MBCC: Emerging Therapies for Triple-Negative Breast Cancer

Joyce O’Shaughnessy, MD

Ahead of the 29th Annual Miami Breast Cancer Conference that starts March 14, CancerNetwork speaks with Dr. Joyce O’Shaughnessy, codirector of breast cancer research at the Texas Oncology–Baylor Charles A. Sammons Cancer Center and the US Oncology Network in Dallas, Texas. Her focus as an oncologist is on breast cancer prevention and treatment.

Dr. O’Shaughnessy will be presenting an overview of new therapies for triple-negative breast cancer at the Miami Breast Cancer Conference. Metastatic triple-negative breast cancer does not overexpress human epidermal growth factor receptor type 2 (HER2), and is estrogen- and progesterone-receptor negative. The trouble with this type of breast cancer is that it is better characterized by what it lacks rather than mutations that it has, making it difficult to identify treatments specific for this disease. Triple-negative breast cancer is aggressive, has a high rate of metastases, and carries a poor prognosis.

-Interviewed by Anna Azvolinsky, PhD

Cancer Network: Dr. O’Shaughnessy, what are the current treatment options for women diagnosed with triple-negative breast cancer? Let’s start with metastatic disease.

Dr. O’Shaughnessy: Metastatic cancer that is triple-negative is difficult to treat because our therapies are generally short-lived in their benefit, if they benefit patients at all. There is a subset of triple-negative metastatic patients who really don’t have responsive disease to any of our standard therapies. Our therapies are basically three, in my opinion, at the Level 1 evidence-where we have enough data from large phase III trials where we can say we know what the level of efficacy is-and that is 1) paclitaxel-bevacizumab, 2) gemcitabine-carboplatin, and 3) ixabepilone-capecitabine. These are the 3 options I think we have enough focused data on triple-negative breast cancer evidence to give them Level 1 evidence. There are a number of other agents we use such as the new drug eribulin which has a survival advantage in late-line metastatic breast cancer. That is certainly a reasonable option. And we certainly can use single-agent taxane as well, but those are the treatments that I think are most established for triple-negative breast cancer.

Cancer Network: Just a quick follow-up. Is eribulin usually used as a second- or third-line treatment? Or is it used up front?

Dr. O’Shaughnessy: Eribulin is approved by the FDA for patients who have had at least 2 prior chemotherapy regimens in the metastatic setting. So it is used in later-line.

Cancer Network: And what about options for women diagnosed with early-stage triple-negative breast cancer?

Dr. O’Shaughnessy: Early-stage triple-negative breast cancer we mostly cure. About 70% to 75% of patients with early-stage triple-negative breast cancer are cured by standard anthracycline-usually doxorubicin in our country-cyclophosphamide (A/C), and one of the taxanes, either paclitaxel or docetaxel. Node-negative patients have a higher cure rate, it is probably in the 85-plus percent range but if you put all of the early-stage triple-negative breast cancer patients together, including node-positive, our cure rate is in the 70% to 75% range with standard adjuvant chemotherapy.

Cancer Network: The patients that do have metastatic disease, is that more a function of a diagnosis at a late stage, or is it patients that have progressed. How are we at identifying early-stage disease?

Dr. O’Shaughnessy: The patients who develop metastatic triple-negative breast cancer generally do not present with metastatic disease. They simply recur usually within 2 or 3 years of their original adjuvant chemotherapy. We do not have a way yet to identify up front, those patients who will not be cured with standard A/C and taxane chemotherapy. That is one of the holy grails, to be able to pick those patients out up front who we are not going to cure and those we are going to cure, so that obviously we could put patients we are not going to cure onto clinical trials to try to better their outcome-but we don’t have a way to do that yet.

Cancer Network: There is data out there that shows triple-negative breast tumors, at least some of them, have defects in the DNA-repair pathway. These are mutations in either BRCA1 gene, p53, the MRE11 complex. So are there any current treatments that are being developed specifically to target some of these DNA-repair pathways?

