Personalized Medicine Shows Extended Reach Throughout Breast Cancer

Carla Falkson, MBChB, MMed, MD

Molecular markers, risk, and response are being used to better tailor escalated and de-escalated treatment approaches for women with breast cancer, explained Carla Falkson, MBChB, MMed, MD, who added that one of the most exciting examples of this has been the introduction of olaparib (Lynparza) into the adjuvant setting for patients with germline BRCA-mutated early disease. 

“It’s very exciting to see things changing so rapidly, and it’s very exciting to be able to see translations from the bench to the bedside, and then also advances from metastatic disease into early adjuvant therapy, which translates into cure for patients. There certainly are several areas where we are also being able to look at further defining subgroups so that we can minimize toxicity while optimizing the benefit of some of these treatments,” Falkson, a professor at the University of Rochester Medical Center, said in an interview with OncLive^® during an Institutional Perspectives in Cancer (IPC) webinar on breast cancer.

In the interview, Falkson, who is also director of the Breast Medical Oncology Clinical Research Program and Breast Cancer Service Line at the University of Rochester Medicine Wilmot Cancer Institute and medical director of Pluta Cancer Center, discussed the takeaways from the virtual meeting, which covered personalized approaches in HER2-positive breast cancer, de-escalation of endocrine therapy in locoregional breast cancer, optimization of endocrine therapy in metastatic breast cancer, and management of high-risk, BRCA-positive triple-negative breast cancer (TNBC).

OncLive^®: What trials have shown the value of evaluating de-escalated and escalated therapy in HER2-positive early breast cancer?

Falkson: The biggest takeaway from those trials is that the focus is to try to identify subgroups of patients who don’t need as much treatment, so in other words, to de-escalate therapy and identify which patients can benefit from less chemotherapy.

The compassHER2 trial [NCT04266249], which is still ongoing, is one of those trials that is asking that question. The Adapt trial [NCT01779206] was a German study that was presented at ASCO was a nice proof-of-principle trial, because it suggests that there may even be a subgroup of patients with HER2-positive disease who could get away with no chemotherapy and only HER2-targeted therapy. That trial evaluated THP [docetaxel, trastuzumab (Herceptin), and pertuzumab (Perjeta)] vs HP [trastuzumab and pertuzumab].

The question was: Could you de-escalate and avoid the carboplatin in some group of patients? The KATHERINE trial [NCT01772472] was practice changing because it showed that patients who have residual disease after they receive neoadjuvant HER2-directed therapy have a significantly improved outcome if they receive T-DM1 [ado-trastuzumab emtansine; Kadcyla] as opposed to just trastuzumab.

We have a very exciting space in the HER2-amplified early breast cancer group, both for patients who could benefit from less treatment and less toxicity vs those who need more treatment.

An additional study that’s also ongoing is trying to evaluate if adding tucatinib [Tukysa], which is a small molecule TKI to T-DM1 would further improve the outcome of the T-DM1 in patients per the KATHERINE trial design. That then immediately brings me to the next area that we will be looking at in the future and that is other conjugated trastuzumab molecules, such as, for example, fam-trastuzumab deruxtecan-nxki [Enhertu].

What needs to be done to further refine personalized approaches in HER2-positive breast cancer?

The challenge is to accurately identify and to find predictors of how to discern which patients can have their therapy de-escalated and which can’t. [This is better and] more clearly defining the subgroups. I’m looking forward to seeing future data, where some of the molecular markers have been applied to the HER2-amplified group. We know that they are being used quite extensively in the hormone receptor (HR)–positive breast cancers that are HER2 non-amplified, which would bring us to the next topic of talks that was given by Ajay Dhakal, MBBS, of the University of Rochester Medical Center.

In his talk, he was looking at whether we can de-escalate endocrine therapy in a subgroup of patients. We have been waiting for the results from the NSABP B-42 study [NCT00382070]. This was an adjuvant trial where patients received 5 years of tamoxifen and then were randomized to continue letrozole, an aromatase inhibitor, or observation.

