Treating triple-negative breast cancer (TNBC), one of the more lethal breast cancer subtypes, remains a challenge. By definition, TNBC lacks the three telltale molecular signatures known to spur tumor growth: estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). A growing amount of literature shows that these frequently aggressive tumors harbor a rich array of molecular characteristics but no clear oncogenic driver.
"TNBC is incredibly heterogeneous, which makes it challenging to treat," said Rita Nanda, MD, director of the Breast Oncology Program and associate professor of medicine at University of Chicago Medicine. "We have subsets of TNBC that don't respond to currently available therapies and, as of yet, have no identifiable therapeutic targets."
Overall, about 40% of patients with TNBC show a pathologic complete response after first-line neoadjuvant chemotherapy — typically anthracycline and taxane-based agents. But for 50% of patients, chemotherapy leaves behind substantial residual cancer tissue. These patients subsequently face a 40%-80% risk for recurrence and progression to advanced disease.
When triple-negative disease metastasizes, survival rates plummet. The most recent data from the National Cancer Institute, which tracked patients by stage of diagnosis between 2010 and 2016, showed steep declines in 5-year survival as TNBC progressed from local (91.2%) to regional (65%) to advanced-stage disease (11.5%).
Experts have started to make headway identifying and targeting different molecular features of advanced TNBC. These approaches often focus on three key areas: targeting cell surface proteins or oncogenes, stimulating an anticancer immune response, or inhibiting an overactive signaling pathway.
"For a patient with metastatic breast cancer, finding a molecular target or an oncogenic driver is essential," said Kelly McCann, MD, PhD, a hematologist/oncologist in the Department of Medicine at the David Geffen School of Medicine, University of California, Los Angeles. "Because TNBC encompasses many different molecular subsets of breast cancer, the development of effective new therapeutics is going to depend on subdividing TNBC into categories with more clear targets."
A Targeted Strategy
The accelerated approval recently granted by the US Food and Drug Administration (FDA) for the first antibody-drug conjugate to treat metastatic TNBC marked an important addition to the TNBC drug armamentarium. "Sacituzumab govitecan is one of the most exciting drugs available for the treatment of metastatic disease," Nanda said.
Sacituzumab govitecan, approved as third-line therapy for metastatic TNBC, works by targeting the cell surface protein TROP2, expressed in about 88% of TNBC tumors but rarely in healthy cells. The FDA's endorsement of the antibody-drug conjugate stemmed from the phase 1/2 ASCENT trial that reported median progression-free survival of 5.5 months and overall survival of 13.0 months in 108 patients with metastatic TNBC who had received at least two prior therapies. A subsequent phase 3 trial reported progression-free survival of 5.6 months vs 1.7 months with physician's choice of chemotherapy and median overall survival of 12.1 months in the antibody-drug conjugate group vs 6.7 months in the chemotherapy cohort.
But, according to the analysis, TROP2 expression did not necessarily predict who would benefit from sacituzumab govitecan. A biomarker study revealed that although patients with moderate to high TROP2 expression exhibited the strongest treatment response, those with low TROP2 expression also survived longer when given the antibody-drug conjugate compared with chemotherapy alone.
In other words, "patients did better on sacituzumab govitecan regardless of TROP2 expression, which suggests we do not have a good biomarker for identifying who will benefit," Nanda said.
Two other investigational antibody-drug conjugates, trastuzumab deruxtecan and ladiratuzumab vedotin, show promise in the metastatic space as well. For instance, the recent phase 2 trial evaluating trastuzumab deruxtecan in patients with HER2-positive breast cancer reported treatment response in 44% of patients with HER2-low tumors.
Given that about 36.6% of TNBC tumors exhibit low levels of HER2 expression, "trastuzumab deruxtecan represents potential in treating HER2-low TNBC," said Yuan Yuan, MD, PhD, medical oncologist at City of Hope, a comprehensive cancer center in Los Angeles County. Early results from a phase 1b study evaluating the antitumor activity and safety of treatment with trastuzumab deruxtecan "showed a response rate of 37% in patients with HER2-low breast cancer."