Dr. O’Shaughnessy: Yes, there definitely are. Those patients in general may do fairly well. These may be almost highly curable patients with regard to standard A/C plus taxane, or A/C plus DNA-damaging agents. We are also looking at whether or not cisplatin or carboplatin should be added to standard therapies. The Cancer and Leukemia Group B CALGB is conducting a preoperative trial adding carboplatin to paclitaxel following A/C to see whether the pathological response rate increases in triple-negative patients.

This approach to DNA-damaging agents and optimizing them is really aimed at these patients who you are referring to, those who have defects in repairing double-stranded DNA. In addition to asking the question of adding carboplatin in the preoperative setting, for example, Dr. Kathy Miller and colleagues are conducting a study of a PARP inhibitor that is aimed at exploiting the vulnerability of cancer cells that cannot repair double-stranded breaks by inhibiting base-excision repair with a PARP inhibitor to really knock out all of the DNA-repair capacity in the cancer cell, in combination with cisplatin chemotherapy.

Dr. Miller is conducting a study in triple-negative breast cancer patients who do not achieve a pathologic complete response with preoperative A/C and paclitaxel chemotherapy, combining cisplatin with a PAPR inhibitor vs cisplatin alone in those patients to see whether really trying to exploit these DNA-repair pathways in a certain population of patients will benefit some patients. We know that not all of the triple-negative breast cancer patients, however, have this defect, it is just a subset of them and we are looking into whether we can identify those patients.

Cancer Network: Any other promising therapies on the horizon that are being explored?

Dr. O’Shaughnessy: There are a number of hypotheses. I think it is very important to realize, because they see the heterogeneity in their clinic every day, that the biology subtypes of triple-negative are not uniform. There are, just as we said, those that are the basal, which are generally very fast growing, they tend to have homologous recombination, DNA-repair deficits, and preclinical work suggests that these are the ones that may particularly benefit from cisplatin and also from interrupting base-excision repair so that they have no escape pathway so they cannot repair double-stranded breaks.

The more difficult to target group is the so-called mesenchymal breast cancers, and these are cancers that have defects that we are still ascertaining. We presented data at San Antonio from the TGen whole genome sequencing effort showing that some of these mesenchymal drug-resistant triple-negative breast cancers have amplicons in KRAS or BRAF in the RAS pathway that may explain some of the drug-resistant, invasive disease. Another hypothesis that is being looked at is whether some of these patients are signaling through the JAK2-STAT3 pathway. There is a clinical trial going on at the Dana-Farber Cancer Institute looking at the JAK2 inhibitor ruxolitinib in triple-negative patients, because of work published by Dr. Polliak’s laboratory showing that activation of the JAK2 pathway can occur particularly in some of the triple-negative breast cancer stem cells in the laboratory, so that is being looked at.

The Vanderbilt group and the Alabama group and the Translational Breast Cancer Research Network, I believe, are looking at a TRAIL inhibitor. Inhibition of the TRAIL receptor-it is actually an agonist of the death receptor, the TRAIL receptor-to see whether the triple-negative breast cancers can be killed by that strategy as well. And then there are clinical trials going on looking at MEK inhibitors which is downstream of the KRAS amplicon, the BRAF amplicon that I eluded to, in combination with either PI3Kinase inhibitor or AKT inhibitors because activation of the PI3Kinase pathway also occurs in these cancers through a variety of mechanisms. So combining a MEK inhibitor with an AKT inhibitor is also ongoing in triple-negative breast cancers. I think it is also important to point out that we are waiting for the results of the BEATRICE trial which is an adjuvant trial conducted in Europe specifically in early-stage triple-negative breast cancer patients and they received standard adjuvant chemotherapy with or without bevacizumab. And we are waiting for the results of this adjuvant bevacizumab trial in triple-negative patients so that could potentially be an advance in this population.

Cancer Network: Thank you so much Dr. O’Shaughnessy for joining us and we look forward to your presentations at the Miami Breast Cancer Conference. Thank you.

Dr. O’Shaughnessy: Thank you very much.