There were 2 substudies of this looking at whether molecular assays applied to these data sets could assist us in predicting benefit for extended endocrine therapy for these patients. The first study that was presented by Eleftherios P. Mamounas, MD, of Orlando Health, was looking at the Breast Cancer Index [BCI], which is a tool that we have been using quite a lot to try to predict the utility of extended endocrine therapy, and it looks at 2 different genes to give you a ratio of an HSI high or low. High would predict benefit and low would imply no benefit.

Unfortunately, on the surface, the study was negative and did not show that the BCI could predict extended endocrine therapy benefit. But if one looks a little deeper, under the surface,

NSABP B-42 (NCT00382070) is an underpowered study. If we look at the way the curves start diverging at about 4 years of disease-free survival, and then apply the BCI beyond that, then it does give you some indication of benefit. This is not surprising because the patients who are high risk, really high risk, would have relapsed early on. We need more information on that.

The other substudy looked at MammaPrint, which is the 70-gene scoring system that divides patients into high scores or low scores. [Patients with] high scores have high risk, and they did not benefit from extended endocrine therapy. Again, that’s not surprising because they would relapse early and develop their recurrences earlier on. The low scores were somewhat predictive of benefit, but then the low scores were divided into low vs an ultra-low score, and the patients who had ultra-low scores could have further de-escalated therapy and benefit from even shorter duration of therapy. Certainly not extended endocrine therapy, but the other low score group then had some benefit from extended therapy.

Dr Dhakal also discussed optimizing endocrine therapy in metastatic breast cancer. What are some of the best practices or considerations in that patient population?

We have been using the CDK4/6 inhibitors and at the 2021 ASCO Annual Meeting, further data was presented for the PALOMA-3 [NCT01942135] and the MONALEESA-3 [NCT02422615] trials. Since then, the MONALEESA-3 trial has been further updated at the 2021 ESMO Congress as well. It’s very encouraging for patients and doctors alike to see that the overall survival [OS] is improved.

The MONALEESA trial, which used ribociclib [Kisqali] plus endocrine therapy, showed a very nice OS benefit for patients, and this is both in the frontline and second-line setting that we see these CDK4/6 inhibitors in combination with endocrine therapy. The PALOMA trial tested palbociclib [Ibrance] with fulvestrant [Faslodex], so there seems to be quite a variation of different endocrine therapies that are effective in combination with the CDK4/6 inhibitors. With MONALEESA, there were also patients who received tamoxifen, so this is very encouraging for when we treat patients who have advanced disease.

The other interesting study that Dr Dhakal briefly discussed was a Chinese study, which was looking at patients who had triple-positive disease, so endocrine and HER2-amplified disease. This study looked at endocrine therapy plus trastuzumab vs chemotherapy plus trastuzumab and found that the endocrine therapy and trastuzumab combination was noninferior to the chemotherapy combination. This is another option for patients who have triple-positive disease if one wants to try to minimize toxicity.

Ruth M. O’Regan, MD, of the University of Rochester Medical Center, discussed the management of high-risk BRCA-positive TNBC. What are some of the developments we have seen with PARP inhibitors in this space?

In the past few years, we have seen some really encouraging data for TNBC. The OlympiA study [NCT02032823] was presented during one of the plenary sessions at the 2021 ASCO Annual Meeting. This was a study for patients with early germline BRCA1- or BRCA2-mutated breast cancer. These patients could have had TNBC or HR-positive breast cancer but HER2 negative, not HER2 amplified. Patients then received neoadjuvant or adjuvant therapy. If they received neoadjuvant therapy, there was 1 caveat; they were not to have a complete remission, so they had residual disease if they had neoadjuvant therapy. If they had endocrine therapy, they had slightly more advanced disease. These were patients that had stage II or III disease.

Patients were randomized to receive 1 year of olaparib or observation. Olaparib has already been approved for metastatic breast cancer in this kind of situation with the germline BRCA-mutated cancers. This was, of course, very exciting to see that this translated into benefit for patients in the early setting as well, and that was what this study showed. At a median follow-up of 2.5 years, we saw that there was an improvement in invasive DFS from 77% to 85% for the patients who received olaparib, which is good. There was also distant DFS curves, which continued to diverge, so the benefit is impressive.