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Can you talk about PARP inhibitors in general? What are these drugs, and what do they target?

 PARP inhibitors inhibit poly (ADP-ribose) polymerase (PARP), which is an important enzyme in the repair of DNA errors. The original work on PARP inhibitors came from researchers who studied DNA repair, such as Alan Ashworth, PhD, FRS, in the United Kingdom. They realized that if the PARP enzyme was blocked, there would be breaks in the DNA that could not be well repaired, and those breaks might kill cancer cells. So, researchers looked for cells that would be unable to repair errors after the PARP inhibitor caused them. When you think about chemotherapy in general, there are mistakes and breaks that occur in the DNA all the time. When it’s effective, it is often because those breaks are fatal to the cell, and there are so many breaks that the cells can’t recover. Tumors that lack functioning BRCA1 or BRCA2 are good targets for PARP inhibitors. Most breast and ovarian cancers do not have mutations in the 

 genes. When tumors develop in people who have inherited mutations in one copy of their 

 genes in all of their cells, including in their normal breast or ovary, these tumors have often lost the second normal copy and are missing functioning BRCA1 or BRCA2, and, therefore, are particularly susceptible to killing by PARP inhibitors.

There is a second mechanism of action in which the PARP enzyme can be trapped on the DNA, trying to repair the DNA breaks caused by the PARP inhibitors. The PARP enzyme is in the way and the DNA is not repaired, and that can cause cells to die. We think that may explain why even people who do not have a germline mutation or are not born with mutations in either 

 can still have tumors that are susceptible to killing by PARP inhibitors. If you look at ovarian cancer, for example, there is activity even in women who do not have these mutations, and that speaks to the biology of ovarian cancer, which is similar to that of BRCA1- or BRCA2-deficient tumors. In breast cancer, that has generally not been the case, and it is usually people with inherited mutations in 

 or BRCA2 who are susceptible to PARP inhibitors-although not exclusively. Thus, the five PARP inhibitors that are now being studied are all being rated on how effectively they trap PARP, and not just on their synthetic lethality function. Researchers are investigating the possibility that the efficiency of these agents at trapping PARP may predict their efficacy at treating breast cancer.

2. What do we know about how PARP inhibitors work in triple-negative breast cancer patients? Is it only a subset of triple-negative disease that may be susceptible to PARP inhibitor treatment?

 Primarily, PARP inhibitors have been studied in patients with triple-negative breast cancer who have a 

 mutation. The original work from Karen Gelmon, MD, of the BC Cancer Agency in Vancouver, showed that those were the breast cancers that would be sensitive to killing by PARP inhibitors, rather than tumors that did not carry 

 germline mutations. One of the first studies that had been done, the so-called ICEBERG trial led by Andrew Tutt, PhD, from King’s College London School of Medicine in the United Kingdom, used olaparib for those with 

 mutations. About 40% of patients with metastatic disease and a germline 

 mutation responded to the agent even after pretty significant pretreatment. This was true for both triple-negative and estrogen receptor (ER)-positive patients. Current guidelines indicate that patients with triple-negative breast cancer should be tested to see if they carry a 

 mutation, as long as they are diagnosed before age 60 or have a family history of breast cancer. We are identifying carriers, but we haven’t had great options for these patients.

There are some other tests that have tried to identify what is called “BRCAness”; that is, identifying breast tumors that might behave like BRCA1- or BRCA2-deficient tumors even if they occur in someone without a mutation. Earlier tests, such as the myChoice HRD (homologous recombination deficiency) test and others like it, have not been very successful in predicting response to PARP inhibitors. A recent test called HRDetect was looked at in 560 samples[1] and it was actually quite good at identifying the responders among patients with triple-negative breast cancer. What was so interesting was that the test not only identified those patients who knew they had 

 mutations when they entered the study, but it also identified patients with the mutations who had not been previously tested and did not know that they had these inherited mutations in their germline. In addition, the researchers found responders among patients who did not have inherited mutations but whose tumors had a somatic or acquired mutation in 

; however, these patients responded only if their tumor also had lost the second copy of 

. Patients who had a mutation but did not lose the second copy did not respond to PARP inhibitors. Still, the fact that both those with an inherited mutation and some whose tumor had developed a mutation did respond suggests, perhaps, that PARP inhibitors will have some activity beyond use in patients with inherited risk.

