Q: What testing is recommended for triple negative breast cancer that is not routinely done for hormone receptor (HR)-positive or HER2-positive breast cancer?
A: Routinely, there really isn’t any other testing that’s done for triple negative breast cancer. As you know, the hallmark is HR negativity and HER2 negativity, and these are usually high-grade cancers with high Ki67, which is one of the test markers that is usually done. However, there is a lot of interest in trying to determine different subtypes of triple negative breast cancer, and one subtype that is often used synonymously with triple negative breast cancer is basal-like cancers. Not all basal-like cancers are triple negative, however, and not all triple negative breast cancers are basal like. The reason for mentioning basal-like cancers is that they tend to express epidermal growth factor receptor and cytokeratin 5 and 6 are essentially the hallmarks of the basal-like subtypes. However, in practice, they’re not routinely used because we don’t really change our treatment based on whether a patient has the basal-like variety of triple negative breast cancer or just regular triple negative breast cancer. So, I think this question brings up a key issue, which that there are probably multiple types of triple negative breast cancers, and at this point, we don’t really have a good feel for what those different subtypes are and whether we need to treat them differently. So, for now, most of this testing is at a research level, but there are some interesting targets that are being looked at, including epidermal growth factor receptor and androgen receptors. So, standard practice is to do nothing outside of routine testing, except perhaps Ki67.
Q: Would you comment on the effectiveness of iniparib and the status
of the phase 3 clinical trial?
A: Iniparib is an intravenous PARP inhibitor and it was initially looked at in a randomized phase 2 trial in which patients with triple negative breast cancer were randomized to chemotherapy with gemcitabine plus carboplatin plus or minus iniparib. That phase 2 trial, which was presented as a plenary session at ASCO, was recently published in the New England Journal of Medicine, and the results showed a markedly improved response rate for patients who received iniparib plus chemotherapy compared with iniparib alone. The response rate went from being about 16 % in the chemotherapy alone group up to almost 50% in the patients who got iniparib plus chemotherapy. There is interest to look at other possible combinations, for example, gemcitabine, but we really need more data.
In the above mentioned study, progression free survival and overall survival were also significantly improved in the patients who received iniparib. To register this agent, however, the manufacturer was required to carry out a phase 3 study that was essentially identical. So again, patients with metastatic triple negative breast cancer treated in the first-, second-, or third-line settings were randomized to carboplatin and gemcitabine plus or minus iniparib. We haven’t see the results of this trial, but the manufacturer issued a press release at the end of January stating the trial had not met its endpoints. So, essentially, it was a negative trial. There were co-primary endpoints of progression free survival and overall survival in the study and, unfortunately, the PARP-inhibitor arm did not meet those criteria with statistical significance. The information we are getting about this trial has been suggesting that there was a significant benefit with the addition of iniparib to chemotherapy in the second- and third-line settings, but we have not seen that data yet, and it’s very hard to understand why that would be the case. So, one of the questions, of course, why the results of the phase 3 trial are negative when the phase 2 trial had such impressive results. It has been suggested that one of the possible answers to that question might be that the phase 2 trial could have been enriched with patients who had a positive family history, and, therefore, may have had a BRCA mutation; this might explain the benefit seen in the phase 2 trial. We know the PARP inhibitors do appear to work as single agents in cancers that have defects in the other DNA repair mechanisms, including homologous recombinations, which is what happens with BRCA mutations and BRCA deficiencies, so, that’s a possible reason for this.
In summary, it’s really not clear at this time what the future of this drug is. It is being looked at in the preoperative setting along with chemotherapy, and there were some adjuvant-setting studies as well, although these are now on hold. I think, going forward, we probably need to be a little bit more stringent with the PARP inhibitors and really try to use them in cancers that we know have defects in DNA repair. So, that’s essentially what’s going on with iniparib. And, again, no one has actually seen the results of the phase 3 trial, although I imagine they will be presented at ASCO.
