		Lymphoma Division Chief John Theurer Cancer Center at HackensackUMC

		Chief Science Officer and Director of Research and Innovation Regional Cancer Care Associates

Numerous epidemiological factors affect the likelihood of developing breast and ovarian cancer, but no other predictor is as powerful as an inherited mutation in BRCA1 or BRCA2, genes involved in both tumor suppression and DNA repair.

Although hereditary breast cancer accounts for only 5% to 10% of all breast cancer cases, individuals carrying mutations in one of these genes have an approximately 60% to 85% lifetime risk for breast cancer and a 10% to 40% risk for ovarian cancer (a much higher risk over their lifetime compared with the general population: 12% for breast cancer and 1.5% for ovarian cancer).

Consequently, since the identification of BRCA1 and BRCA2 genes in 1994 and 1995, respectively, patients with a strong personal and/or family history of breast and/or ovarian cancer have been counseled to seek molecular genetic testing. For those who test positive, the treatment decision can range from close monitoring for early detection to bilateral prophylactic mastectomy and/or prophylactic salpingo-oophorectomy, procedures that have been shown to reduce the risk of both ovarian and breast cancer and reduce overall mortality, as well.

There are clearly differences in the reported incidences of BRCA1 and BRCA2 that reflect true variability in populations from different geographic regions and ethnicities.

There is an ongoing discussion regarding cohort selection criteria and mutation ascertainment methods that might be very critical in explaining some of these discrepancies. Additionally, most studies reported so far—by definition&mdash; have looked at women tested because of their family history/risk factors, though there are also mutations of BRCA1 and BRCA2 in the “non—high-risk” population, as well. One could argue that “identifying a woman as a carrier only after she develops cancer is a failure of cancer prevention,”1 said Mary-Claire King, PhD, who was recently awarded the 2014 Lasker-Koshland Special Achievement Award in Medical Science for her pioneer work in identifying the BRCA1 gene and its oncogenic role in the early 90s. Among Ashkenazi Jewish populations, BRCA1 and BRCA2 mutations are equally common in males and females and are inherited at equal rates from mothers and fathers. In Israel, three inherited founder mutations in BRCA1 and BRCA2 cause 11% of breast cancers and 40% of ovarian cancers in Ashkenazi Jews.

For carriers of these mutations, risk-reducing salpingooophorectomy significantly reduces morbidity and mortality. An important new study recently reported by Gabai- Kapara attempted to look at breast and ovarian cancer risk among BRCA1/BRCA2 carriers in the general population compared with that among carriers who had been tested because they had cancer or had a family history of breast or ovarian cancer.

In the study, families harboring mutations in BRCA1 or BRCA2 were ascertained by identifying mutation carriers among more than 8000 healthy Ashkenazi Jewish males recruited from health screening centers and outpatient clinics. Female relatives of the carriers were then enrolled, genotyped, and followed.

Results showed that female relatives with BRCA1 or BRCA2 mutations developed either breast or ovarian cancer at the same rate as women from families with a history of cancer. Though by design—prior history of cancer was not a prerequisite&mdash;authors reported that about half of the families (85/167) harboring BRCA1 or BRCA2 mutations had little or no history of relevant cancer. Gabai-Kapara et al concluded that general screening would identify and potentially benefit many carriers who are not evaluated by current genetic testing based on family history criteria. In a recent editorial in JAMA, King and two coauthors recommended that genetic screening for BRCA1 and BRCA2 should be offered routinely to every woman at about age 30, with special screening and counseling for women with these mutations.

A number of comments from experts in the field suggest being more cautious, given the complexity of the issue, including the remaining uncertainties regarding the best recommendation with a positive genetic screening result. In addition, it is debatable to use data from a high-risk population based on ethnicity and apply it to the average person. Furthermore, in the non-Jewish population, the range of mutations is much wider than the three genes examined in that study (testing would thus be more complex and costly). Finally, there are many more genes that can put women at risk outside BRCA1 and BRCA2.