Investigators are now recruiting for an open-label phase 3 trial to determine whether trastuzumab deruxtecan extends survival in patients with HER2-low metastatic breast cancers.
Immune checkpoint inhibitors represent another promising treatment avenue for metastatic TNBC. Pembrolizumab and atezolizumab, recently approved by the FDA, show moderate progression-free and overall survival benefits in patients with metastatic TNBC expressing programmed cell death ligand 1 (PD-L1). Estimates of PD-L1 immune cells present in TNBC tumors vary widely, from about 20% to 65%.
Yet, data on which patients will benefit are not so clear cut. "These drugs give us more choices and represent the fast-evolving therapeutic landscape in TNBC, but they also leave a lot of unanswered questions about PD-L1 as a biomarker," Yuan said.
Take two recent phase 3 trials evaluating atezolizumab: IMpassion130 and IMpassion131. In IMpassion130, patients with PDL1–positive tumors exhibited significantly longer median overall survival on atezolizumab plus nab-paclitaxel (25.0 months) compared with nab-paclitaxel alone (15.5 months). Similar to the trend observed in the TROP2 data for sacituzumab govitecan, all patients survived longer on atezolizumab plus nab-paclitaxel regardless of PD-L1 status: 21.3 months vs 17.6 months with nab-paclitaxel alone. However, in IMpassion131, neither progression-free survival nor overall survival significantly improved in the PD-L1–positive group receiving atezolizumab plus paclitaxel compared with paclitaxel alone: Progression-free survival was 5.7 months vs 6 months, respectively, and overall survival was 28.3 months vs 22.1 months.
"It is unclear why this study failed to demonstrate a significant improvement in progression-free survival with the addition of atezolizumab to paclitaxel," Nanda said. "Perhaps the negative finding has to do with how the trial was conducted or perhaps the PD-L1 assay used is an unreliable biomarker of immunotherapy benefit."
Continued Efforts to Understand TNBC
Given the diversity of metastatic TNBC and the absence of clear molecular targets, researchers are exploring a host of therapeutic strategies in addition to antibody-drug conjugates and immunotherapies.
On the oncogene front, researchers are investigating common mutations in TNBC. About 11% of TNBC tumors, for instance, carry germline mutations in BRCA1 and BRCA2. These tumors may be more likely to respond to platinum agents and PARP inhibitors, such as FDA-approved olaparib. In a phase 3 trial, patients with metastatic HER2-negative breast cancer and a germline BRCA mutation who received the PARP inhibitor exhibited a 2.8-month longer median progression-free survival and a 42% reduced risk for disease progression or death compared with those on standard chemotherapy.
When considering signaling pathways, the phosphoinositide 3 (PI3) kinase/AKT/mTOR pathway has been the target of numerous clinical trials. Dysregulation of signaling through the PI3 kinase and AKT signaling pathway occurs in 25%-30% of patients with advanced TNBC, and AKT inhibitors have been shown to extend survival in these subsets of patients. Data show, for instance, that adding capivasertib to first-line paclitaxel therapy in patients with metastatic TNBC led to longer overall survival — 19.1 months vs 12.6 with placebo plus paclitaxel — with better survival results in patients with PIK3CA/AKT1/PTEN altered tumors.
But there's more to learn about treating metastatic TNBC. "Relapses tend to occur early in TNBC, and some tumors are inherently resistant to chemotherapy from the get-go," said Charles Shapiro, MD, medical oncologist, Icahn School of Medicine at Mount Sinai, New York City. "Understanding the causes of drug response and resistance in patients with metastatic TNBC represents the holy grail."
Nanda agreed, noting that advancing treatments for TNBC will hinge on identifying the key factors driving metastasis. "For TNBC, we are still trying to elucidate the best molecular targets, while at the same time trying to identify robust biomarkers to predict benefit from therapies we already have available," she said.
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Cite this: Treating Metastatic TNBC: Where Are We Now? - Medscape - Mar 29, 2021.