Stacy L. Moulder, M.D., M.S.C.I. of MD Anderson Cancer Center graciously agreed to discuss Metaplastic Breast Cancer and the DAT trial with our group. Dr. Moulder is the Associate Professor, Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center and Associate Director of the Breast Center, Department of Breast Medical Oncology.
Q: Please help us understand what the term metaplastic means as it relates to breast cancer. How is metaplastic breast cancer (MpBC) different from other types?
A: Metaplastic tumors are identified based upon the presence of cancer cells that look like ordinary breast cancer cells (epithelial carcinoma cells) and cancer cells that do not look like ordinary breast cancer cells (non-epithelial cells). The non-epithelial cancer cells can include squamous type cells (resemble cells typically seen in lung, skin or head and neck cancers), sarcomatous elements (resemble cells typically seen in muscle cancers) and even osseous (resemble cells typically seen bone tumors) or neuroendocrine (resemble cells typically seen nerve/glandular tumors) cells. No one knows for sure why this happens; however we do know that cells that make up these tumors are molecularly similar, so they arise from a single cancer cell and are not two different cancers which have ‘grown together’ as hypothesized prior to our ability to molecularly characterize these tumors. Some metaplastic tumors have a low grade appearance (don’t look aggressive under the microscope) and are associated with an indolent behavior. Most have a more aggressive, high grade appearance with a higher tendency for recurrence or metastasis.
Q: Will you please also address the statistics in terms of the rarity of metaplastic breast cancer and its various subtypes.
A: Metaplastic breast cancers account for 0.2-5% of breast cancer diagnoses, but their incidence is increasing; likely due to WHO guidelines establishing the diagnosis. Metaplastic tumors with sarcomatous or squamous elements are the most common subtypes and the medical literature contains mixed reports regarding survival outcomes based upon subtypes. It is most likely that tumor grade and initial stage at diagnosis are more important than the subtype of metaplastic cancer.
Q: The issue of genetic profiling of cancer tumors is being discussed more and more. What are your thoughts on tumor profiling for MpBC patients? Should we consider this option for our first primary tumors or is it only necessary if we have additional tumors, local recurrence or distant metastasis? What is the benefit to the patient? Is there a particular genetic mutation that you are more likely to see in MpBC? Do you think there are some potential mutations specific to MpBC that are yet unidentified?
A: We are very interested in molecularly profiling metaplastic breast cancers and have been actively doing this for our patients through clinical trials. Genomic analyses have revealed that metaplastic tumors with squamous and sarcomatoid elements more closely resembled the claudin-low rather than basal subtype of breast cancers. Though most triple-negative breast cancers are classified as basal-like by microarray analysis, approximately 30% of triple negative tumors are molecularly distinct from basal-like breast cancers as they display mesenchymal features, including enrichment in epithelial-to-mesenchymal transition (EMT) and stem-cell like characteristics. These types of breast cancers have been described by different investigators and have been labeled ‘claudin-low’ ‘mesenchymal’ and ‘mesenchymal stem cell-like’.
Preliminary data suggest that these mesenchymal-like TNBCs carry a high rate of molecular aberrations that activate the PI3K/Akt/mTOR pathways suggesting that these subgroups may be responsive to drug regimens targeting this pathway. Interestingly, when a set of molecularly identified claudin-low tumors were evaluated under the microscope, 10% of these tumors were metaplastic. We and other investigators have also found that metaplastic tumors contain a relatively high rate of molecular aberrations that lead to activation of the PI3Kinase/Akt/mTOR pathway. Drugs that target this pathway are an active source of clinical investigation and are proving beneficial in estrogen receptor-positive breast cancers, so we are hopeful that they will lead to benefit in metaplastic and mesenchymal subtypes of TNBC as well.