The debate is certainly not closed, and Angelina Jolie’s decision to receive a double mastectomy based on a positive BRCA1 mutation status sparked an enormous increase in women seeking genetic screening. A number of issues remain unresolved: Will broader sequencing (especially as it becomes cheaper) help target better populations truly at risk? Will early proteomics facilitate earlier and better intervention? Can targeted chemoprevention and/or behavioral changes help compensate/neutralize some of the genetic risk factors in oncology? Hopefully, the answers to some of these questions will come from the emerging science of applied systems biology and its fascinating potential.

			King MC, Levy-Lahad E, Lahad A. Population-based screening for BRCA1 and BRCA2: 2014 Lasker Award [published online September 8, 2014]. JAMA. doi:10.1001/jama.2014.12483.

			Gabai-Kapara E, Lahad A, Kaufman B, et al. Population-based screening for breast and ovarian cancer risk due to BRCA1 and BRCA2 [published online September 5, 2014]. Proc Natl Acad Sci USA. pii: 201415979.

Articles

Genetic Cancer Screening for All?: The Evolving BRCA1/BRCA2 Story

At the 13th Annual Congress on the Future of Breast Cancer, Sara Hurvitz, MD, UCLA Jonsson Comprehensive Cancer Center (JCCC), discussed “

 Mutations in HER2+ Breast Cancer.” In an interview with 

, Hurvitz, who is director of the Hematology/Oncology Breast Cancer Program and an Associate Professor in the Department of Medicine at UCLA, highlighted the key points of her 

 discussion, and addressed several other key topics in the field of breast cancer.

 mutations in HER2-positive breast cancer. Please discuss significant research involving 

 mutations as potential biomarkers for the efficacy of HER2-targeted therapies, including the biomarker analyses from the EMILIA trial.

: A number of studies have looked at whether or not patients with tumors that have a mutation in 

 have a better or worse outcome. Some preclinical data suggests a 

 mutation may make tumors resistant to trastuzumab. There has also been analyses of patients who have never received trastuzumab and those patients who have both HER2 amplification and a PIK3CA mutation seem to do better than those who do not. However, in analyses of patients treated with trastuzumab, those patients who have a 

 mutation seem to do worse. They seem to have a lower chance of pathologic complete response (pCR) and a lower or less favorable progression-free survival. There are several studies that have looked at this. There is the NeoALTTO study, which looked at trastuzumab or lapatinib or the combination of the two in the neoadjuvant setting; there is the 

tudy, which looked at trastuzumab or lapatinib in the neoadjuvant setting; and there is GeparSixto, which looked at trastuzumab and lapatinib in all patients with HER2-positive breast cancer.

These studies consistently showed that those patients whose tumors have a 

-activating mutation have a lower chance of having a pCR or a worse PFS. Moreover, it appears to be most predictive of pCR in patients treated with both trastuzumab and lapatinib.

Analyses of patients treated with pertuzumab and/or trastuzumab comes from the NeoSphere study. In this study, again, patients with tumors that had an activating mutation of 

 had a lower chance of pCR, whether or not they were treated with trastuzumab, pertuzumab, or both. In the CLEOPATRA study—a metastatic HER2-positive breast cancer trial in which patients were treated with either trastuzumab-based chemo or trastuzumab and pertuzumab&mdash;again, patients whose tumors had a 

 mutation had a worse progression-free survival.

These data are in contrast to those data from patients treated with T-DM1. In the EMILIA study—a HER2-positive metastatic breast cancer study in which patients were treated with either lapatinib and capecitabine or T-DM1&mdash;those patients treated with lapatinib and capecitabine who had a 

 mutation in their tumor had a worse progression-free survival. But those patients treated with T-DM1 whose tumors had a 

 mutation had the same outcome as those patients treated with T-DM1 whose tumors were wild-type. It was a small subset of patients. There were only about 130 patients treated with T-DM1 included in that analysis. And so whether or not those findings will be confirmed in prospective studies is unclear at this point.

Were you surprised by the results of the ALTTO trial? Specifically there was a lack of benefit with dual HER2 blockade, despite the benefit in pCR in NeoALTTO?