Q: What remedies does a patient have when all other treatment modalities fail? What would you recommend?
A: I think the simple answer here is clinical trials. Unfortunately, this is something that we see all too often with metastatic triple negative breast cancers because it does develop resistance to the treatments that we have available fairly rapidly. Clinicians can go to www.clinicaltrials.gov and see options that are available for their patients. There are different trials looking at targeting different proteins in the cell, like targeting epidermal growth factor receptors and targeting other growth factors in the triple negative cells. I would strongly encourage physicians to look into a clinical trial for patients in which the prior treatments have not worked or are no longer working.
Q: Could you comment a little bit about surgery? Do we have to use mastectomy every time, or can we also try for breast-conserving surgery with sentinel lymph nodes? In your opinion, which of these is the most beneficial technique?
A: Right now, depending on the tumor size, we give many patients the option to proceed with lumpectomy and radiation therapy, or mastectomy. There are certain patients, of course, who have very large tumors who benefit from having a mastectomy. But, in general, this situation may be a little different in patients who have triple-negative breast cancer than it would be in patients who have, for example, BRCA mutations because patients who have true inherited mutations have a higher risk of in-breast recurrence and contralateral breast cancer. So, in those cases, we tend to favor mastectomy. For the majority of the patients with triple-negative breast cancer, lumpectomy and radiation remain a very good strategy for local management.
Q: Would you please comment on tumor size criteria in adjuvant therapy? Does this matter anymore?
A: Despite the tremendous advances that are being made in terms of tumor profiling and nodal status, tumor size still plays a role in the decision to use adjuvant therapy. We have a variety of tools that can be used. We can perform molecular profiling using one of two commercially available technologies, MammaPrint® or Oncotype DX (although the latter is only appropriate for patients with ER+ breast cancer), to help determine whether patients need a specific treatment or no treatment at all. Still, if patients have large tumor sizes or if patients have lymph node metastases, anatomy plays an increasing role in the use of adjuvant therapy in those cases. So yes, tumor size still matters.
Q: What are the cisplatin-based regimens that are commonly used in the treatment of triple-negative breast cancer? Is there more than one regimen?
A: Cisplatin has not received FDA approval for the treatment of patients with either advanced or early stages of breast cancer. However, a variety of studies have looked at platinum agents in patients with newly diagnosed metastatic breast cancer or refractory metastatic breast cancer over the years.
In terms of cisplatin, one of the first things we need to figure out is its real activity as a single agent. We also need to evaluate its activity in combination strategies for patients with triple-negative breast cancer. A report was recently presented at the 2010 ESMO (European Society for Medical Oncology) Congress in Milan just last month that evaluated this. It was a randomized phase 2 trial comparing cisplatin alone and cisplatin with cetuximab in patients with triple-negative disease. It was a particularly good trial because it reflected that the single-agent activity of cisplatin in terms of response rate for patients with triple-negative breast cancer was only 10%. When the investigators added the EGFR inhibitor cetuximab, the response rate went up to 20%. So, based on those data, we can conclude that neither of those regimens would be treatments that we would traditionally recommend in clinical practice. Although there is interest to look at additional combinations with cisplatin, let’s say, with gemcitabine, for example, we really need more data to draw additional conclusions.
There is also interest to look at carboplatin in triple-negative breast cancer. Although there is an ongoing randomized phase 3 trial testing its use as a single agent in triple-negative disease, results are not yet available. This trial is comparing single-agent docetaxel with single-agent carboplatin in patients with triple-negative breast cancer—or specifically in patients who have BRCA1 mutations. Patients enrolled in this study are randomized to one of these treatments and, at the time of progression, are crossed over to the other treatment. I think that this trial, which has mainly been conducted outside of the United States, will clarify the role of carboplatin as single-agent therapy. There is also interest in looking at carboplatin in combination with gemcitabine and/or iniparib, and we are currently waiting for the results of a randomized phase 3 trial examining this that completed accrual February of this year.
