Breast cancer is the most frequent malignancy in women, with an estimated 291,000 new cases expected in the United States in 2022 [6]. While breast cancer is curable at early stages, advanced or metastatic cancer is still a significant therapeutic challenge.
Breast cancer can be broken down into three biologic subgroups, each of which has a direct bearing on treatment choices:
HER2 overexpression is determined with immunohistochemistry (IHC) and graded as follows:
IHC Score
Description
0-1
Negative (or HER2-low)
2
Indeterminate
3+
Positive
Indeterminate HER2 testing (IHC +2) should trigger reflex HER2 testing using ISH (in situ hybridization) on the same specimen or a new test using a different specimen with either IHC or ISH. Results from ISH are defined as the ratio of gene amplification of HER2 and the chromosome 17 enumeration probe (CEP17). Results are reported as ISH positive if the HER2/CEP17 ratio is ≥2.0 and the HER2 copy number signals/cell is ≥4.
Approximately 15-20% of metastatic breast cancers are HER2-positive and thus eligible for treatment with HER2-targeted therapies. The remaining 80% of metastatic breast cancers are HER2-negative [7].
As a rule, patients with advanced breast cancer featuring low HER2 expression levels are diagnosed with HER2-negative disease because HER2-targeted therapies are typically ineffective in this setting. The DESTINY-Breast04 trial upends this paradigm, opening the door to a new treatment option for the approximately 60% of patients referred to as “HER2-low” (IHC score of 0-1) [8]. In this double-blind Phase 3 trial, patients with HER2-low metastatic breast cancer treated previously with one to two prior lines of chemotherapy for metastatic disease were randomized to receive trastuzumab deruxtecan (a HER2-directed antibody and topoisomerase inhibitor conjugate) or the physician’s choice of standard chemotherapy.
The study showed that progression-free survival (PFS) was nearly double for trastuzumab deruxtecan versus standard chemotherapy (9.9 versus 5.1 months), and the overall survival (OS) was significantly better with trastuzumab deruxtecan compared with standard therapy (23.4 versus 16.8 months). Safety analysis did not identify new safety concerns and showed fewer treatment-emergent adverse events (TEAE) with trastuzumab deruxtecan than with standard chemotherapy (52.6% versus 67.4%). These practice-changing findings establish patients with HER2-low metastatic breast cancer as a targetable population with trastuzumab deruxtecan as a new standard of care in this setting. DESTINY-Breast04 is the first randomized clinical trial to show that targeting HER2 provides clinically meaningful benefits for patients with HER2-low metastatic breast cancer. “Traditionally, we would have offered patients in this setting single-agent palliative chemotherapy,” said lead investigator Shanu Modi, MD (Memorial Sloan Kettering Cancer Center, New York, USA). “However, we can now offer these patients the opportunity to receive a targeted therapy that is associated with superior outcomes and a survival advantage.”
However, we can now offer these patients the opportunity to receive a targeted therapy that is associated with superior outcomes and a survival advantage.”
Patients with HR+/HER2- metastatic breast cancer represent another therapeutic challenge with a five-year survival rate of 30%. Treatment of such patients typically includes the first-line combination of endocrine therapy with a targeted agent, and once a patient fails it, the next step is several lines of endocrine therapy with or without other targeted agents. Eventually, the disease becomes refractory to endocrine therapy, and sequential use of a single chemotherapy agent is the standard of care. The prognosis for the single-agent chemotherapy is poor, mandating a search for advanced treatment options. The TROPiCs-02 Phase 3 clinical trial enrolled patients with HR+/HER2- unresectable locally advanced or metastatic breast cancer who had received two to four prior chemotherapy regimens for advanced disease [9]. Patients were randomized to receive either sacituzumab govitecan (an antibody-drug conjugate) or standard chemotherapy (capecitabine, eribulin, vinorelbine, or gemcitabine). The trial showed that sacituzumab govitecan improved median PFS compared to standard chemotherapy (5.5 versus 4.0 months) and a trend (statistically not significant) for improvement in OS (13.9 versus 12.3 months). The overall response rate (ORR) was also higher with sacituzumab govitecan compared to standard therapy (21% versus 14%); the median duration of response was 7.4 versus 5.6 months, respectively. The safety profile of sacituzumab govitecan was comparable to standard chemotherapy, with an incidence of adverse events (AEs) of 74% versus 60%. CDK4/6 inhibition with endocrine therapies is the standard of care in HR+/HER2- metastatic breast cancer with a median PFS of 24 months. However, there are no good therapeutic options for patients who progressed on that treatment. In the MAINTAIN study, patients with HR+/HER2- metastatic breast cancer that had progressed on endocrine therapies in combination with any CDK4/6 inhibitor were randomized to receive fulvestrant or exemestane with or without ribociclib [10]. The study showed improved PFS when patients received ribociclib plus a different endocrine therapy (either fulvestrant or exemestane) than the one they had received previously. Median PFS was approximately 5.0 months in the study group versus 2.7 months in the placebo group. While switching to a different CDK4/6 inhibitor after progression showed statistically significant benefit in terms of PFS, it is still only five months and did not show clear evidence of OS improvement; thus, more extensive Phase 3 studies are necessary. In other words, this is not a practice-changing study but may signal a potential direction for future studies in this cohort of patients.