There are multiple considerations that go into a decision to have a tumor molecularly profiled. As a clinical scientist, I strongly believe that we are only going to learn more about aggressive or chemotherapy refractory tumors by studying their molecular characteristics and comparing these characteristics across multiple patient samples. To this effect, MDACC and several other research-based cancer centers have the capability to actively profile and collect data on rare tumors using clinical trials that also relay the results of the profiling to the patients. Patients with metaplastic tumors should be aware that there are no data to support acting upon these results for selection of neoadjuvant or adjuvant therapy for their primary tumor; however these results do take time to acquire, so by profiling the primary tumor at the time of diagnosis we feel that we are one step ahead of the game should the patient develop recurrent disease. Our institution has seen a moderate to strong concordance between genetic aberrations in primary tumors and recurrent/metastatic sites for breast cancers (most of which were non-metaplastic) though it has been noted that metastatic sites may harbor additional molecular aberrations from the primary tumor in approximately 20-30% of paired tumor samples. I do think that there are additional molecular aberrations to be found in metaplastic breast cancer and that is why we strongly encourage participation in clinical trials that involve molecular profiling. Also, because this type of profiling is commercially available, it is important to emphasize the value of having profiling done through a clinical trial where data generated from multiple samples of metaplastic breast cancer can be evaluated and compared to discover trends that may lead to future targeted therapies to improve outcomes for patients.
Q: As we understand it, most MpBC is negative for the expression of ER, PR and HER2. We are often treated with the same triple negative drug regimens as other triple negative breast cancers. It appears that the results of the most commonly used chemo regimens are ineffective as evidenced by frequent recurrences and distant metastases. We have heard it said that metaplastic breast cancer is “chemo resistant.” Can you elaborate on this and talk about how specific chemo regimens are selected to help us understand why this issue of resistance may or may not be true.
A: Because metaplastic tumors are rare, they make up a small fraction (if any) of patients treated on randomized clinical trials. This means that most of the data that has been generated to determine outcomes for metaplastic cancer are from retrospective reviews of clinical data. These retrospective data collections are an important source for data in rare cancer subtypes, but not considered the gold standard to determine therapy benefit for cancer treatments.
We feel the best way to determine disease sensitivity to chemotherapy in patients with localized disease is by studying response in patients treated in the neoadjuvant setting (therapy before surgery) to determine the rate of pathologic complete response (pCR) in the breast and draining lymph nodes. pCR is the complete absence of invasive cancer in the breast and draining lymph nodes at the time of surgical resection in patients who have been treated with pre-operative therapy. If this occurs, patients have an excellent prognosis with <10% chance of developing recurrent disease. Several published studies have demonstrated pCR rates of 20-30% in triple-negative breast cancer (TNBC) patients treated with anthracycline/taxane containing chemotherapy regimens. Data are emerging that adding platinum based drugs such as carboplatin or cisplatin may further improve the rates of pCR in TNBC. When reviewing the patients with localized MpBC treated with chemotherapy at MDACC, the pCR rate was 10%, which is lower than that seen in TNBC, but not zero; thus, chemotherapy in the neoadjuvant setting should be strongly considered for patients with localized MpBC because there is a subset of patients who do derive benefit. It is also important to note that not all patients who have residual disease after neoadjuvant chemotherapy develop recurrent disease. The data regarding response to therapy in the metastatic setting is even more limited. In a retrospective evaluation of 7 patients with metastatic MpBC treated with a variety of chemotherapy regimens at the Mayo clinic, 1 patient developed a partial response of 4 months duration when treated with doxorubicin. Other investigators have described similar clinical experiences in small numbers of patients.
Q: Can you tell us about your clinical trial related to MpBC?
A: Through the Center for Targeted Therapy at MDACC, we have studied the DAT regimen which consists of liposomal doxorubicin (Doxil, a chemotherapy drug similar to doxorubicin), bevacizumab (Avastin, a drug that affects blood vessel formation) and temsirolimus (Torisel, a drug that blocks mTOR, a kinase involved in signaling through the PI3Kinase/AKT/mTOR pathway). Two patients have developed complete responses (disappearance of metastatic disease by imaging studies); one of which has been ongoing for the past 4 years, and several patients have had a partial response (decrease in tumor size by at least 30%) or stabilization of their disease for 6 months or more.
Q: Why did you select the specific drugs for the DAT trial?
A: The trial was ongoing in the Center for Targeted Therapy and the first patient with metastatic MpBC treated on the study had a complete response to therapy. She remains in complete response (no evidence of cancer) to date (4 years later).
Q: How do you purpose that this combination may be more effective than other current drug regimens?