3. Are there any clinical trials that you could highlight that are testing PARP inhibitors for triple-negative breast cancer patients beyond those who have inherited 

 In breast cancer trials so far, investigators have mainly focused on patients with 

 mutations. The two studies reported at the American Society of Clinical Oncology (ASCO) Annual Meeting this year are particularly important because the agents involved are likely to be on the path to approval. There have been many studies of PARP inhibitors-mostly small studies-in heavily pretreated patients and sometimes in combination therapy, but these studies presented at ASCO were single-agent trials in patients with first- or second-line recurrence of breast cancer. These patients did not all have triple-negative disease, but they were all 

The first study, the OlympiAD trial, compared the PARP inhibitor olaparib with one of three chemotherapy drugs-capecitabine, eribulin, or vinorelbine. All patients included were 

 mutation carriers and had received one or two prior treatments for metastatic disease. The study showed a significant progression-free survival advantage with olaparib (the primary endpoint); there was no overall survival benefit from the drug, however. The researchers looked at triple-negative and ER-positive patients and observed that the benefit was confined to the triple-negative patients. Patients who had prior platinum therapy as part of their treatment did not benefit, whereas those who did not have prior platinum treatment had more of a benefit. It is important to note that these were pretty small subsets of patients, so we don’t want to over-interpret these findings. As for toxicity, the advantage was in favor of olaparib vs the chemotherapy drugs. One of the sobering parts of the study, however, was that a large group of collaborators was needed to enroll only a few hundred patients.

The ABRAZO trial looked at the PARP inhibitor talazoparib and compared it with other physician-choice single agents. In this study, there was also a benefit in 

 mutation carriers. This trial had two cohorts: the first included patients who had received prior platinum treatment, and those in the second cohort had not had prior platinum treatment. One issue to note is that for the group that had prior platinum therapy, the longer the interval from the prior platinum, the better the patients did. There was really no benefit when they were less than 2 months from treatment, but they did have benefit when they were at least 6 months from treatment. An even greater benefit was observed in the group that had not received prior platinum therapy. Unlike in the OlympiAD trial, there was a benefit in the ER-positive patients as well. This is important because

 mutation carriers are more likely to have ER-positive disease; this study suggests that these patients can still benefit from PARP inhibitors. There are ongoing trials for all five PARP inhibitors currently under development: olaparib, niraparib, talazoparib, rucaparib, and veliparib.

4. Lastly, are there any ongoing trials with PARP inhibitors whose results you and your colleagues are anticipating for patients with triple-negative disease? 

 The OlympiA trial is studying individuals with triple-negative breast cancer or ER-positive high-risk breast cancer with four or more positive nodes, who are carriers of 

 mutations and have completed all other treatments, to test whether adjuvant olaparib for 1 year vs placebo will offer a survival advantage. This trial will complete accrual next year and should have data by 2020, so that is an exciting development for these drugs. The future of PARP inhibitors is probably going to be as part of combination therapies, the most exciting of which involve immunotherapies. Such combination therapies are a natural next step because the PARP inhibitors are busy causing DNA breaks and creating new antigens in the tumors, which creates targets for immunotherapy. A number of ongoing neoadjuvant and combination trials are already presenting preliminary results at meetings. Hopefully there will be more activity to come.

Dr. Garber has served as a co–principal investigator for AstraZeneca.

 This interview was originally published October 4, 2017, on OncoTherapy Network.

Davies H, Glodzik D, Morganella S, et al. HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures. Nat Med. 2017;23:517-25.

In this Q&A we discuss the role of PARP inhibitors in cancer treatment, their role in triple-negative breast cancer patients and look forward to ongoing trials in this setting.

Judy Garber on PARP Inhibitors for Triple-Negative Breast Cancer

As part of our coverage of the 2017 American Association for Cancer Research (AACR) Annual Meeting, held April 1–5 in Washington, DC, we are speaking today with Peter Schmid, MD, a medical oncologist and director of the breast cancer center at the Barts Cancer Institute in London. At the AACR meeting, Dr. Schmid presented long-term data on the anti–programmed death ligand-1 (anti–PD-L1) immunotherapy atezolizumab in metastatic triple-negative breast cancer. 

As background, can you tell us about the rationale for targeting triple-negative breast cancer with an anti-PD-L1 antibody?

Triple-negative breast cancer is a subtype of breast cancer probably with the highest need at the moment. Unfortunately, the median survival of patients with metastatic triple-negative breast cancer is still in the range of 9–12 months, and there is an urgent need for targeted therapies. Triple-negative breast cancer is associated with a higher rate of mutations, and therefore a higher rate of neo-antigens. It also has more frequent tumor-infiltrating lymphocytes than other breast cancer subtypes, which are more prognostic in triple-negative disease than in other subtypes. These are all conditions that suggest that cancer immunotherapy could play a significant role in triple-negative breast cancer and that was partly the basis and rationale for setting up this expansion cohort for patients with metastatic triple-negative breast cancer.

