This trial, among the largest prospective clinical trials limited to TNBC, allowed us to examine a therapeutic question, define the subtype composition of TNBC, and illustrate the behavior and prognosis of this phenotype. Findings included a high degree of visceral involvement; 2-month TTP, with several patients experiencing rapid progression; and OS < 1 year. Response to cetuximab alone was uncommon, and there was low-level activity (RR, 17%) of combination platinum plus cetuximab.
Many studies in TNBC are based on its overlap with the basal-like molecular subtype. However, concordance between TNBC on clinical assays and basal-like gene expression patterns is debated. We found that basal-like breast cancer comprised approximately 75% of TNBCs; the remaining 25% represented all other subtypes, including the claudin-low subtype.12,20
Although a moderately effective enrichment tool if one is interested in biology of the basal-like subtype, this molecular heterogeneity must be considered when using triple-negative clinical assay status as an eligibility criterion.
Both breast cancer type 1 (
BRCA1) –associated and sporadic basal-like breast cancers have characteristics consistent with aberrant DNA repair and genome-wide instability,21,22
supporting the use of DNA-damaging agents such as the platinum in this study. Clinical data are controversial. Evidence suggests high responsiveness to cisplatin in BRCA1-associated breast cancer23
; in non-BRCA1 carriers, neoadjuvant cisplatin results in a pathologic CR rate < 20%.24
The expected RR to platinum agents in unselected patients ranges from < 10% (pretreated) to 25% (chemotherapy naive).25
Although TNBC may be more chemosensitive in general,26–28
in a recently reported trial, RR to cisplatin in first- and second-line treatment of TNBC was only 10%,29
and the pretreated cohort in this study demonstrated an RR of 17%. CALGB 40603 (Cancer and Leukemia Group B; clinicaltrials.gov identifier NCT00861705), a randomized neoadjuvant study of carboplatin added to taxane-based therapy, includes embedded correlative studies addressing mechanisms of platinum sensitivity and resistance. In the meantime, existing clinical data do not support preferential use of platinum agents in sporadic TNBC.
Given the asymptomatic nature of most of the patients in this study and the short PFS typical in TNBC, both response and prolonged SD may be worthy therapeutic goals; however, these remained minorities. Only 31% of patients had disease control for at least 6 months with combined EGFR inhibitor plus platinum agent in this study, and PFS for the group as a whole was only 2.1 months, suggesting that the majority without CB had a particularly aggressive course. One limitation of this study is that it was not possible to assess the relative contribution of EGFR inhibitor versus chemotherapy. However, in the randomized phase II trial BALI-1 (NCT00463788), cetuximab added to cisplatin increased RR from 10% to 20% and PFS from 1.5 to 3.7 months.29
The TNBC subset of a randomized study of cetuximab added to irinotecan plus carboplatin also found improved RR, but no improvement in PFS or OS was seen; as in this study, a few patients had sustained long-term responses.16
In fact, the one patient experiencing PFS > 3 years with single-agent cetuximab had a luminal A metastatic tumor. A broad body of literature implicates EGFR in endocrine resistance; however, EGFR inhibition in ER-positive breast cancer without additional selection criteria has similarly had mixed and generally disappointing results. Although EGFR
is a key gene in the basal-like gene cluster, and EGFR expression is consistent among basal-like breast cancers, TNBC does not select for EGFR inhibitor sensitivity. Important lessons can be learned from embedded correlative science, especially if serial fresh tissue is obtained. Despite interest and expertise among participating institutions, fewer than 20% of patients underwent serial biopsy. Rational therapeutic development in the molecular era requires that we improve this rate. This serial biopsy substudy, which included patients in both single-agent and combination arms, found that most TNBCs had EGFR pathway activation, as assessed by a genomic signature. However, after 1 to 2 weeks of EGFR inhibitor therapy, only a minority demonstrated pathway inhibition. This suggests that either cetuximab is ineffective against this target (unlikely, given activity in other tumor types) or that there are alternate mechanisms that do not depend on ligand-dependent EGFR-mediated activation. In this limited sample, we found biologically plausible candidates such as the EGFR pathway and KRAS
amplicon. As was seen with the preoperative endocrine prognostic index for neoadjuvant endocrine therapy,30
we also found that tumor biomarkers may be more informative 1 to 2 weeks after beginning therapy. Preliminary data from a combined data set of TNBC treated in this and another study16
suggested that certain molecules, such as phosphatase and tensin homolog loss and alpha B-crystallin expression, may affect responsiveness to EGFR inhibitor–based therapy.31
We believe that many TNBCs may be EGFR pathway dependent, but the constitutive pathway activation in many cases may not be via EGFR but instead by downstream components such as KRAS
amplification or CRYAB
expression. From the clinical and correlative studies, it is clear that EGFR inhibition alone is unlikely to provide disease control in most TNBCs; combination strategies targeting other components of the pathway and dedicated tissue–based studies are likely to be necessary.
Metastatic TNBC carries a poor prognosis, and treatment is limited to chemotherapy. This study demonstrated that although most TNBCs were basal like, a breast cancer subtype characterized by higher expression of EGFR, there was little activity seen with an EGFR inhibitor added to a platinum agent. Serial biopsies of the target tumor in a subset of patients before and after therapy revealed that although most had EGFR expression and pathway activation, the EGFR inhibitor seldom inactivated this pathway. Therapy targeting growth factor pathways in this subtype may require a far better understanding of the pathways maintaining EGFR activity, molecular inhibitors of the downstream pathways, and combinatorial strategies. In practical terms, this means that clinical advances in TNBC are unlikely to be successful unless we can seamlessly incorporate tissue-based studies in parallel with clinical trials and do it in 100% of patients.