A: Temsirolimus: We noted that metaplastic tumors had a relatively high rate of molecular aberrations that could result in activation of the PI3K/Akt/mTOR pathway and knew that cell lines that shared characteristics of metaplastic tumors, such as mesenchymal or mesenchymal stem cell-like cell lines, demonstrated response to PI3K inhibitors in pre-clinical models. Since we knew that temsirolimus blocked activity of mTOR, an important component of the PI3K/Akt/mTOR pathway, we thought it may be beneficial for this group of patients. Bevacizumab: Mesenchymal and mesenchymal stem cell-like tumors are hypothesized to develop from immature breast precursor cells, thus retaining stem cell-like features. Metaplastic and claudin-low cancers closely resemble cancer stem cells (CSCs) and, given the role of the Akt pathway in stem cell maintenance, may be one reason metaplastic tumors are sensitive to mTOR inhibition. Preclinical data suggests that treatment with bevacizumab induces low oxygen content within tumors (hypoxia) which increases the population of CSCs in TNBC tumor models. This was associated with increased activation of the PI3K/Akt/mTOR pathway suggesting that treatment with bevacizumab may actually prime tumors with CSC like characteristics for response to temsirolimus.
Q: We understand your trial includes metaplastic tumors found in other areas than the breast. What are the other places in the body where metaplastic tumors appear?
A:Basically, metaplastic tumors are tumors where epithelial cancer cells are found in the presence of non-epithelial cancer cells. Such tumors are known by names other than ‘metaplastic’ (for example: carcinosarcoma) and can originate outside of the breast, in areas such as the uterus, ovary, lung, gastrointestinal tract, and head and neck.
Q: Do you think metaplastic breast cancer tumors should be treated like breast cancer or should it be treated with the subtype as the primary consideration. For example if squamous cell carcinoma is more frequently found in the lung or other organ, should the treatment for squamous cell of the breast be treated as if it were found in the lung?
A: This is a very good question and one that is not easily answered based upon existing data. Fortunately, chemotherapy drugs commonly used in breast cancer treatments do have activity in sarcomas and squamous type cancers, which are the two most common forms of high grade metaplastic cancers.
Q: Will you share the results of your trial so far (generally speaking) and tell us when the next phase is to begin? Are there any efforts being made to allow for trial participation through other NCI designated cancer centers?
A: We are attempting to activate a randomized phase II study of DAT through the Southwest Oncology Group (SWOG). The study is currently under review at the national level.
Q: Because of the aggressive nature of these tumors many of us (especially those of us with recurrences) wonder if we should have insisted on mastectomy rather than lumpectomy for our first tumors. Do you know of any data, anecdotal or otherwise, that a mastectomy should be considered more often for metaplastic tumors? There are a number of studies suggesting lumpectomies are just as effective as mastectomies in the treatment of more common forms of BC but with these aggressive and sometimes chemo-resistant MpBC tumors it would be nice to have a study looking at MX vs Lumpectomy to help guide our decisions.
A: The best way to answer this question is through a randomized trial; however, the number of patients required to demonstrate equivalence between breast conserving surgery and mastectomy would make the trial unfeasible for rare tumor types such as metaplastic cancers. In a retrospective review published in the Annals of Oncology by Brian Hennessey in 2006, the type of surgery a patient received did not have a statistically significant impact on overall survival; however, breast conserving surgery was associated with a higher rate of local recurrence. The lack of impact of the type of surgery on overall survival is most likely related to the propensity of metaplastic tumors to metastasize to distant sites in the body, a process that is not affected by the type of surgery that a patient receives. It is also important to note that some patients who develop local recurrence after breast conserving surgery remain cancer free after undergoing ‘salvage’ mastectomy.
Q: During the San Antonio Breast Cancer Symposium this year (2013), there were multiple studies suggesting platinum based drugs may be effective in a neo-adjuvant setting for triple negative patients. 1.) What are your thoughts on these studies? Do you feel like they may apply to some MpBC patients? And 2.) Many of the women in the group who have had neo-adjuvant treatment had to stop because their tumors progressed during treatment. As a result, many of us are afraid of this kind of treatment. Could you explain how neo-adjuvant treatments might someday benefit us and when this course of treatment is appropriate.