I wasn’t really surprised by ALTTO. First of all, it was not well powdered given the low event rate in the overall study. The majority of patients had hormone receptor—positive breast cancer and approximately 40% of patients were lymph-node negative. With so few events being accrued, it was hard to power it to know whether or not the event-free survival was truly different between the two arms.

Additionally, something that isn’t discussed so much is the fact that dose reduction has to occur in patients treated with lapatinib because of GI toxicity. And [in the plenary presentation of the ALTTO study at the 2014 ASCO Annual Meeting], Dr. Martine Piccart presented a slide toward the end showing the percentage of patients who received at least 85% of the anti-HER2 drugs and showed up to 40% of patients did not receive 85% of the protocol-specified amount of lapatinib. And that may be limiting the impact of dual HER2-targeted therapy.

So I think [the results] really do not tell us a whole lot. It seems that dual HER2-targeted therapy leads to a higher rate of pCR in the neoadjuvant setting, be it pertuzumab with trastuzumab or trastuzumab with lapatinib. We have several studies that have shown that. The lack of difference in EFS in ALTTO do not discourage me from using a neoadjuvant approach in the HER2+ setting given that study was relatively underpowered and given the toxicity-induced dose reductions.

So what does this mean for the use of pCR as a clinical trial endpoint/surrogate marker in clinical trials going forward?

I think we need more studies to sort this out. And we need studies in higher-risk patient populations so that enough events accrue to perform a powered analysis. I’m hoping that we have follow-up data from the studies looking at pertuzumab and trastuzumab and other ongoing neoadjuvant studies to further address the correlation between EFS and pCR. But I think it is a fairly good surrogate endpoint and I am not—with the data from this one trial&mdash;pessimistic about it at this point.

Moving to triple-negative disease, please discuss significant emerging therapies, trials, or treatment hypotheses in this area.

Triple-negative breast cancer is a heterogeneous disease. To better treat it likely requires us to distinguish the molecular subtypes within this classification. While data is emerging to help us distinguish the various subtypes, it is not clinically applicable at this time. Focusing on the basal-like breast cancer or BRCA-associated breast cancer, which accounts for much of triple-negative breast cancer; platinums might be a more effective form of chemotherapy and there may be promise for the use of PARP inhibitors.  

Currently PARP inhibitors are primarily being evaluated in patients who carry a deleterious BRCA mutation, but might actually have benefit in basal-like triple negative breast cancer. Several years ago a randomized study in triple-negative metastatic breast cancer that compared chemo alone to chemo plus a drug that was reportedly targeting PARP showed no difference in efficacy with the use of the investigational agent. It was subsequently understood that the drug being tested was actually not inhibiting PARP to an appreciable extent, but this negative data discouraged many companies from evaluating their PARP inhibitors in a large trial of triple-negative breast cancer given the concern that they will miss a signal and not see benefit. That said, a lot of triple-negative breast cancers probably have down regulation or under-expression of the BRCA proteins where inhibiting PARP may be particularly effective. So I think that PARP inhibition is something that really should be explored and is exciting to explore.

There are some studies now looking at inhibiting the Notch pathway in triple-negative breast cancer. Notch has been implicated as a stem cell marker, being important in stem cell survival. Antibodies and antibody-directed therapies that are being evaluated against the Notch pathway are particularly exciting, as well.

CDK4/6 inhibitors are an exciting area in breast cancer right now. Can you discuss these agents and, in particular, palbociclib?

Cyclin dependent kinases are critically involved in control of cell cycling. Several years ago, Drs. Richard Finn and Dennis Slamon brought an inhibitor of CDK4/6 into our laboratory and evaluated its activity against 51 breast cancer cell lines to see where it would be most effective. Luminal types of breast cancer—those that have estrogen receptor expression&mdash;were observed to be particularly sensitive to inhibition of CDK4/6. This included HER2-positive tumors. Conversely, the basal or triple-negative cancers did not appear to have any sensitivity.

