Evolution Boston 2023: Current Status and New Frontiers in Triple-Negative Breast Cancer
Presentation by Reshma Mahtani, DO, Miami Cancer Institute
At the Total Health 2023 Evolution conference held in Boston, Massachusetts, Dr Reshma Mahtani, Chief of Breast Medical Oncology at Miami Cancer Institute, presented a review of current and emerging therapies for triple-negative breast cancer (TNBC), which is defined as breast cancer that lacks expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2).
Dr Mahtani began with an overview of TNBC (BOX 1), which is typically seen in about 10-15% of all breast cancer patients, particularly younger women, and Black women also have a higher incidence of TNBC relative to other races. In the past, the only treatment for this aggressive and highly proliferative subtype of breast cancer was chemotherapy, owing to its lack of expression of ER, PR, and HER2. Despite an initial response to chemotherapy, however, resistance develops rapidly, and recurrences tend to occur earlier (within the first 5 years) rather than later, as seen, for example, with other hormone receptor (ER/PR) positive subtypes of breast cancer. Recurrences for TNBC also tend to occur in the visceral organs (e.g., liver, lung) and as many as 46% of TNBC patients can develop brain metastases.
Box 1. Overview of Triple-Negative Breast Cancer
TNBC is defined by what it is not:
TNBCs lack expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2).
TNBC patients are not candidates for hormonal therapy or HER2-directed therapies.
TNBC is an aggressive subtype of breast cancer that is highly proliferative and responsive to chemotherapy, although resistance develops rapidly.
TNBCs tend to occur in younger women, and Black women have a higher incidence than other races.
Recurrences tend to occur early and in the visceral organs (liver, lung) and in the central nervous system (brain metastasis)
TNBCs have been associated with mutations in the p53 gene and the breast cancer associated gene (BRCA) pathway.
It is now known that, despite the common features shared by all TNBCs (i.e., lack of receptor expression), there are some different subtypes of TNBC that can be recognized, with different biologic features. In addition, over the last decade, treatment options for TNBC have expanded beyond chemotherapy alone, and treatment can be guided based on the use of biomarkers, or molecular features of the TNBC tumor that can be assessed with a biopsy. For example, about 40% of TNBCs have expression of a biomarker called programmed death ligand 1 (PD-L1), and these patients can be treated in the first line (1L) setting with a combination of chemotherapy and immunotherapy, which helps the patient’s immune system to more effectively recognize and kill the cancer cells. For the smaller subset of TNBC patients who have a mutation in the breast cancer associated (BRCA)-1 or -2 genes, these patients are candidates for another type of therapy called a poly-ADP-ribose polymerase or PARP inhibitor, such as olaparib or talazoparib. Additional targeted therapies are now available for metastatic TNBCs that have other less common molecular features, such as an NTRK gene fusion, and the availability of these agents has helped to expand options for TNBC overall in the first, second (2L) and third line (3L) treatment settings (BOX 2). The use of these therapies requires appropriate molecular testing of the tumor biopsy sample using next-generation sequencing (NGS) technology, and may also include an assessment of the tumor mutational burden, or TMB, and the microsatellite instability (MSI) status (low or high). Dr Mahtani indicated additional clinical factors, such as prior therapies, toxicities of prior treatments, the length of time that the patient was free of disease (disease-free interval), and comorbid conditions of the patient, such as heart disease, diabetes, and their performance status, or fitness, are important to consider when selecting further appropriate therapy.
