Putting Key Developments in Two Tumor Types in Focus

Joyce A. O’Shaughnessy, MD

Co-Director, Breast Cancer Research, Baylor Charles A. Sammons Cancer Center, Texas Oncology/US Oncology, Dallas, TX

As the molecular understanding of breast cancer continues to evolve, the search for treatment targets based upon tumor subtypes and gene expression patterns is intensifying.

Joyce A. O’Shaughnessy, MD, who has focused much of her own research on novel therapeutics, has made the translation of emerging concepts to clinical practice a feature of the conferences she organizes through Physicians’ Education Resource (PER). O’Shaughnessy is the program director for the 11th International Congress on The Future of Breast Cancer, scheduled for July 26-28 in Coronado, California, and the 9th Annual School of Breast Oncology, slated for November 1-4 in Atlanta. Georgia.

In this interview, she discusses several broad trends in HER2-positive and triple-negative breast cancers.

OncologyLive: What will the addition of new agents to the treatment armamentarium for HER2-positive breast cancer mean for current treatment paradigms? O’Shaughnessy: Pertuzumab will change the standard of care for first-line, metastatic HER2-positive disease. Instead of the standard being a taxane and trastuzumab, pertuzumab will be added as a third agent, and it will further improve the progressionfree survival substantially for patients. Then, it is also being evaluated in adjuvant and neoadjuvant studies. Usually such an active agent in the metastatic setting will translate into benefit in the adjuvant setting as well. Although it will be some years before we have that data, it’s something we’ll be able to anticipate that we’ll be able to bring pertuzumab into the adjuvant setting in the future. But for now, it will change the first-line, metastatic HER2-positive standard.

Triple-negative breast cancer has proved particularly challenging with regard to finding a target that responds to drugs. What makes this subtype different?

Two things make it difficult to really nail down targets. One is that there are so many different subtypes of triple negative. The basal and the luminal are the biggest differentiators, but at San Antonio in 2011, I presented an oral presentation on total genome sequencing of 14 metastatic triple-negative breast cancers, and what is so striking about those data is how unique each cancer is.

I think that is because one of the hallmarks of triple-negative breast cancer is genomic instability— problems with DNA repair. There are a number of ways to become a cancer, and with genomic instability, the cancer can go in many different directions in terms of which mutations it’s going to pick up to become a cancer.

There are a number of subtypes within triple-negative breast cancer that we still don’t fully understand, although we’re making progress. But even within those subtypes, within the basal, within the luminal, within the apocrine androgen receptor-positive, there’s going to be differences in driving mutations. This may end up being true personalized medicine in terms of identifying targets that patients will benefit from.

Snapshot of Breast Cancer Subtypes

Incidence Among 1501 Women

A population-based study of the tumor status of women diagnosed with breast cancer in the Atlanta, Georgia, metropolitan area yielded these incidence rates by broad subtype.

ER indicates estrogen receptor; HER2, human epidermal growth factor receptor 2; PR, progesterone receptor; TNBC, triple-negative breast cancer.

Adapted from Lund MJ, Butler EN, Hair BY, et al. Age/race differences in HER2 testing and in incidence rates for breast cancer triple subtypes: a population-based study and first report [published online ahead of print March 24, 2010]. Cancer. 2010; 116(11):2549-2559. doi:10.1002/cncr.25016.

Considering the results with the PARP inhibitors in triple-negative breast cancer, is there still interest in targeting DNA repair pathways?

Yes, there really is. The key, however, is to really be able to identify the subset of patients with triple-negative breast cancer where homologous recombination defects are very, very dominant and really provide an Achilles heel of the cancer. The leading hypothesis is that the patients who have the true basal cancers may be the subtype of triple-negatives that have homologous recombination defects.

There are some very interesting clinical trials ongoing or starting that will look at preoperative PARP inhibitors and look for other biomarkers of this doublestrand DNA repair defect such as RAD51 foci. We need to validate some biomarkers to be able to identify these cancers that have problems with double-strand DNA repair breaks, and then find out whether these are the cancers that benefit from PARP inhibitors. There is still quite a bit of research and interest going on.

Are there any specific ongoing clinical trials for triple-negative or HER2-positive breast cancer that you find particularly exciting?

With regard to triple-negative breast cancer, I think we’re still very much in the discovery phase of trying to subset these breast cancers. There are clinical trials going on with an antibody against the TRAIL death receptor. There’s a study that Denise Yardley at the Sarah Cannon Research Institute has conducted: paclitaxel plus bevacizumab with or without everolimus for first-line metastatic breast cancer patients—they could have either triple-negative or estrogen receptor-positive disease—and we await the results of that trial.

There are expansion cohorts going on at the end of phase I trials bringing together MEK inhibitors that block the Ras pathway with Akt inhibitors that block the PI3 kinase signaling pathway, because a lot of data, including data from the sequencing study that I presented at San Antonio, suggest activity of both the Ras and PI3 kinase pathways in these cancers, so there are combination strategies going on as well.

The story on EGFR [epidermal growth factor receptor] is still interesting. I’m particularly interested in a study that Ruth O’Regan is doing at Emory [University] based on preclinical data in triple-negative preclinical models combining lapatinib, now being used as a HER1 or EGFR inhibitor as opposed to a HER2 inhibitor, together with an mTOR inhibitor. She is doing a phase I/II trial of lapatinib with everolimus in triple-negative breast cancer patients, with a double blockade of the HER1 pathway. I think that is a very interesting hypothesis.

So there are pilot trials going on. We’re not at the level of the big phase IIIs that we have in the HER2- positive subtype, but there are pilot studies going on to generate hypotheses.