Understanding the Characteristics and Behavior of Breast Cancer

Advances in molecular profiling technologies have made it easier to understand the molecular characteristics and clinical behavior of breast cancer. Profiling can be especially beneficial in HER2-positive patients, as the subtype is particularly heterogeneous. Two recent studies investigating HER2-positive cancers using molecular profiling were presented at the 2015 annual meeting of the American Society of Clinical Oncology (ASCO), a gathering of nearly 30,000 oncology professionals in Chicago.

One of the studies used the Breast Cancer Index, a gene expression-based assay, compared HER2-positive/hormone receptor (HR)-positive tumors and HER2-negative/HR-positive tumors to determine which histology had a higher risk for recurrence and could benefit from extended endocrine therapy. The study found that 59 percent of tumors were classified as Breast Cancer Index High-Risk in the HER2-positive cohort compared to 19 percent in the HER2-negative cohort. Nearly twice as many HER2-positive tumors were predicted to benefit from extended endocrine therapy compared with the HER2-negative cohort, at 69 versus 38 percent, respectively.

The second study was an analysis of 561 archival tumor samples from the BOLERO-1 and BOLERO-3 studies, which both examined the combination of Herceptin (trastuzumab), Afinitor (everolimus), and chemotherapy in patients with HER2-positive breast cancer. Based on molecular profiling, a PI3K pathway gene alteration was seen in 45 percent of samples. It was determined that patients with PIK3CA mutations or low PTEN derived a greater benefit from the combination therapy.

CURE spoke with the lead author on the two studies presented at ASCO, Ruth M. O'Regan, division head of hematology and oncology in the Department of Medicine at the University of Wisconsin School of Medicine and Public Health. O'Regan shared her insight on the impact of both studies and the next steps in utilizing molecular profiling in HER2-positive breast cancer.

CURE: How can the Breast Cancer Index provide insight into patients with HER2+/HR+ breast cancer?

O’Regan: The Breast Cancer Index is a molecular profiling assay that has been used to estimate the benefit of endocrine therapy for patients with estrogen receptor (ER)-positive breast cancer. Currently, its main utilization is determining which patients need more than five years of endocrine therapy. Our research is focused specifically on HER2-positive/HR-positive breast cancers, a group for which it is important to have these molecular assays.

What the oncology community learned is, for patients with HER2-positive/HR-positive cancers, the majority actually have a higher risk of recurrence than was previously understood. The use of endocrine therapy beyond five years is actually effective in about two-thirds of these cancers. It appears that the Breast Cancer Index demonstrates that patients with HER2-positive tumors who are also HR-positive may benefit even more from extended adjuvant therapy than those who are HER2-negative/HR-positive.

It’s an important finding because if you look at the adjuvant Herceptin trials, it was generally thought that if you make it to five years, you are not going to have a recurrence. Clearly, within the HER2-positive cancers, particularly the ones that are HR-positive, there is a group where late recurrence is possible, similar to what we see in HR-positive/HER2-negative cancers. The data, which looked at approximately 150 patients, require some validation, but I would consider using it in my practice for patients. It is worth consideration and worth more investigation. For some doctors, this could be practice-changing.

What are the next steps in this research?

Overall, I think there is a lot of interest in the HER2-positive/HR-positive space because it has become more apparent that they are very heterogeneous. Some of them even appear to be driven more by ER than HER2. It is possible that we are overtreating some of these patients, as well. If we could work out which patients could avoid chemotherapy, and just have endocrine therapy and HER2-directed therapy, that would be very useful going forward. The next step in evaluating this is to look at more tissue and tumor samples.

What can community oncologists take away from this research?

They should think of cancers that are HER2-positive/HR-positive the same way they think of cancers that are HR-positive/HER2-negative. If there is a patient with HER2-positive/HR-positive cancer who they think may be a candidate for extended endocrine therapy, they should do it the same way they would if the cancer was HR-positive/HER2-negative. Just because a patient makes it to five years, it does not mean they do not have a risk of recurrence.

In what other ways has molecular analysis been used to determine best treatment methods for HER2-positive breast cancers?

The BOLERO-1 and BOLERO-3 trials both looked at the addition of Afinitor to Herceptin and chemotherapy. Overall, they both showed that there was no significant benefit to adding Afinitor with Herceptin and chemotherapy.

However, there was a benefit in HER2-positive/ER-negative breast cancers. There was not, interestingly, a benefit in adding Afinitor to those with HER2-positive/HR-positive cancers. A molecular analysis was performed on a large number of patients in BOLERO-1 and BOLERO-3. What this analysis showed is, if patients have activation of the PI3-kinase pathway or if they have low PTEN, they will benefit from the addition of Afinitor. Therefore, we have another biomarker.

What impact will these findings have?

I don’t think this is going to change practice for oncologists. At the moment, there is not a huge amount of interest in adding Afinitor to Herceptin and chemotherapy for HER2-positive cancers. However, it at least gives us the indication that there are some patients who will benefit. Also, if another trial was planned, we could enrich the population with patients who have cancers with activation of the PI3 kinase pathway.

Is there a role for Afinitor in HER2-positive breast cancer?

We have some data that we presented at the 2014 ASCO Annual Meeting, which showed that patients who had cancers that were resistant to endocrine therapy could benefit from Afinitor in addition to endocrine therapy.