Q: Would you talk a little bit about adjuvant therapy for triple-negative breast cancer and maybe share your opinions on what you have seen in practice and what you think is the best approach available today?
A: We have actually looked at these data quite carefully, and, right now, the optimal strategy for managing patients with triple-negative breast cancer in terms of chemotherapy is quite similar to the strategy that we use in patients with ER+ breast cancer or even HER2+ breast cancer. That means that the patient should receive at least six cycles of chemotherapy, and it could be in the form of TAC, or it could be a sequential approach of AC chemotherapy followed by a taxane—either docetaxel once every 3 weeks or paclitaxel weekly. Paclitaxel can also be administered every other week. Although there is interest in looking at the platinum agents in metastatic triple-negative breast cancer, it would be premature—at least in practice—to use a platinum agent for patient management in the adjuvant setting. The standard is still AC followed by T to optimize patient outcomes.
Q: Do patients with triple-negative disease have a worse prognosis if they are BRCA mutated?
A: No one has done a large enough analysis to be able to look at the prognostic impact of triple-negative in the presence or lack of BRCA1 mutations. To answer this question, we would need to have access to a large cohort of patients, look at genotyping for BRCA mutations, and develop an assay to test tumor specimens for the function of the BRCA1 gene because in the setting of these patients, one or the other may occur. That is, some patients may have mutations and some may have dysfunction of the gene at the protein level, which can also impact what happens in the clinic.
This is one of the big questions of research at this time: can we develop a test to measure the function of the BRCA1 gene? In the clinical trials that are currently underway, we are enrolling patients based on the lack of ER/PR/HER2 expression, but I think we need to devote more effort into looking at tumor biology so we can optimize patient selection for the new treatments that are currently under evaluation.
This question is also related to a previous question about another combination therapy we are testing within our cooperative group, the NCCTG (the North Central Cancer Treatment Group), in patients with refractory triple-negative breast cancer: cisplatin combined with a novel compound called brostallicin, which is a synthetic second-generation DNA minor-groove inhibitor with enhanced efficacy in the presence of the BRCA1 mutation. This demonstrates that we are interested in looking at novel compounds to try to optimize a treatment for patients with this mutation.
Q: Is there a difference in EGFR/C-KIT positive triple-negative disease and EGFR/C-KIT negative triple negative disease in terms of epidemiology, survival, and patient outcomes?
A: The specific role of c-kit or EGFR as prognostic or predictive of systemic therapies in patients with triple negative breast cancer is unknown. The very preliminary data available do not appear to suggest that there is a direct correlation between expression of these genes and benefit to anti-EGFR or anti-c-kit therapies, although all studies have been limited in terms of having specimens from the metastatic tumors for validated assays of these markers. Other markers may be more promising but still need further evaluation. These include stem cell markers, GRB-7, PARP-1, functional BRCA1 genes, markers of homologous recombination, and others.
Q: Given the recurrence pattern in women with triple-negative disease who have had a pCR, should I screen for brain metastases in the absence of symptoms?
A: Emerging data do suggest that patients with TNBC have a higher risk of developing brain metastases. There are no data, however, to determine whether screening for brain metastases makes sense or whether detecting a brain metastasis early is associated with an improved outcome. Looking at the I-SPY trial, it appears that patients with TNBC who obtain a pCR have a very low recurrence rate, which would include recurrence in the brain. At this point, there are no data to support screening the brain in these patients, although this is clearly an interesting and important issue.
Q: For the same population, is a mammogram every 12 months sufficient, or is it wise to screen these women more frequently than those with other breast cancer subtypes?
A: TNBC has a propensity to recur in distant sites, rather than local sites. Nonetheless, appropriate screening is important. At this point, there are no data to support administering mammograms more frequently than annually. The role of MRI in these patients is unclear, but would be recommended in patients with BRCA1 mutations.