Can you talk about the particular design of the study and the specific expansion cohort on which you presented data?

The data we presented were on 115 patients with metastatic triple-negative breast cancer who were treated within a large, non-randomized phase I study with single-agent atezolizumab. This is an expansion cohort that included patients mainly with pre-treated metastatic disease, but also a smaller group of patients who had not received prior chemotherapy for their metastatic breast cancer. All patients were required to have measurable breast cancer with metastatic lesions.

There were three significant findings in my opinion. The first finding was that we see a clear difference in response to single-agent atezolizumab with regard to the line of therapy. Whereas patients who received atezolizumab as first-line therapy had a response rate of 26%, the response rate in pre-treated patients was 7%.

The second finding was a substantially longer duration of response than what we frequently see with other treatments-although this is obviously a non-randomized study. The median duration of response to atezolizumab was 21 months, which in my opinion, is an important result.

The third finding was with regards to survival. When we assessed patients who responded to atezolizumab and compared them to patients who did not have a treatment benefit from atezolizumab, there was a clear difference in outcomes. Unfortunately, all patients who did not respond to atezolizumab passed away in the first 2 years, with a 1-year survival rate of 38%. All patients who responded to atezolizumab were still alive after 2 year’s time.

 Did you and your colleagues look at PD-L1 tumor expression or any other biomarkers that may predict response, particularly as triple-negative breast cancer patients can be a heterogeneous population of patients.

So this study did assess the link between PD-L1 expression and outcome and also looked into other biomarkers for treatment, as well as changes in biomarkers while on treatment. There is a weak and non-significant correlation between PD-L1 expression and response. If you look at immune-related response, then the response in patients with high PD-L1 expression was 70% compared to 8% in PD-L1–low or PD-L1–negative patients. But again, PD-L1 taken on its own does not seem to be a good biomarker for selecting patients for these treatments. We will probably require a more composite set of biomarkers incorporating different features and some of this work is still ongoing.

Just lastly, what is the follow-up plan for this study? Are there other studies that are starting soon or are being planned?

There is a large program that is ongoing with immune checkpoint inhibitors in triple-negative breast cancer and also a large program with atezolizumab as one of the immune checkpoint inhibitors. Most of the efforts at the moment are focusing on combinations of chemotherapy and immune checkpoint inhibitors. There is probably only a small group of patients who will benefit from single-agent checkpoint inhibition. In our trial overall we had only 15 patients who responded out of more than 100 patients-so a relatively small group will respond to single-agent therapy. The focus going forward will be on combination studies. There are randomized studies ongoing and near completion in terms of recruitment-for example, paclitaxel with or without atezolizumab in first-line metastatic triple-negative breast cancer-that will hopefully give us some answers on the role of immune checkpoint inhibitors in triple-negative breast cancer in the near future.

Thank you so much for joining us today, Dr. Schmid.

American Association for Cancer Research Annual Meeting (AACR)

In this interview we discuss long-term data on the anti–PD-L1 immunotherapy atezolizumab in metastatic triple-negative breast cancer.

Atezolizumab in Triple-Negative Breast Cancer Improved Survival Among Responders

Ahead of the annual San Antonio Breast Cancer Symposium held December 4

8 in San Antonio, Texas, we discuss the evolving role of molecular profiling in the diagnosis and treatment of breast cancer. We speak with Dr. Antonio Wolff, professor of oncology at the Kimmel Cancer Center at Johns Hopkins University, a breast cancer clinician and recently appointed associate editor of the 

. Dr. Wolff will be speaking during the "Practical Use of Molecular Profiling" session at this year's symposium.

Dr. Wolff, as a practicing medical oncologist, what do you see as the most patient outcome-changing genetic or molecular test that is currently being used in practice?

Dr. Wolff: Thank you for the opportunity to speak to you today. It is actually quite interesting for those of us who take care of patients to realize how important attention to proper collection of tissue and a better understanding of even existing assays. We are beginning to see several molecular assays coming into the clinic. Some of them have already undergone some evidence of measure of prospective validation and others are still in development. It is quite interesting to see that many of them, especially those that are currently being used to determine whether a patient should be treated with adjuvant chemotherapy or not, especially patients who have estrogen-receptor (ER)-positive disease.

Many of these assays in a way are a reflection of proliferation that measure, in essence, grade and differentiation. We have known for a long time that patients with so-called high-grade tumors are patients who may have high-risk tumors and may be at higher-risk for recurrence, and I think we are now integrating that information with measures of estrogen-receptor status. Consequently, we have seen several assays which are now commercially available but not very well prospectively validated in terms of the clinical utility. But maybe these assays now can be used to identify which patients could potentially be treated or should be treated with adjuvant chemotherapy or not, in addition to anti-estrogen therapy for those with ER-positive disease.

