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High TIL levels predict positive outcomes in HER-2–positive breast cancer
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High levels of tumor-infiltrating lymphocytes served as an independent positive predictive marker for EFS and pathological complete response in HER-2–positive early breast cancer treated with chemotherapy and anti–HER-2 agents, according to a secondary analysis of the NeoALTTO trial.
“Increasingly, oncogenic addiction, in which tumors become dependent on a sole oncogenic pathway for growth, is thought to promote a tumor microenvironment conducive to immune escape,” Sherene Loi, MD, PhD, of the Peter MacCallum Cancer Centre at the University of Melbourne, and colleagues wrote. “Although this had not been shown yet for HER-2 oncogenic signaling, one could speculate that anti-HER–2 therapy may not only work in a cell-intrinsic manner but may also reserve HER-2–induced immunosuppression as a mechanism for action.”
The NeoALTTO trial included 455 women with HER-2–positive early-stage breast cancer between 2008 and 2010. The researchers randomly assigned patients to neoadjuvant treatment with trastuzumab (Herceptin, Genentech), lapatinib (Tykerb, GlaxoSmithKline) or both.
Patients received the initial treatment for 6 weeks, followed by weekly paclitaxel for 12 weeks and three treatment cycles of fluorouracil, epirubicin and cyclophosphamide after surgery.
Loi and colleagues evaluated data from 387 tumor samples collected during the NeoALTTO trial. Researchers sought to evaluate the association between levels of tumor-infiltrating lymphocytes (TILs) at diagnosis and the study’s primary endpoint — pathological complete response rates in the breast and lymph nodes — and the secondary endpoint, EFS.
The median TIL level was 12.5% (interquartile range [IQR], 5-30).
Patients with HER-2–positive tumor samples demonstrate significantly lower TIL levels than patients with HER-2–negative tumor samples (10% vs. 12.5%; P = .02).
TIL levels greater than 5% were linked to higher pathological complete response rates regardless of treatment regimen (adjusted OR = 2.6; 95% CI, 1.26-5.39).
Researchers evaluated EFS after a median follow-up of 3.77 years (IQR, 3.5-4.22). Results showed that every 1% increase in TIL levels was linked to a 3% reduction in event rates (adjusted HR = 0.97; 95% CI, 0.95-0.99) across treatment regimens. A high TIL value — or a value greater than the median TIL value — at the time of diagnosis was associated with an EFS rate of more than 90%.
Researchers noted that patients with TIL levels higher than median who did not achieve pathological complete response displayed EFS rates similar to patients who achieved a pathological complete response.
The poorest survival rates were observed in patients with low TIL levels who did not achieve pathological complete response. There was no significant interaction between TIL presence and the combination therapy vs. trastuzumab alone and EFS.
The researchers acknowledged limitations to their study. Because the combination therapy was not statistically superior in the control group, it is not likely to be used in future studies. Additionally, pathological complete response was not a recognized surrogate endpoint for EFS improvement, and the number of EFS events were low.
“We propose that a group of patients with high TIL levels can have an excellent outcome with the current standard of trastuzumab therapy alone with chemotherapy, although we acknowledge the difficulty of proposing such cutoffs for clinical implementation,” Loi and colleagues concluded. “If a TIL cutoff can be identified and robustly validated using the large adjuvant HER-2–positive data sets, future clinical trials of anti-HER–2 therapy may be better placed to test the efficacy of new therapies in the poor prognostic group.”
The results of this secondary analysis of NeoALTTO trial raise additional questions that will need to be answered by further study, Sibylle Loibl, MD, PhD, of the German Breast Group, wrote in an accompanying editorial.
“Pathological complete response is an excellent surrogate marker for long-term outcome and remained, together with level of TILs, the only independent prognostic factor in this analysis” Loibl wrote. “It may be that patients achieving a [pathological complete response] with initially high levels of TILs could have been spared the anthracycline-containing post-neoadjuvant therapy. But this cannot be answered using these data and remains speculation. Therefore, although TIL assessment is simple, cheap and can be easily integrated into routine histopathology reporting to assess the prognosis as well as the treatment response, it remains only a semi-quantitative marker. An immune gene panel — although single immune markers are highly correlated with TILs — could outperform TIL assessments.” – by Cameron Kelsall
Disclosure: The NeoALTTO study was funded by GlaxoSmithKline. Loi reports no relevant financial disclosures. Please see the full study for a list of all other authors’ relevant financial disclosures.
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