Using Germline Testing to Inform Treatment Decisions in Breast Cancer

Jennifer K. Litton, MD

Ahead of the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting, we are speaking with Jennifer Keating Litton, MD, associate professor in the department of breast medical oncology at the University of Texas MD Anderson Cancer Center, about the use of genetic testing and poly (ADP-ribose) polymerase (PARP) inhibitors in patients with BRCA-positive breast cancer. Dr. Litton will be speaking at an Education Session titled, “Germline Testing in the PARP Inhibitor Era,” on Monday, June 3, at the meeting, which is being held May 31–June 4 in Chicago.

-Interviewed by Bryant Furlow

Cancer Network: What proportion of women with breast cancer have germline BRCA1or BRCA2 mutations?

Dr. Litton: These mutations are found in roughly about 5% of patients with breast cancer. We’ve been able to look at some groups of women with breast cancer who have a higher risk than the 5% and some that have a lower risk. But overall it’s still a significant minority of the patients who are diagnosed every year with breast cancer.

Cancer Network: Which patients should be tested for these mutations? What risk factors should trigger germline mutation testing?

Dr. Litton: I think that if someone has a diagnosis of breast cancer and has a very strong family history of breast cancer, I think it always warrants a conversation with their healthcare providers. Patients who have breast cancer who are under the age of 45 or who have triple-negative breast cancer and are under the age of 60, or those who have multiple diagnoses of breast cancer themselves, or ovarian cancer, should be tested.

Additionally, we can also look further into the family, not just in the patient, but also at the first- and the second-degree relatives. Specifically for breast, ovarian, prostate cancers-especially the more aggressive subtypes of prostate cancer, as well as pancreatic cancer and melanoma.

When we’re looking at family history, we are looking at the ages of onset, how closely they are related, if the people in your family have cancer on either side of the family or if it is all in one side. I think one of the questions that often doesn’t get asked when we’re trained to ask people about their family history is their family structure.

For example, you might ask someone, “Do you have a family history of breast cancer or ovarian cancer?” If they say no, you’d think that they might not be at risk. But then you look and you see that that patient is an only child and their father was an only child, and there wasn’t a large family to properly evaluate the risk and how much family history plays into the risk for that particular patient.

So, I think really spending time understanding the family history, the types of cancers, the ages of onset, and the overall family structure is really important when we’re looking at properly doing genetic assessment and making sure we’re ordering the right genetic testing for that particular patient.

Cancer Network: Just to reiterate, you had mentioned a moment ago that it’s not only a family history of breast cancer that should trigger germline testing for patients, it’s also a family history of melanoma and prostate cancer?

Dr. Litton: Right, we’re also looking outside of just breast cancer; we’re also looking for other types of cancers. When I think of BRCA1 and BRCA2, now we’re certainly looking at prostate, we’re looking at melanoma. We’re looking at pancreatic when we’re assessing the family history, and we might pick up other kinds of cancers that might go with other genetic syndromes outside of BRCA. So, looking at the family history and making sure we’re ordering the right tests for that patient may be very important.

Cancer Network: How can germline BRCA1 and BRCA2 mutation testing inform treatment decision making?

Dr. Litton: In an early setting, when patients do find out they have a BRCA mutation, certainly one of the things that we can discuss is whether risk-reducing mastectomies may be the right answer for them. I feel pretty strongly that risk-reducing and bilateral mastectomy is not the answer for everyone and it needs to be discussed with each patient, so that they understand the risks of recurrence. For example, a 75- or 80-year-old woman with their first breast cancer does not have the same increased risk of a second breast cancer as someone who has their first breast cancer at 40. So, I think we do need to personalize this more than just saying, “everyone needs mastectomies.” But I think they are certainly a very reasonable intervention for many of our patients.

For patients with metastatic cancer with BRCA germline mutations, we now have two PARP inhibitors, olaparib and talazoparib, that have been approved by the FDA for use.

Patients with metastatic germline BRCA-associated breast cancer have been shown to have an improvement in progression-free survival, as well as an improvement in quality-of-life measures, with these PARP inhibitors seen in two pivotal phase III trials. So, these PARP inhibitors are certainly something that we may want to offer our patients with metastatic breast cancer.

I also want to mention the TNT trial done by Andy Tutt and his group, looking at patients with BRCA mutations who showed significant benefit with carboplatin when compared with docetaxel in the metastatic setting. So, understanding this status may change how we might offer different therapeutics for our patients.

Cancer Network: Are there also overall survival data that are mature enough to have been reported yet for PARP inhibitors?