Could you go over the types of tests that are currently available for both diagnosis and to facilitate treatment decisions for breast cancer patients?

Dr. Wolff: One of the assays that is most commonly used today is the so-called 21-gene assay or Oncotype Dx. This is an assay that was prospectively developed and validated using retrospective samples from previous clinical trials. This one example appears to identify a subset of patients with ER-positive disease that would potentially benefit from the addition of chemotherapy to anti-estrogen, and who without the use of chemotherapy would have a greater risk of disease recurrence after 10 years. This is the assay that is most developed at this point.

There is another commercial assay right now called MammaPrint, which has undergone validation of its prognostic utility in terms of identifying among patients with ER-positive disease those who are at greater risk of recurrence. However, it is an assay that is still at this point undergoing clinical utility validation in terms of its ability to identify patients who will have a better outcome if a treatment decision is made on the basis of this specific assay. These are the two assays that are the most developed at this point in the United States.

However, one major limitation of many of these assays is that for the most part, they appear to provide in different ways, a measure of tumor proliferation, of the tumor grade. It appears that their utility seems to be limited, at this point, to the two-thirds of patients who are newly diagnosed who present with ER-positive disease. These assays at this point do not have any utility for patients with triple-negative disease or HER2-positive disease.

Where is the field right now in terms of broader genomic profiling of patients' tumors? Is this still an analysis still largely confined to academic research centers and studies?

Dr. Wolff: I think it is fair at this point to say that these assays are considered to be investigational, and they are not yet ready for prime time. We are beginning to see a series of papers coming out from various groups such as the International Cancer Genome Consortium and also in the United States, the Cancer Genome Atlas, showing on multiple levels a better understanding of so-called "omics" of the tumor in terms of the transcriptome, in terms of the protein expression, in terms of DNA pathways, mutations, copy-number variations. We are beginning to understand that actually, breast cancer is a very complex disease. We do have some difficulty in applying some of this knowledge in the clinic today.

Today in the clinic, the assays we have are essentially the more traditional immunohistochemistry ones, and in the case of HER2, also in situ hybridization. But essentially, what we have are routine pathology measures, such as measure of expression of the estrogen or progesterone receptor, measure of expression or amplification of HER2 and measures of proliferation such as tumor grade, an assay for which we still have a lot of difficulty. For the most part, they provide us with information on the various phenotypes and allow clinicians in practice to make clinical decisions. At the same time, we do understand that many of the assays have a very important negative predictive value. For instance, tumors that are ER-negative, these are patients that we will not recommend adjuvant endocrine therapy, the same way that for patients who do not have HER2 tumors, we will not recommend HER2-therapy. But on the other hand, these assays are imperfect, at least the current phenotypes we have are imperfect from a positive predictive value standpoint in the sense that not all patients with ER-positive disease will benefit from anti-estrogen therapy, not all patients with HER-2 positive disease will benefit from anti-HER2 therapy. This is even more critical for the small number of patients, about 15% or so, with so-called triple-negative disease. We now understand that triple-negative disease is not just one type of phenotype but an umbrella within a larger umbrella of breast cancer in which we may have patients that have what is now described as the basal-like phenotype which is derived from DNA expression studies. We have tumors that have more of a 

 mutation or "BRCAness" to them. We have tumors that appear to have even improved prognosis because not all patients with triple-negative disease have a high risk of recurrence. Some of these tumors may have a more immune profile. So all of that information is beginning to be dissected in laboratory studies where we are trying to describe the "omics" of all of these subtypes and generate information that at some point in the future will be ready for prime time, but we are not there yet.

Do you have any advice for both academic and community oncologists on how to best use molecular testing to guide their diagnosis and treatment decisions now?

Dr. Wolff: I think this is a critical question. There are a few things that can be done from a more basic standpoint. What I think we have learned in the last couple of years is actually the critical nature of proper collection of tissue specimens. Even for assays which we thought were simple such as ER and HER2, it is critical that the time it takes from the moment the tissue is collected from the patient to the moment that it is properly handed and delivered to the pathology lab, this is the time we call cold ischemia where tissue necrosis can happen, it is important that that is kept to a minimum to make sure that the integrity of the tissue and all of its molecular processes are preserved, whether it is going to be for routine testing for ER or HER2 or whether it is going to be for future submission of these tissues for assays like the 21-gene assay that we discussed. So that information alone becomes critical for treatment decisions. I think we all should be, and must be very excited about the new studies that are taking place. I think we should, if we have the opportunity whether you are at an academic center or participating in clinical trials in the community, if you have access to some of these studies, I think it is incredibly important to join studies that are beginning to try to better understand the molecular profiling of tumors and also beginning to help clinicians to make decisions. But we are not at that point yet, where we can profile an individual tumor toward what we will call, in the future, precision medicine.

