Triple-negative breast cancer (TNBC) defined by lack of estrogen, progesterone, and the HER2 receptor accounts for 15% of all newly diagnosed breast cancers. With limited treatment options, the median overall survival of these patients is just over one year. TNBC as compared to other subtypes of breast cancers are more likely to have a robust immune infiltrate and have a high level of tumor-infiltrating lymphocytes. They can also have a higher level of PD-L1 expression and are generally genetically unstable and have a high tumor mutation burden. This makes this tumor type amenable to different therapies.
At the AACR virtual conference, Dr. Rita Nanda talked about different therapies that were approved in the past and the ones that are currently under investigation for TNBC. According to her, a number of observations from monotherapy checkpoint inhibitor trials show that TNBC is reactive to anti-PD-1 therapies in the front-line setting. So earlier the patients get these agents in the disease course, the more likely they are to respond to the treatment. This response also goes up when TNBC has higher tumor infiltration lymphocytes and is positive for PD-1 marker.
Dr. Rita Nanda, University of Chicago
While there is a modest monotherapy response to checkpoint inhibitors, combination strategies are likely going to be more effective. Combination strategies with chemotherapies, radiotherapies, and other targeted therapies are also being investigated. Dr. Rita Nanda talks about five categories of therapies that are currently being approved or investigated for TNBC.
1. Checkpoint inhibitors
Immune checkpoint inhibitors have demonstrated efficacy in the advanced breast cancer setting. Two anti-PD-1/PD-L1 agents are approved for PD-L1 positive metastatic TNBC. Pembrolizumab and Atezolizumab are approved for the indication in combination with nab-paclitaxel or paclitaxel chemotherapy. There is an emerging role of immune checkpoint inhibition in individuals with early-stage TNBC.
The Impassion 130 trial demonstrated that combination treatment with Atezolizumab and nab-paclitaxel improved progression-free survival as well as overall survival with the combo treatment. This effect was even more pronounced for patients whose tumors were positive for PD-1 marker. Keynote 355 trial showed that the combination of Keytruda and Chemo significantly improved median PFS and duration of response in these patients. The combo got the FDA approval in November last year.
2. PARP inhibitors
PARP inhibitors are another class of drugs that received FDA approval for the treatment of metastatic HER2 negative breast cancer. Olaparib and Talazoparib could improve progression-free survival and quality of life of patients with breast cancer. However, they failed to improve overall survival. OlympiA trial also tested Olaparib in an early setting in patients with HER2 negative breast cancer. The drug was found superior to placebo and the results from the trial will be out soon.
3. Antibody-Drug Conjugates
A number of ADCs are in the development for TNBC and Sacituzumab Govitecan has gained accelerated regulatory approval in 2020. Ladiratuzumab Vedotin, Trastuzumab Deruxtecan and Trastuzumab Duocarmazine is still under investigation for this indication.
4. Targeting AKT pathway
Researchers are investigating the AKT pathway in TNBC which can be deregulated in ~35% of cases. Despite this, Ipataserib, an ATP-competitive AKT inhibitor failed to show any improvement in PFS in the Phase 3 trial.
5. Targeting androgen receptor
Androgen receptor blockade in androgen receptor-positive cancers is also being investigated in small trials. Some of the treatments such as Bicalutamide, Enzalutamide, Abiraterone have shown modest response in PFS in patients who have androgen receptor expression of 10% or more. These are also being tested in combination with chemotherapy.
Copper Depletion in the Tumor Microenvironment
Copper is an essential micronutrient relevant in a myriad of normal biological processes and processes related to cancer such as angiogenesis, stromal and extracellular matrix remodeling, and mitochondrial respiration. Copper is critical for the TNBC cell line for migration and invasion.
To understand the role of copper in cancer metastasis, Dr. Linda Vahdat from Memorial Sloan Kettering Cancer Center tested the effect of a copper chelating agent tetrathiomolybdate (TM) in breast cancer patients who were at high risk. These are the key inferences from the trial:
- Event-free survival of 71.4% and overall survival of 64.7% was observed following TM treatment
- The event-free survival was similar for patients with either TNBC or HER2 positive breast cancer.
- The median overall survival for stage 4 TNBC at the time of design of the study was 11 months, which doubled to 20 months after the treatment.
Dr. Linda T Vahdat, Memorial Sloan Kettering Cancer Center
While copper managed to improve survival and other parameters for cancer patients, its mechanism of action is not clear. Dr. Linda used a mice model seeded with breast cancer cells to understand copper’s action on tumor growth and metastasis.
While copper failed to reduce primary tumor growth, it prevented metastasis of the tumor. It was observed that TM reduced levels of lysyl oxidase (LOXL2) protein, which in turn reduced collagen crosslinking as well as collagen fibrillar length in the premetastatic lungs. Low levels of LOXL2 were also seen in tumors derived from patients. Moreover, lower levels of LOXL2 were found associated with a better outcome. Besides, LOXL2 few other markers associated with collagen degradation were found associated with better outcomes. Overall, TM works by modulating LOX levels and collagen tumor microenvironment.
With the positive effect seen with TM in breast cancer patients, it will also be tested in an adjuvant setting in combination with Capecitabine.
Cellular Landscapes of TNBC
Breast cancer landscapes are dominated by copy number aberrations than by point mutations. Dr. Carlos Caldas from Cancer Research UK Cambridge Research Institute talked about the classification of TNBC tumors in different clusters. Depending upon the copy number aberrations and gene expression data, breast cancer can be classified into 10 clusters. TNBC falls in two clusters-cluster 4 and cluster 10. Cluster 10 expresses genes that are highly unstable whereas cluster 4 expresses genes, which are mostly silent.
Dr. Carlos M. Caldas, Cancer Research UK Cambridge Research Institute
These clusters also have differences in their prognosis. TNBC cancers in cluster 4 are more prone to relapse and their probability of relapsing up to 20 years after surgery is high. On the other hand, TNBC cancers in cluster 10 are less prone to relapse and have a lesser chance of relapsing up to a 20-year time point. This shows that TNBC patients that fall in cluster 4 need tailored therapies that could prevent their chances of relapse.
Even though there are differences in the prognosis, the two clusters are not very much different in their mutational profile. Dr. Carlos explains that these differences lie in the cellular landscape of the tumor microenvironment. Using imaging mass cytometry that identifies different cell types in the tumor, Dr. Carlos determined that cells in TNBC cluster 10 tumors consisted of epithelial cells such as basal cells and hypoxic cells and a particular type of macrophages. The cellular landscape, however, is very different for cluster 4 TNBC tumors. Dr. Carlos notes that this could contribute to differences in the prognosis of two clusters.
Besides looking at the tumor microenvironment, Dr. Carlos also looked at cell-autonomous compartments of TNBC tumors. With imaging mass cytometry, Dr. Carlos’ group identified 11 cancer cell phenotypes, which could be classified into mesenchymal, basal, luminal, and other mixed/epithelial cells. TNBC cells had one basal cell phenotype and three different mesenchymal cell phenotypes. Upon further characterization, TNBC tumors can be classified into basal cell dominant tumors or mesenchymal cell dominant tumors. The two tumor types have different drug responses. For example, tumors dominated by mesenchymal cell phenotype are more responsive to AstraZeneca’s CHEK1/2 drug than those dominated by basal cell phenotype.
By combining multidimensional data, which includes, clinico-pathological variables, genomic variables, and gene expression variables, Dr. Carlos’ team is now developing a prediction algorithm that could predict the response of the tumor to different drugs.
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