High levels of immune infiltrates are strongly prognostic for favorable outcomes independently of nodal status in triple-negative breast cancer (TNBC).
Tumor-Infiltrating Lymphocytes (TILs)
High levels of tumor-infiltrating lymphocytes (TILs), which are easy to obtain and report, indicate an active antitumor immune response, said Roberto Salgado, MD, PhD, of the Peter MacCallum Cancer Centre in Melbourne, Australia. They can be complementary to genomic technologies to predict response and prognosis.
In a retrospective study of an international patient population, higher levels of TILs in TNBC not treated with systemic therapy correlated with significantly better survival, with a 5-year distant relapse-free survival rate of 78% among patients with stage I TNBC and a TIL level less than 30% compared with 94% for those with levels of 50% or greater, and 5-year overall survival (OS) rates of 82% versus 95%, respectively.
Previous studies also showed that patients with early TNBC and high TIL levels in breast tumors have after adjuvant chemotherapy and higher rates of after neoadjuvant chemotherapy.
Moreover, studies have shown that tumors with higher levels of TILs appear to respond well to immunotherapy.
Tumors with a high level of TILs also have high expression of PD-L1, "but PD-L1-negative tumors can still have TILs and respond to checkpoint inhibition," Salgado said. "When you see PD-L1-negative tumors responding to immunotherapy, it's probably because they have TILs."
In an in the phase III KEYNOTE-119 study, a high level of TILs was significantly associated with better clinical outcomes with pembrolizumab (Keytruda), but not chemotherapy. When stratified by TIL levels (<5% vs ≥5%), the median OS for patients with TILs ≥5% was 12.5 months with pembrolizumab compared with 11.3 months in the chemotherapy arm, and the 18-month OS rates were 35% versus 27%, respectively.
In the , patients with unresectable or metastatic TNBC experienced a survival benefit with first-line atezolizumab (Tecentriq) plus nab-paclitaxel if they were positive for PD-L1 expression and had a high level of TILs.
Finally, in the , five of 15 patients with early-stage TNBC and levels of TILs ≥50% had a pathologic complete response with 6 weeks of neoadjuvant nivolumab (Opdivo) plus ipilimumab (Yervoy). All five patients chose to omit adjuvant chemotherapy.
Beyond TILs
Justin Balko, PharmD, PhD, of the Vanderbilt-Ingram Cancer Center in Nashville, Tennessee, told ľֱ that other immune biomarkers may also have implications for the clinical management of TNBC, including high tumor mutational burden, which may be predictive of immunotherapy benefit in early-stage TNBC.
In an exploratory biomarker analysis of the KEYNOTE-522 study presented at this year's San Antonio Breast Cancer Symposium, tumor mutational burden was associated with improved event-free survival for patients with high-risk, early-stage TNBC who received pembrolizumab plus chemotherapy compared with those who received placebo plus chemotherapy.
Although immune checkpoint inhibitors are currently a cornerstone of treatment for TNBC, clinical benefit is not uniform nor universal. Therefore, biomarkers predictive of response to immunotherapy are pivotal to optimal patient selection and improved outcomes, Balko said.
"In my lab, we've stopped thinking so much about markers of sensitivity and benefit, and thinking more about markers of resistance," he noted.
The cancer immunity cycle starts with antigen release into the lymph nodes followed by the licensing of lymphatic cells that circulate back to the area of inflammation (i.e., the tumor), killing the cancer cells. "Typically, we're looking for a break in the cycle," Balko said.
Although many proposed biomarkers have interesting biology, they aren't necessarily useful in clinical decision making, he added. For example, enrichment of response in a population with expression of a biomarker does not justify withholding a treatment from the rest of the population at the risk of subjecting nonresponders to potential treatment-related toxicities and costs.
Major histocompatibility complex class II (MHC-II) on tumor cells is considered a pan-cancer biomarker. Its presence on melanoma tumor cells predicted improved outcomes with single-agent pembrolizumab in the , and patients with had a favorable response to nivolumab when MHC-II was present on Hodgkin Reed-Sternberg cells. In a , cancer cells that exhibited MHC-II expression correlated positively with T-cell expansion during anti-PD-1 treatment.
An unpublished study co-authored by Balko, which included patients with early high-risk TNBC or locally advanced unilateral breast cancer, showed no improvement in the rate of pathologic complete response with the addition of neoadjuvant atezolizumab to carboplatin and nab-paclitaxel in those with low expression of MHC-II on tumor cells, which offered further evidence of the clinical utility of MHC-II as a biomarker.
"We want to see that the benefit [from immunotherapy] is confined to the biomarker-positive group," Balko said, as opposed to an enriched benefit within the MHC-II-high patient population, "because in the end, that doesn't tell us who to withhold treatment from or how to optimize care in that setting."
Other developing biomarkers of note are B-cell markers, T follicular helper cells, and tertiary lymphoid structures, which have shown predictive ability in a pan-cancer approach, said Balko. The microbiome may also serve as a valuable biomarker and possibly an interventional biomarker, such that transfer of a responding patient's microbiome to a nonresponding patient might positively influence outcome.
Disclosures
Salgado reported relationships with Bristol Myers Squibb, Roche, AstraZeneca, Daiichi Sankyo, Exact Sciences, Puma, and Merck.
Balko reported relationships with Eli Lilly, AstraZeneca, Incyte, and Genentech/Roche. He also holds a patent on immunotherapy biomarkers.