We are getting to a point where we are moving away from a more traditional qualitative, descriptive diagnosis that in the past has served us mostly for diagnostic purposes. We are gradually moving into a future where we are beginning to understand the role of molecular observations that can allow us to do a more quantitative, a more predictive assessment of what is actually the future risk of cancer recurrence for someone diagnosed with early-stage disease, and most important, if we make a treatment decision guided by these findings, whether we will, ultimately, improve patient outcome, which is the true meaning of clinical utility. So we are not there yet. But it has been impressive to see what has happened in the last 15 years, which truly builds on the investigations that have started years ago and are taking us to a moment where we can begin to individualize treatment decisions, not just for patient populations or groups of patients or patients participating in clinical trials, but increasingly for patients that we see in the clinical on a day-to-day basis.

Thank you so much for joining us, Dr. Wolff.

San Antonio Breast Cancer Symposium (SABCS)

To kick off SABCS 2012, we discuss the use of molecular testing for the diagnosis and treatment of breast cancer patients in the clinical setting with Dr. Antonio Wolff of the Kimmel Cancer Center at Johns Hopkins University, one of the presenter's during the "Practical Use of Molecular Profiling" session at this year's symposium.

SABCS: Using Molecular Assays for Breast Cancer in the Clinic

Ahead of the 29th Annual Miami Breast Cancer Conference that starts March 14, 

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.

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.

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.

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.

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.

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.

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.

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.

Miami Breast Cancer Conference (MBCC)

Triple-negative breast cancer is aggressive, has a high rate of metastases, and carries a poor prognosis. Dr. Joyce O’Shaughnessy, who will be presenting at the Miami Breast Cancer Conference, discusses an overview of new therapies for triple-negative breast cancer.

MBCC: Emerging Therapies for Triple-Negative Breast Cancer

a US-based study and a study by the German Breast Group showed the activity of bevacizumab (Avastin) in early breast cancer. In this interview

chairman of the German Breast Group and professor of gynecology at the University of Frankfurt in Germany,

Neoadjuvant Chemotherapy and Bevacizumab for HER2-Negative Breast Cancer

," which showed that bevacizumab in addition to neoadjuvant chemotherapy significantly increased the rate of pathological complete response in patients with early stage HER2-negative breast cancer.

CancerNetwork: Dr. von Minckwitz, could you briefly go over the rationale of both studies, in which patients were given chemotherapy plus bevacizumab before surgery to remove their tumors?

Dr. von minckwitz: So the approach to use systemic treatment before surgery is used more and more in breast cancer, as we can get immediate information about how effective treatment is in the individual patient. The pathologist can examine the tissue that is removed during surgery (after the medical treatment), and tell us how far the tumor has shrunk or disappeared, and we know that those patients where no tumor cell is left-and no tumor cell can be detected by the pathologist-have a highly favorable outcome over the long-term in general. So the idea of our 2 studies was to try to improve, to increase the number of patients, the frequency of patients where no tumor is left at surgery. The idea is based on the studies in metastatic breast cancer: to try to improve the effect of chemotherapy by adding bevacizumab as part of the neoadjuvant treatment. Bevacizumab is an agent that inhibits the building of new vessels around the tumor and therefore can inhibit tumor growth.

CancerNetwork: And just to follow up on the differences between the chemotherapies that were used in these 2 studies: Is that difference just based on the difference between the European versus the US regimens?

Dr. von minckwitz: There are quite some similarities between the treatments that were used-they both used a tetracycline taxane combination sequence as a baseline. The main difference is probably that in the US study there was a second chemotherapy question in the trial. Patients got either 1 of 2 other agents, and so there are some differences. And then the sequence was different in the NSAB American study. First, the taxane was given together with the new agent, and then it was followed by the anthracycline cyclophosphamide, whereas in our study we used the more conventional sequence by having first the anthracycline cyclophosphamide, followed then by the taxane.

Dr. Gunter von Minckwitz discusses the recent paper he authored that showed that bevacizumab in addition to neoadjuvant chemotherapy significantly increased the rate of pathological complete response in patients with early stage HER2-negative breast cancer.

Triple-Negative Breast Cancer

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