Improving Long-Term Outcomes in HER2+ Breast Cancer

Sara M. Tolaney, MD, MPH:Prior to the availability of KATHERINE [study findings], in patients who were getting preoperative therapy for HER2-positive disease, generally speaking, I was uniformly treating them with HER2-directed therapy in the adjuvant setting. For example, if the patient had gotten [docetaxel/carboplatin/trastuzumab/pertuzumab] in a preoperative setting, regardless of their pathologic response, I was then administering trastuzumab and pertuzumab in the adjuvant setting.

I think this has changed dramatically since the availability of KATHERINE. So KATHERINE did show us that we can alter someone’s outcome, someone’s long-term outcomes, by tailoring therapy based on pathologic response, and where we now know that administering T-DM1 to someone who has residual disease is associated with better outcomes than giving trastuzumab-based therapy.

We also had data though from ExteNET, which looked at the use of neratinib in patients who had completed a year of trastuzumab and then had gone on to get randomized to get either a year of neratinib or placebo. We know from that study that using neratinib after completion of trastuzumab was associated with an absolute benefit of 2.5% in the overall population. But what I think was very interesting was that in patients with hormone receptor-positive, HER2-positive disease, the absolute benefit was 5%, whereas there was really no difference in the hormone receptor-negative, HER2-positive patients. So really no benefit to the use of neratinib in that population.

Again, prior to the availability of KATHERINE, I was taking patients who had hormone receptor-positive, HER2-positive tumors, who had completed their year of HER2-directed therapy and then offering them neratinib. I think the caveat with that is that most of our patients are getting pertuzumab-based therapy, and the ExteNET study really enrolled patients who were pertuzumab-naïve. So we have no data for what the benefit is for using a year of neratinib after completion of pertuzumab-based therapy.

That being said, if I had a very high-risk, node-positive, hormone receptor-positive patient who had completed their year of treatment, I was still offering them neratinib, acknowledging that the exact benefit of the use of neratinib in that population isn’t clear. I think, however, now with the availability of KATHERINE, our perspective has changed on how best to select therapy after someone has completed surgery.

The KATHERINE study enrolled patients who had received preoperative trastuzumab-based therapy and had residual disease at the time of surgery and then randomized these patients to receive 14 cycles of T-DM1, or 14 cycles of trastuzumab. The study found a very impressive improvement in invasive disease-free survival. There was a hazard ratio of 0.5. So 50% reduction in invasive disease-free survival events, and an absolute difference between the 2 arms of 11%. So it was very clear that patients who had residual disease did much better when given T-DM1 compared with trastuzumab. I think this, however, does bring up several questions, and one being you know the control arm in KATHERINE was trastuzumab, and I think many people would now argue that perhaps the control really should be trastuzumab and pertuzumab, given data we have from APHINITY suggesting that pertuzumab-based therapy may be more effective than trastuzumab-based chemotherapy.

And so while we do not have data directly comparing T-DM1 to trastuzumab and pertuzumab, I do think the data still likely would have been positive, suggesting T-DM1 is better than trastuzumab and pertuzumab, because the benefit is so striking when comparing T-DM1 to trastuzumab with the hazard ratio of 0.5. Whereas when we look at APHINITY, there was only a 1.7 % absolute difference at 4r years between the pertuzumab arm and the non-pertuzumab based therapy.

I think one has to also realize that some of these patients also got pertuzumab-based therapy in the preoperative setting and had residual disease. So the additional benefit from continuing pertuzumab in someone who failed to achieve a pathologic CR [complete response] to pertuzumab-based therapy is also likely not to be as great as using T-DM1. I still think that these data are very pertinent and practice changing even in the era of pertuzumab-based therapy.

It’s also important to note that while only 20% of the patients in KATHERINE received pertuzumab prior to surgery, their benefit was similar to the overall population, with the 50% reduction in invasive disease-free survival events, suggesting that even in this particular case where this patient had received preoperative [docetaxel/carboplatin/trastuzumab/pertuzumab], that using T-DM1 in a patient who had residual disease after treatment is likely to yield significant benefit compared with trastuzumab.

Transcript edited for clarity.

Case: A 49-Year-Old Woman With HER2+ Breast Cancer

H & P

• A 49-year-old woman was referred by gynecology for a mass in her right breast
• No children, menopause at age 45
• No history of cardiovascular disease, otherwise good health
• PE: revealed a woman of normal weight (BMI = 21 kg/m²), with a palpable mass in her right breast

Imaging

• Mammogram revealed 3.5-cm tumor in right breast
• CT: confirmed a tumor in right breast with no lymph node involvement

Biopsy and labs:

• Histology: ductal, grade 2
• ER(-), PR (-)
• HER2IHC: 3+
• BRCA1/2: negative

Treatment

• Diagnosed with ER/PR negativeHER2+ breast cancer; she received neoadjuvant TCH-P (docetaxel + carboplatin + trastuzumab + pertuzumab and achieved a partial response
  • Residual disease of 1.5 cm after neoadjuvant therapy
• Underwent mastectomy
• After discussing with her the options for adjuvant therapy, benefits and risks of each, and her goals, she was started on ado-trastuzumab emtansine (T-DM1)
• At present, she has completed 3 cycles of T-DM1
  • Reports numbness in her fingers, “like wearing gloves” that sometimes interferes with small tasks like buttoning a shirt