Box 2. Current Treatment Options for Triple-Negative Breast Cancer
First line (1L):
For PD-L1+: Immunotherapy (checkpoint inhibitor) + Chemotherapy
For PD-L1-: Taxane or platinum chemotherapy
For patients with BRCA 1/2 mutation: PARP Inhibitor (olaparib, talazoparib) or platinum chemotherapy
Second Line (2L):
For patients with BRCA 1/2 mutation: PARP Inhibitor (olaparib, talazoparib) or platinum chemotherapy
For TMB >10 mut/Mb or MSI-high: Checkpoint inhibitor (pembrolizumab)
Sacituzumab govitecan [a]
Trastuzumab deruxtecan for patients with ‘HER2-Low’ disease [b]
Single agent chemotherapy
Third Line and Beyond (3L+):
For patients with BRCA 1/2 mutation: PARP Inhibitor (olaparib, talazoparib) or platinum chemotherapy
For TMB >10 mut/Mb or MSI-high: Checkpoint inhibitor (pembrolizumab)
NTRK Fusion: Larotrectinib or entrectinib
Sacituzumab govitecan [a]
Trastuzumab deruxtecan for patients with ‘HER2-Low’ disease [b]
Single agent chemotherapy
[a]>2 prior lines of therapy 1 in the metastatic setting
[b]1 or more prior lines of therapy 1 in the metastatic setting
Antibody-drug conjugates in TNBC
Dr Mahtani also reviewed results for the antibody-drug conjugates (ADCs), another type of therapy that has become increasingly important for TNBC. ADCs are composed of an antibody that recognizes and binds to a specific target on the cancer cell, linked to a payload, a cytotoxic drug which kills the cancer cell after it binds and enters the cell. Some of the more important ADCs used in the treatment of TNBC include sacituzumab govitecan (SG) and trastuzumab deruxtecan (T-DXd). Importantly, these ADCs each have different targets and different payloads (BOX 3). Another important concept that has emerged in TNBC is the ‘HER2-Low’ subtype. Patients with HER2-Low breast cancer have disease that is not completely HER2 negative, and this subtype, which is defined by specific histologic and molecular testing, is now known to account for about 50% of metastatic breast cancers overall, including about a third of TNBC.
ADCs have become increasingly important for the treatment of HER2-Low breast cancer, for example, in the ASCENT trial, SG was found to improve both progression-free survival (PFS) and overall survival (OS) over chemotherapy, and this was true for tumors where HER2 status was completely negative, as well as those tumors deemed to be HER2-Low. In an exploratory analysis from a different trial (Destiny-Breast-04) T-DXd was also shown to improve both PFS and OS over chemotherapy for patients whose tumors were ER/PR negative and HER2-Low.
Box 3. Antibody-Drug Conjugates in TNBC
|
Agent |
Target |
Payload |
Efficacy in HER2-Low? |
||
|---|---|---|---|---|---|
|
Trop-2 |
SN-38 |
Yes |
||
|
Trastuzumab deruxtecan (T-DXd) |
HER2 |
|
Yes |
||
|
Trop-2 |
|
Not Determined |
Agents in bold are currently approved for use in TNBC.
New Frontiers in TNBC and Unanswered Questions
In the final portion of her presentation, Dr Mahtani highlighted several trials, including TROPION-PanTumor01 which is examining the efficacy of another ADC, datapotomab-DXd (Dato-DXd) in advanced TNBC. She noted the overall response rate (ORR) of 34% for this agent in a heavily pre-treated population, which she described as “quite remarkable”, with duration of responses of up to 7 months. She also noted that some of these patients had already received a prior ADC therapy and that the trial provides some hints there may be sequential activity of ADC therapies (i.e., a different ADC after a prior ADC).
She also highlighted the BEGONIA study, which is a study combining an immunotherapy (durvalumab) with various novel agents, including T-DXd and Dato-DXd for 1L treatment of metastatic TNBC. In one arm of BEGONIA, Dr Mahtani noted that patients with HER2-Low TNBC treated with durvalumab + T-DXd had a very encouraging ORR of 56.9% and a median PFS of 12.6 months. In another arm of BEGONIA, for patients treated with durvalumab + Dato-DXd, the ORR was 73.6% for metastatic TNBC, and she noted that results from BEGONIA suggest that adding immunotherapy with durvalumab to ADCs can enhance efficacy and durability of responses, without increasing toxicity. Dr Mahtani also noted an ongoing trial at her institution and others TROPION-Breast-02, which is examining the use of Dato-DXd versus chemotherapy for 1L treatment of locally advanced or metastatic TNBC.
With 2 ADCs currently approved for TNBC and likely others including Dato-DXd to follow (BOX 3), Dr Mahtani noted that several unanswered questions remain, for example, will one ADC work after another if they have the same target and different payloads, and what is the optimal sequence and/or combination of therapies. She noted although data are limited, there is some evidence for clinical responses when using one ADC after another, although large, prospective, randomized trials will be needed to inform clinical practice.
Speaker Disclosure Information: Dr Mahtani lists her disclosures as follows: Consultant/Advisor: Agendia, Amgen, Astra Zeneca, Daiichi, Eisai, Genentech, Gilead, Hologic, Lilly, Merck, Novartis, Pfizer, Puma, Sanofi, Seagen, Sermonix, Stemline.