A: It is difficult to know if the platinum-based studies are applicable to MpBC patients; however, if at final publication the results remain as promising as the initial presentation, adding platinums would be a strong consideration for any triple-negative breast cancer, which would include metaplastics.
While metaplastic tumors are less likely to have complete responses to neoadjuvant therapy, there is clearly a subset of patients (the MDACC experience would suggest 10%) that have a complete response to treatment and, as such, have an extremely good prognosis. There are likely other patients who have a partial response to therapy that also derive some benefit from the treatments. Because of the relatively high risk of developing distant metastasis, patients should consider systemic chemotherapy as a treatment option, and given that we cannot currently identify the tumors that are either responsive or refractory to therapy prior to initiating treatment; my usual recommendation is that patients receive therapy using a neoadjuvant approach so that the tumor can be carefully monitored (I do a physical exam every 3 weeks and breast imaging every 6 weeks) for response to therapy. Using this approach, chemotherapy can be halted and the patient taken to surgery if there is an increase in the size of the tumor. Such an approach spares these patients from receiving drugs that can have significant side effects and are not likely to be of benefit to the patient. If the patient goes to surgery first and there is no tumor in place to monitor for response, then the chemotherapy must be given ‘blindly’ knowing that there is an unidentified sub-group of patients with chemorefractory disease that will derive no benefit from the treatments.
Q: During our recent phone conversation, you suggested that the incidence of metaplastic breast cancers may grow in the next few years? Can you explain why you believe this? Will more women be getting MpBC or will more tumors that were missed in the past be correctly identified as metaplastic in the future?
A: Since the WHO developed criteria defining metaplastic cancers, more pathologists are aware of the diagnosis and tumors previously characterized as ‘poorly-differentiated’ may actually meet criteria for a diagnosis of metaplastic cancer.
Q: Because of the mixed nature of our tumors we are often not given a complete picture of the tumor type in the narratives within our pathology reports. What percentage of the tumor must have characteristics of one or more of the subtypes in order to be classified metaplastic?
A: The WHO criteria are descriptive, so a tumor must essentially have the presence of a non-epithelial component to meet the criteria.
Q: What inspired you to become interested in MpBC? What do you find most rewarding professionally when working with patients with MpBC and what are the most challenging aspects of this disease?
A: As a clinical investigator with a research interest in drug development and phase I trials, I usually see more disease progression than response to treatment. Having a patient develop a complete response to treatment that has been durable was exciting; but piecing that clinical information together with the data defining the molecular characteristics of metaplastic cancers made the research incredibly compelling.
It is easy to discuss the most challenging aspect of a clinical research interest in metaplastic cancer: the rarity of the disease. Concerns over low patient accrual rates often limit pharmaceutical company interest in sponsoring clinical trials and call into question the feasibility of randomized trials, which are the gold standard for determining the benefit of new therapies in cancer patients.
There are many rewarding aspects of working with patients who have metaplastic breast cancer. Probably the most rewarding include having informed discussions with patients about their disease, the ability to test these tumors for molecular aberrations that may help in guiding therapy, and the option of offering a promising therapeutic clinical trial to patients who have previously been told that they have limited chance of response to standard therapy.
Q: Are there any myths or issues of patient misinformation that you see regularly? Will you kindly use this opportunity to clarify areas of misinformation and also provide us with some positive thoughts about this rare diagnosis.
A: Yes, would like to use this opportunity to comment on the assumption that patients with metaplastic tumors should not receive neoadjuvant or adjuvant chemotherapy because the tumors are ‘refractory’ to treatment. Because of the relatively high risk of developing distant metastasis, patients should consider systemic chemotherapy as a treatment option, preferably in the neoadjuvant setting so that the tumor can be monitored for response to therapy.
I am very hopeful that we may be able to use a targeted therapy approach to treating metaplastic breast cancer based upon the results that we have seen in the phase I trial as well as the molecular characteristics that have been identified in MpBC.
Q: Is there anything we can do as patients to help further your research?
A: Patient advocacy has been a game changer for breast cancer research in general, so anything that you can do to spread awareness and to advocate for clinical research, not only in metaplastic tumors, but also rare tumors as a whole would be greatly appreciated.