So this preclinical data was advanced into a phase I study that looked at first-line ER-positive postmenopausal metastatic breast cancer. Patients were treated with letrozole with the CDK4/6 inhibitor. This combination was shown to be safe and to have exciting efficacy. The thing that distinguishes this treatment is it really is quite tolerable. Patients don’t develop mouth sores or pneumonitis or severe fatigue. But what is seen is a non—life-threatening, leukopenia that can include grade 4 neutropenia. The cytopenias are dose limiting but does not appear to be associated with an increased risk for fever or infection. However, the low white count does cause dose delays often.

So the data were very promising in the phase I setting and was taken to a phase II randomized study that compared letrozole alone to letrozole plus palbociclib. The palbociclib-treated patients had a significantly improved progression-free survival that was (approximately 10 month improvement or doubling compared to letrozole alone). And so this led to the first-line phase III clinical trial that is looking at palbociclib in approximately 650 patients with metastatic breast cancer in the postmenopausal, ER-positive setting. That study closed to accrual in spring 2014.

The FDA has granted palbociclib breakthrough status, which means they will be looking closely at the data as it emerges to determine whether or not accelerated approval will be granted.

There are other studies looking at palbociclib in later lines of therapy—second- and third-line therapy after one line of chemo. While palbociclib is the furthest along in development, it is not the only drug in its class. There are a number of other companies that are developing CDK4/6 inhibitors with differing side-effect profiles and differing potencies. So it will be interesting to see where they fall out and low they compare.

An area I am particularly interested in is seeing is how palbociclib will work in HER2-positive breast cancer, especially HER2-positive breast cancer that co-expresses estrogen receptor. Because it has such low rates of toxicity, I think that this would be a nice option in combination with trastuzumab.

Staying with CDK4/6 inhibitors, what are your thoughts on LY2835219 (abemaciclib) and LEE011, which have shown promise in early-stage research?

Abemaciclib is quite a potent inhibitor of CDK4/6. In phase I studies, it appears to have more GI toxicity and less of the cytopenias than we see with palbociclib. It does appear also in phase I testing to have single-agent activity, which is very promising. But we don’t have beyond phase I results at this point. I am excited to see how it turns out and whether or not it is more potent or efficacious than palbociclib.

In terms of LEE011, that is also being looked at in ER-positive breast cancer in the metastatic setting and also in the neoadjuvant setting, so we’ll have to see what the clinical trial results show.

Immunotherapy seems to be a major focal point across many tumor types. Are there any emerging immunotherapeutic agents in breast cancer? What have been some obstacles in developing them for this disease?

Up until recently, immune therapies have not proven to been particularly effective in breast cancer. Breast cancer is not one of the most immune-responsive tumors, unlike lymphoma, renal cell carcinoma, or melanoma, which are highly responsive to immune manipulation. However, some studies are now indicating that activation of the immune system predicts a better outcome for patients. There are some vaccines that are looking at targeting HER2 in HER2-amplified breast cancers that are promising but we are waiting the randomized phase III data. We also are now seeing that trastuzumab-treated patients who have tumor-infiltrating lymphocytes do better than those who do not. So the immune system may be important in antibody-directed therapy response.

The use of PD-L1 or PD-1 inhibitors is being explored in breast cancer, in particular, triple-negative breast cancer. Right now, I believe they are primarily in phase I or early phase II testing. And so this is an area that is hopeful, but we don’t have adequate data to know whether or not it is going to be promising.

What is thought to be the role of androgen receptor expression in breast cancer, and what is the available/emerging evidence supporting the use of abiraterone acetate in patient treatment?

Androgen receptor (AR) has been shown to be expressed in a portion of all subtypes of breast cancer including a portion of triple-negative breast cancers. Abiraterone has some ongoing clinical trials that are evaluating its use and we’ll have to see what these randomized studies end up showing. AR expression in triple-negative may denote a less aggressive or deadly form of triple-negative breast cancer. But whether or not inhibiting it actually works against the cancer has yet to be tested.

Sara Hurvitz, MD, highlights key points on the PIK3CA mutation, and addresses several other key topics in the field of breast cancer.

September 2014 | Oncology & Biotech News

Genetic Cancer Screening for All?: The Evolving BRCA1/BRCA2 Story

Hurvitz Discusses PIK3CA Mutations, pCR, CDK4/6 Inhibitors, and Immunotherapies in Breast Cancer