Testing, Treating, and Targeting Triple Negative Breast Cancer
Presentation by Dr Gregory Vidal, West Cancer Center
Written By Bailey Mars, NP | Saint Luke's Health System
At the 2023 West Oncology conference, Dr Gregory Vidal from West Cancer Center discussed the principles of testing, treatment, and targeted therapy for triple negative breast cancers (TNBC), which are generally defined as breast cancers that are negative for expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Dr Vidal began by noting results from the SAFIR-02 trial, which showed that metastatic breast cancer patients who were endocrine-therapy resistant with a maximum of 1 prior chemotherapy treated with a targeted treatment approach matched to their specific molecular tumor profile had better overall outcomes compared to those receiving chemotherapy.
He noted that in the Early Breast Cancer Trialist’s Collaborative Group (EBCTCG) meta-analysis from 2010, endocrine therapy with tamoxifen showed a clear benefit for ER positive patients, whereas in low expressing “ER-poor” patients, there was no benefit. Similarly, whereas addition of the anti-HER2 therapy trastuzumab to chemotherapy showed efficacy in breast cancers defined as “HER2 positive” (defined as immunohistochemical [IHC] 3+ expression), with a benefit in both progression free survival (PFS) and overall survival (OS), those who were defined as “HER2 Low” (defined as IHC 1+), or with no detectable expression of HER2 (IHC 0) had no benefit of trastuzumab versus chemotherapy alone. He also noted that an increase in ER expression correlated with an increase in disease-free survival (DFS) overall, and this was also true in metastatic disease and in the HER2-Low population. Overall, Dr Vidal considers TNBC a diagnosis of exclusion, and although at present the treatment approach has been similar for all TNBC subtypes, they are heterogeneous and cannot be regarded as all the same.
Expanding Treatment Options in TNBC
Dr Vidal described results from the Destiny Breast 04 study, which enrolled patients with unresectable ‘HER2 Low’ breast cancer, as defined above, with or without metastases, and one to two prior chemotherapies. The results showed a benefit of the targeted agent trastuzumab deruxtecan (T-Dxd), with a median PFS of 8.5 months and a median OS of 18.2 months. Dr Vidal highlighted the mechanism of action for T-Dxd, an antibody drug conjugate (ADC), which also has a so-called ‘bystander effect’, whereby, following its internalization into the target cell, the cytotoxic payload is released, and because the payload is freely diffusible across cell membranes, this results in the death not only of the target cell, but also the neighboring tumor cells.
Dr Vidal noted that immunohistochemistry (IHC) is the current standard for HER2 testing, and because this can identify patients with clinically relevant ‘HER2 Low’ disease, he encourages IHC testing for all breast cancer patients, with appropriate controls. He further emphasized that results from IHC testing should also be expressed according to the IHC level of HER2, specifically 0, 1+, 2+, or 3+, as opposed to simply the HER2 ‘negative’ or ‘positive’ designation, particularly in patients with metastatic disease. In addition, he noted that clinicians should consider those HER2 negative patients with low ER and PR levels (1-10% expression per the ASCO-CAP guidelines) as ‘triple negative’ as the biology of these low hormone receptor cancers is largely similar to that of TNBC.
Dr Vidal also described results for sacituzumab govitecan (SG) in TNBC, an antibody drug conjugate directed against a cell surface molecule known as TROP2. TROP2 is a transmembrane calcium signal transducer that is highly expressed in approximately 80% of breast cancers, and it has been linked to both tumor progression and poor prognosis. Dr Vidal detailed results from the ASCENT trial, which examined the efficacy of SG in patients with relapsed/refractory metastatic TNBC. The results showed a median PFS of 5.6 months and a median OS of 12.1 months (as compared with 1.7 and 6.7 months for placebo, respectively). Notably, in this study, the degree of clinical response correlated with TROP2 expression, such that higher levels were associated with better PFS, OS and overall response rate (ORR). Despite these findings, Dr Vidal noted that even patients with low TROP2 expression did better with SG as compared to the standard of care for metastatic TNBC, and as such, Dr Vidal suggested SG should be the new standard for 2nd line and greater metastatic TNBC, regardless of TROP2 status. In addition, he noted that SG should be used before T-Dxd for patients with TNBC and metastatic disease, as this was the primary endpoint of the ASCENT trial whereas this was only a subset analysis from the trial of T-Dxd.
