Decision Factors for Choosing Early HER2-Positive Therapy

Ruth O’Regan, MD:In general, cancers that are hormone receptor negative and HER2 [human epidermal growth factor receptor]—positive are more likely to have a complete pathologic response compared [with] cancers that are estrogen receptor [ER] positive and HER2-negative, HER2-positive. This has been shown in almost every trial that has looked at preoperative HER2-directed therapy. We don’t really know why that is, but it does appear that these HER2-positive cancers are quite heterogenous at a molecular level. For example, most estrogen receptor–negative, HER2-positive cancers have a HER2 phenotype if you’re use intrinsic subtyping. But very interestingly, the ER-positive, HER2-positive cancers tend to be much more heterogeneous, with most of them being luminal B, but actually a fairly significant number have been luminal A cancers.

That, perhaps, explains the difference in pathologic complete response, because [for] luminal A cancers, generally most patients do not get a pathologic complete response to preoperative chemotherapy versus some of the other subtypes of breast cancer.

I think overall this is a pretty typical presentation of a cancer like this. And the fact she had a pathologic complete response rate is what we would really expect because we do see that in 50% to 60% of patients with the regimen of this patient received.

As far as doing other molecular testing, I wouldn’t have done anything else. But as I mentioned, if you use intrinsic subtyping, it is interesting from a research perspective in that these cancers are heterogenous. We also know, looking in intrinsic subtyping, that the HER2 phenotype is more likely to have a pathologic complete response compared [with] the luminal A or luminal B phenotype, even for HER2-positive cancers.

I would consider this patient a high risk because she does have a node-positive breast cancer and also [is] estrogen receptor negative. Looking at the early adjuvant studies that were done, interestingly the risk of relapse with longer follow-up is in the range of about 25%. So although we are curing the majority of these patients and they’re not having relapses, there’s still a fairly significant percentage of patients [who] actually do read up with longer follow-up from these adjuvant trials.

Based on the data that we available, the NCCN [National Comprehensive Cancer Network] does recommend consideration of a preoperative approach for cancers that are certainly over 2 cm, particularly if they’re node positive. But some people would actually consider [giving] preoperative treatment for cancer that’s over 1 cm. The rationale for this is that we know that there’s a high likelihood of pathologic complete response, particularly if the cancers are estrogen receptor negative.

And the achieving of pathologic complete response is associated with a very positive prognosis going forward. In general I think most of us would use a preoperative approach to treat most early-stage HER2-positive breast cancer. Exceptions would be if you think the cancer is under 2 cm and node negative, in which case you can get away with the APT [adjuvant paclitaxel and trastuzumab] regimen, which is essentially 12 weeks of paclitaxel with trastuzumab given weekly through the chemotherapy and then every 3 weeks for a total of a year.

In those very low-stage cancers, there’s a possibility of de-escalating therapy. Those patients I would not necessarily give preoperative treatment to just because I feel like we can get away [with] less treatment for those patients. But by far, [for] the majority of patients we’re going to use a preoperative approach.

I generally use the TCHP regimen that this lady got, which is docetaxel, carboplatin, trastuzumab, and pertuzumab. Other options will be to consider using an anthracycline-based regimen with Adriamycin, Cytoxan, followed by paclitaxel and trastuzumab. I don’t typically use that regimen. I might consider using it in a younger patient, particularly if you’re trying to maintain fertility for that patient. But in general I tend to use TCHP [docetaxel, carboplatin, trastuzumab, pertuzumab] for almost all patients preoperatively.

The question is, you know if you could de-escalate therapy in some patients by maybe giving them paclitaxel-trastuzumab first, maybe taking them to surgery afterward and then giving them Adriamycin-Cytoxan if they don’t have a pathologic complete response. I’m not really in favor of that approach because we now have data from the KATHERINE study basically showing that if you use trastuzumab DM1 [emtansine] in patients who have residual disease after preoperative chemotherapy with HER2-directed therapy, you can really improve their outcome by using trastuzumab DM1 [emtansine] versus trastuzumab alone in that scenario.

Pathologic complete response is a very important prognostic factor for HER2-positive breast cancers, particularly when they’re estrogen receptor negative. And what that basically means is that in patients who have a pathologic complete response, their likelihood of recurrence is very low, probably less than 5% to 10%, versus patients who have residual disease. We do now have an option for patients with residual disease in that we can give them trastuzumab DM1 [emtansine], as was seen in the KATHERINE study.

In ER-positive, HER2-positive breast cancers, pathologic complete response rate still remains a significant prognostic factor, but it’s not as robust of a prognostic factor as it is for estrogen receptor negative HER2-positive breast cancer. And that’s why taking hormone receptor status into account does make sense in these cancers, so that I think that in a patient who isn’t hormone receptor negative, HER2- positive breast cancer, we certainly would be more likely to recommend a preoperative approach in those patients. And then the good news is, like in this patient here, that if they have a pathologic complete response rate, you know that their prognosis is going to be very favorable going forward.

Transcript edited for clarity.

Case: A 52-Year-Old Woman withHER2+ Breast Cancer

H & P

• A 52-year-old, postmenopausal woman presented with a mass in her left breast at her annual gynecologic exam; was referred to oncology
• 2 children, menopause at age 49
• No history of cardiovascular disease, no family history of breast cancer
• PE: reveals a slightly overweight woman (BMI = 26 kg/m²), with palpable masses in left breast and left axillary nodes

Imaging

• Mammogram reveals 2.5-cm tumor in left breast
• CT: confirms tumor in left breast and left axillary node involvement (2.6-mm metastasis in 1 node)

Biopsy and labs:

• Histology: invasive ductal adenocarcinoma
• Histologic grade: G2
• ER (-)/ PR (-)
• HER2IHC, 3+
• BRCA1/2status: unknown

Treatment

• She received neoadjuvant TCH-P (docetaxel + carboplatin + trastuzumab + pertuzumab) and achieved pathologic complete response
  • Developed grade 3 diarrhea during second cycle of chemotherapy, which required a one-level dose reduction of paclitaxel
  • Diarrhea resolved to grade 1/2
• Underwent breast-conserving surgery and removal of left axillary lymph nodes; no residual disease
• Currently completing adjuvant therapy; trastuzumab + pertuzumab (total 18 cycles)