor.
"Our biggest mistake as oncologists is making palliative care referrals too late," said Charles Shapiro, MD, director of translational breast cancer research at Tisch Cancer Institute at Mount Sinai, in New York City. "Sometimes it's hard to tell patients there's nothing else we can do therapeutically, but eventually you run out of treatment options that make sense, and it's important to acknowledge when therapeutics will no longer help patients."
Shapiro explained that the time to consider palliative care in MBC varies from patient to patient, but oncologists should not fear this option. In fact, in 2017, the American Society of Clinical Oncology (ASCO) recommended that all patients with metastatic cancer should simultaneously receive palliative care alongside their cancer regimen within 8 weeks of receiving a diagnosis, not just at the end of life.
"Transitioning to palliative care is not giving up; it is choosing options like symptom relief that we know we can effect in a positive way, rather than giving another chemotherapy with a very marginal benefit and all the side effects," Shapiro said.
4. Some patients with MBC are survival outliers.
Certain patients defy all odds and live for decades with MBC. Mark Burkard, MD, PhD, a medical oncologist at the University of Wisconsin-Madison Carbone Cancer Center, has been studying these extreme survivors. Burkard is currently enrolling patients in the Extreme Long-Term Survivors with Metastatic Cancer study "to identify habits, medical care, and genes that help people live with cancer for a longer-than-expected time," but elucidating these factors a remains a challenge.
So far, preliminary data show that among 647 participants with MBC, the majority (about 70%) have HR-positive, HER2-negative disease and the fewest (3.8%) have triple-negative disease. But in a survey of 476 people with MBC, Burkard and colleagues reported that long and short-term survivors with MBC seemed to share many disease and behavioral features, making it challenging to pinpoint the factors driving long-term survival.
In fact, some preliminary data on apparent distinguishing characteristics of long-term survivors may conflict. Brufsky, who compared 122 long-term survivors with 191 short-term survivors, found that more long-term survivors had HER2-positive (not HER2-negative) or ER-positive primary tumors. Long-term survivors also tended to have lower Charlson Comorbidity Index scores, higher household incomes, and to be diagnosed with de novo MBC.
"We want everyone to be an exceptional responder, but we're not there yet," Carey said. "Understanding this small population of outliers may be critical to getting us closer to that holy grail."
Shapiro said that he has treated about a dozen exceptional responders with MBC over his 30-year career. "If you've been in practice long enough, you've seen these patients — people whose pathology paints a dire picture but who ultimately defy the odds," Shapiro said. "Even with these patients, we can't get rid of the cancer but are able to control it for long periods of time, and at the same time, hopefully, give them a decent quality of life."
5. Monitoring treatment response and disease progression requires a host of screening tools.
Simply identifying key genetic mutations and other biomarkers that can help match a patient's tumor biology to an existing drug does not tell a complete story of that person's disease.
"Would we like to have a molecular test that takes care of all facets of monitoring patients' treatment response and disease progression?" Brufsky said. "Absolutely. But no one tool, no matter the hype, is going to answer every question I have or track all facets of a patient's status. Oncologists need to put a range of screening tools together to evaluate MBC."
According to Brufsky, these tools include imaging modalities — CT scans, MRI, ultrasound — to monitor tumor progression as well as patient visits to check on symptoms, which can signal aspects of a patient's disease status that a molecular test will not pick up. But how often an oncologist should check a patient's symptoms or perform a scan or molecular test is unclear and a topic of debate, especially for patients with MBC whose disease progression has been stable for several years, Brufsky noted.
"Still, that's a good debate to be having," Brufsky said. "I don't want to be overly optimistic, but this debate signals that we're moving into an era where some patients are living long enough with stable disease to even ask that question."
Disclosures: Dr Brufsky has disclosed relevant financial relationships with Puma Biotechnology, Roche, Pfizer, Lilly, Novartis, AstraZeneca, and Daiichi. Drs Carey and Shapiro have disclosed no relevant financial relationships.
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