Dr. Litton: That’s a great question. The OlympiAD study did report overall survival and did not show a difference in the overall group. But I would also say that that was a smaller trial and it was not powered to look at overall survival.

The EMBRACA trial was powered to look at overall survival. When the data were first presented, if it met the primary endpoint of progression-free survival, which it did, the statistical analysis plan did allow to look at overall survival. Although the hazard ratio was favoring improvement in overall survival, it did not reach statistical significance, but that was only 51% of the required events at that time. These data have not yet matured and hopefully will be reported as soon as we meet statistical significance.

Cancer Network: What’s next? Are there trials underway to look at combinations of PARP inhibition and other types or modalities of therapy?

Dr. Litton: There absolutely are. I think the single-agent PARP inhibitors are exciting because we had improved responses and we’ve had improved quality of life from taking an oral medication vs IV therapies in those trials. But unfortunately, the vast majority of patients still had progression of disease at some point, as we see treating patients with metastatic breast cancer. At this point, from other data, we really aren’t seeing huge responses outside of patients with a germline BRCA mutation, by any other biomarker.

I think we need to look to see if we can expand to other groups of patients who may respond to PARP inhibitors-specifically, what about some of the mutations outside of BRCA1 or BRCA2 that are in that same pathway. Now there are multiple ongoing trials looking at those DNA damage repair pathways with genes such as PALB2, BCR, and CHEK2. We’re certainly excited to see the results of those.

Also, looking at breast cancer patients who have somatic mutations, this is one of the things that is very different from the PARP inhibitor trials in ovarian cancer because a much higher proportion of ovarian cancer patients have mutations in these pathways that are in their tumor even if they didn’t inherit them, compared with what we’ve seen so far in the literature and have experienced in breast cancer, where it’s a 1% to 2% chance of finding BRCA mutations just in the tumor.

In addition, we also have exciting data about changes in the immune system from PARP inhibitors. We have two trials that have presented some earlier data: the MEDIOLA trial and the TOPACIO trial. I think the immuno-oncology and PARP inhibitor trials moving forward are very exciting.

We’ve also had some data on PARP inhibitors with radiation-although with full dose there was significant fibrosis in an early radiation study-and several other studies looking at other combinations such as antiangiogenesis factors.

I think a lot is going on in the PARP inhibitor space, but I think the general theme is expanding responses to people outside of the germline BRCA mutation carriers, as well as lengthening the duration of response.

Cancer Network: What about combining PARP inhibitors with carboplatin?

Dr Litton: That’s an excellent question and there have been trials looking at PARP and chemotherapy combinations. I think that there’s a good rationale for it-causing DNA damage and then blocking that DNA damage repair mechanism. But it’s been complicated by overlapping toxicities, specifically the cytopenias and an inability to give the PARP inhibitors at the doses that I think really have been able to truly block PARP.

There are some trials in the metastatic setting, but I think that we get a glimpse of why that may not be the best strategy from the neoadjuvant setting when we look at the I-SPY trial. This trial looked at taxane and carboplatin plus or minus the PARP inhibitor veliparib. This trial looked at predicted pathologic complete response and has graduates that should go on and go into the definitive clinical trial.

The BrighTNess trial not only looked at the combination of carboplatin plus veliparib, but also at carboplatin without veliparib being added to the neoadjuvant regimen. The addition of carboplatin did improve pathologic complete response significantly when compared with the taxane alone. But the addition of veliparib on top of that really didn’t add much.

So, I think that it’s very complicated when adding chemotherapy, and I think that a lot of effort is going to focus more on these DNA damage repair agent combinations that have shown quite a bit of promise in early studies and in some preclinical data as well.

Cancer Network: Is there anything else you’d like to tell readers or spotlight?

Dr Litton: Sure. I think that there’s some other very intriguing trials. I feel very strongly about the use of neoadjuvant therapy for high-risk breast cancer; it would be of benefit to look at this group and see where we can do less and achieve less toxicity. We know their risk of recurrence is very high.

The OlympiA trial is looking at that for those patients who have a germline BRCA mutation and have had neoadjuvant therapy and have residual disease; they’re going to be randomized to receive the PARP inhibitor or not. I think this will be an important study when it reports-and full disclosure-we did a trial at MD Anderson looking at single-agent PARP inhibitors in the neoadjuvant setting instead of chemotherapy, and had a pathologic complete response rate (in a very small trial of 20 patients) of 53%.

Cancer Network:Thank you so much for your time.

Dr. Litton: Thank you.