Triple-negative breast cancer — defined as tumors that lack expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 amplification— is a heterogenous disease and clinically represents a major unmet need in the field of oncology. TNBC is associated with aggressive tumor biology and higher risk of recurrence and visceral metastasis, including brain metastasis.
Aditya Bardia, MD, MPH
Triple-negative breast cancer (TNBC) defined as tumors that lack expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2) amplification is a heterogenous disease and clinically represents a major unmet need in the field of oncology. TNBC is associated with aggressive tumor biology and higher risk of recurrence and visceral metastasis, including brain metastasis.
In the era of precision medicine, recent efforts have attempted to classify TNBC tumors based on their transcriptomic profile and the treatment response1-6. Investigators led by Brian D. Lehmann, PhD, identified 6 subtypes including basal-like 1 (BL1), basal-like 2 (BL2), immunomodulatory (IM), mesenchymal (M), mesenchymal stemlike (MSL), and luminal androgen receptor (LAR) subtypes. Each of these molecular subtypes displays different but overlapping clinicopathological characteristics, heterogenous mutational profiles, and genomic instability. The BL1 subtype shows enriched gene expression pattern in DNA-damage response and cell-cycle regulation with the highest rate ofTP53mutations, and the BL2 subtype has high levels of growth factor signaling and metabolic pathway activity. The IM subtype shows high expression of antigen processing/presentation and immune cell and cytokine signaling through JAK/STAT, TNF, and NF-κB pathways. The M and MSL subtypes display gene-expression profiles associated with cell motility, differentiation, and epithelial-mesenchymal transition (EMT) with unique enrichment in MSL of angiogenesis-related genes. The LAR subtype is most closely related to the gene expression pattern of luminal cancer and shows elevated levels of androgen receptor (AR) expression, mutations inPI3KCA,AKT1, andCDH1genes with higher mutational burden.1 These subtypes were refined into 4 group given that the previously defined IM and MSL subtypes were contributed from lymphocytes and stromal cells in the bulk sequencing. Additionally, another report to distinguish TNBC phenotypes using DNA/RNA profiling indicated 4 distinct subtypes: LAR, mesenchymal (MES), basal- like immunosuppressed (BLIS), and basal-like immune activated (BLIA).4 In the prognostic analysis, BLIA had the best disease-free survival (DFS) whereas BLIS had the worst DFS. Most recently, single-cell RNA sequencing has demonstrated that there are multiple subpopulations within primary TNBC tumors, suggesting that the signature identified through bulk sequencing may not accurately predict the clinical behavior of TNBC tumors.
The advent of immunotherapy has transformed the landscape of oncology, including TNBC7. The IMpassion130 trial, investigating atezolizumab (Tecentriq) plus nab-paclitaxel (Abraxane) versus placebo plus nab-paclitaxel as first-line therapy for metastatic (m)TNBC, demonstrated that patients receiving atezolizumab had improvement in progression-free survival (PFS; 7.5 vs 5.0 months; HR, 0.62; 95% CI, 0.49-0.78;P<.001) and overall survival (OS; 25.0 vs 15.5 months; HR, 0.62; 95% CI, 0.45-0.86) as compared with placebo in the PD-L1positive subgroup, leading to FDA approval of atezolizumab in March 2019 as first-line therapy for PD-L1–positive mTNBC.8Besides immunotherapy, PARP inhibitors, such as olaparib (Lynparza) and talazoparib (Talzenna), are FDA approved for the management of metastatic breast cancer, including mTNBC, with germlineBRCAmutations,9,10and there is emerging interest in AKT inhibitors as first line therapy forPI3K-altered mTNBC.
In terms of later lines of therapy, sequential chemo- therapy remains standard of care in mTNBC, but median PFS with standard therapy is short and response rates are limited. In the EMBRACE trial, which demonstrated that treatment with eribulin was associated with better PFS and OS as compared with physician’s choice of treatment among patients with metastatic breast cancer including mTNBC, the median PFS with eribulin by independent review was 3.7 months and the objective response rate (ORR) was 12%, highlighting the need for better therapies for this patient population.11
Aiko Nagayama, PhD
Over the past few years, there has been emerging interest in antibodydrug conjugates (ADCs) for the treatment of refractory tumors, including mTNBC. While there are a number in clinical development for mTNBC, perhaps the one that is most advanced is sacituzumab govitecan (IMMU132)an ADC compromised ed of an antibody targeting trophoblast cell-service antigen 2 (Trop-2), expressed in a majority of TNBC, linked with SN-38, the active metabolite of irinotecan. In a phase I/II clinical trial, single-agent sacituzumab govitecan demonstrated activity in heavily pretreated patients with mTNBC with an ORR of 33.3% with median duration of response of 7.7 months.12Efficacy was observed in patients who had received prior taxanes and anthracyclines, suggesting a lack of cross- resistance to previous cytotoxic chemotherapy. The impressive results led to breakthrough therapy designation by the FDA13and conduct of the phase III ASCENT trial (NCT02574455) investigating sacituzumab govitecan versus chemotherapy of physician’s choice in mTNBC. More recently, Immunomedics, the company responsible for developing the agent, announced re-submission of the biologics license application for accelerated approval of sacituzumab govitecan for patients with mTNBC in December 2018, after which CMC (Chemistry, Manufacturing, and Control) issues resulted in a complete response letter from the FDA earlier this year.14
Besides sacituzumab govitecan, impressive efficacy has been observed with DS-8201 (trastuzumab deruxtecan), a novel ADC targeting HER2 among patients with “HER2- low” (HER2 expression by immuno- histochemistry score 1+ or 2+, but not 3+) metastatic breast cancer. Ladiratuzumab vedotin, a novel ADC targeting LIV-1, has also demonstrated efficacy in patients with relapsed/refractory metastatic breast cancer.
However, the ADC field has not been with- out its share of drawbacks. For example, theMETRICtrial which investigated glematumumab vedotinnovel ADC targeting gp-NMB—versus capecitabine among patients with gpNMB-overexpressing mTNBC, demonstrated no difference in median PFS (2.9 months vs 2.8 months;P= .76). Post- hoc subgroup analysis suggested the greatest benefit from the ADC was in potentially taxane-sensitive disease, reflecting lack of cross-resistance between the toxic pay- load and taxanes.15Recently, the phase III KEYNOTE-119 trial investigating pembrolizumab (Keytruda) versus chemotherapy of physician’s choice among patients with previously treated mTNBC demonstrated no difference in median OS between the 2 arms, although sub-group analysis suggested improvement in OS with pembrolizumab among high PD-L1positive (combined positive score >20) mTNBC (14.9 months vs 12.5 months; HR, 0.58; 95% CI, 0.38-0.88).16
In summary, TNBC is a biologically heterogeneous tumor and remains a major unmet clinical need. Advances in genomics and molecular profiling have better defined the subtypes of TNBC with distinct biological drivers to guide therapeutic development of targeted agents, such as AKT inhibitors forPI3K-altered TNBC, as well as checkpoint inhibitors for PD-L1positive TNBC. Furthermore, ADCs have emerged as an important therapeutic strategy for targeting genomically complex tumors that lack a single driver oncogenic mutation but express antigens that are usually expressed in mTNBC, such as Trop-2. Future studies combining ADCs with immunotherapy and other targeted therapies as well as biomarker-driven clinical trials could led to further refinement in clinical application of immune-conjugates for patients with mTNBC.