Germline Testing and Molecular Tumor Profiling
Another target for treatment in those TNBC patients having a germline mutation in the BRCA 1 or BRCA2 gene is poly-ADP-ribose polymerase (PARP), which is involved in repairing DNA damage in normal cells. Breast tumors occurring in patients having a germline mutation in BRCA1/2 are candidates for therapy with PARP inhibitors such as Olaparib. Dr Vidal explained that the BRCA proteins are involved in repairing double-stranded DNA breaks and that inhibition of PARP in BRCA-mutated cells leads to apoptosis and cell death, and preferentially kills rapidly dividing cells such as breast cancer.
Owing to the treatment implications for patients with germline BRCA1/2 mutations as noted above, Dr Vidal noted that early germ line testing be considered in all TNBC patients and in those where there are treatment indications, such as age < 50 years old, and in those with strong family history. In addition, clinicians should consider late germline testing in all TNBC patients, although Dr Vidal notes that some somatic testing can fail to detect up to 10% of clinically actionable germline variants. Individuals with somatic mutations in high-risk genes should also be considered for germline testing when clinically applicable (for example, considering family history).
Dr Vidal noted that trials such as the Keynote 355 trial have shown the efficacy of immunotherapy with pembrolizumab in improving both PFS (9.7 months) and OS (23.0 months) in metastatic TNBC patients with high expression of programmed death ligand 1 (PD-L1) status. Similarly, in the Keynote 522 trial, immunotherapy with pembrolizumab, when used in combination with standard of care chemotherapy, significantly improved event free survival (EFS) from 76.8% with placebo to 84.5%. As such, PD-L1 testing may have a role in 1st line TNBC patients being considered for treatment with immunotherapy.
In the final portion of his presentation, Dr Vidal noted that NTRK is another rare potential target for treatment in TNBC, and the most commonly occurring molecular alteration is a gene fusion event between ETV 6 and NTRK 3, which is present in approximately 0.31% of adult tumors overall, but in approximately 90% of secretory type breast cancers. Importantly, patients with NTRK fusions have 2 treatment options, larotrectinib and entrectinib, which have shown very good ORRs of ~80% in highly pre-treated tumors harboring these molecular alterations. Of note, Dr. Vidal explained that not all available genetic testing assays are equivalent for NTRK-fusion detection. As such, if testing for NTRK, it is important to recognize the limitations of the testing that is chosen.
The NP Take Away
For the nurse practitioner, it is important to be aware of the breast cancer patient’s baseline biomarker levels including ER, PR, and HER2 (including those with ‘HER2 Low’ status), and how these may impact treatment options. For example, tumors with HER2 negative status and very low ER/PR levels behave biologically very similar to TNBC, and there are new treatment options such as T-Dxd which have shown efficacy in patients with HER2-Low status. In the past, chemotherapy was the only option for TNBC patients, but now targeted treatment approaches have been shown to have significant benefit over standard of care, and are important to consider in overall treatment planning. These include therapies like Sacituzumab govitecan, immunotherapy, PARP inhibitors (for patients with BRCA1/2 germline mutations), and NTRK inhibitors (for tumors with NTRK fusion). Appropriate genetic testing and tumor molecular profiling is therefore indicated for all TNBC patients.
Quick Summary
The definition of “triple negative” breast cancer (TNBC) is evolving beyond simply the lack of ER, PR, and HER2 expression.
Owing to new treatment implications for patients with “HER2-Low” status, it is important to define patient’s HER2 level on the basis of IHC staining (0, 1+, 2+ ,3+) as opposed to simply ‘positive’ or ‘negative’.
Clinicians should strongly consider treating HER2-, with low levels of ER and PR as TNBC, as these tumors are biologically similar to TNBC.
Antibody-drug conjugates like trastuzumab deruxtecan and Sacituzumab govitecan have changed treatment paradigms in TNBC and have efficacy in the HER2-Low subpopulation.
Other treatments like immunotherapy, PARP inhibitors, and NTRK inhibitors have expanded options for a more targeted treatment approach beyond chemotherapy for TNBC.
With the availability of effective targeted therapies, genetic testing and tumor molecular profiling is indicated for all TNBC patients.
Speaker Disclosure Information: Dr Portnoy listed no disclosures for this presentation.
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