Docetaxel, Carboplatin, Trastuzumab, and Pertuzumab Chemotherapy for HER2-Positive Breast Cancer

Arielle Medford, MD, Massachusetts General Hospital, Boston, MA, details her treatment plan for a patient with ER-negative, PR-negative, HER2-positive breast cancer.

Transcript:

Hi, my name is Arielle Medford. I am a senior medical oncology fellow, and soon to be junior faculty at the Massachusetts General Hospital Cancer Center and Harvard Medical School. I'm very happy to talk to you today about a case of localized HER2-positive breast cancer.

In the grand scheme of things, HER2-positive breast cancer has undergone tremendous advances, and is continuing to do so. I'm hoping through this case, that we'll be able to talk about all the tremendous progress that we've had with HER2-positive breast cancer treatment, and then the future work ahead, to further improve care for our patients.

This is the case of a 57-year-old postmenopausal woman, no significant past medical history. She self palpates a left-sided breast mass and presents for further care and undergoes diagnostics. It appears that this is a 2.1 cm lesion, and biopsy does, in fact, identify an ER-negative, PR-negative, HER2-positive invasive ductal carcinoma.

She doesn't have any palpable lymph nodes, but does undergo a breast MRI, which does identify a much smaller second left-sided lesion, and a suspicious lymph node that hadn't been palpable. Both are biopsied, and do, in fact, confirm, these are also ER-negative PR-negative HER2-positive breast cancer.

Undergoing a review of systems, it does sound like she's had about a 10-pound weight loss, no other major positive findings. She does undergo CT chest, abdomen, pelvis, which shows no evidence of distant metastatic disease. Kind of pausing there, and thinking through first, just the staging: In the setting of those 2 lesions, really, the larger lesion is important for establishing the T component of the stage. This is T2 and with that 1 positive lymph node, it is a T2N1 breast cancer.

Then the question is when do you do systemic staging? Especially in HER2-positive breast cancer, it's important to do a thorough review of systems, and think about the patient's story, presenting in front of you, to establish whether you're going to be managing localized or more advanced disease. Fortunately, in this case, we'll be managing a localized breast cancer.

To that end, now thinking about the HER2 testing, HER2-positive status is something that's been under much discussion recently in the metastatic setting, but in the localized setting, is still pretty set on HER2-positive and HER2-negative. HER2-positive is really based on surface-level expression of the HER2 receptors. We're not just looking for HER2 expression, but amplification, something that the cancer is relying on for growth.

This is initially done via immunohistochemistry (IHC). If a patient has a score of 3-plus, that means quite a significant amount of surface level staining, so that's positive. HER2-0 and 1-plus in IHC staining is definitively negative for the purposes of treating localized breast cancer. Then 2-plus is equivocal, and that's when patients will undergo samples, will undergo fluorescent and in situ hybridization, or FISH. There, you're really looking at the copy number of the HER2 gene itself. A copy number greater than 6 would also establish positivity. If the number is less than 6, you can also look at the ratio as well. If the number is greater than 4, this is kind of some nuance here, but really, you're looking at the ratio of the HER2 gene compared to a controlled locus in the same chromosome as HER2.

This is HER2-positive breast cancer. How do we then think about treating it? In this case, this patient underwent neoadjuvant therapy, and this is a good place to think about why we would do neoadjuvant therapy in the setting of HER2-positive breast cancer.  First, if the patient is, or could potentially be, a candidate for lumpectomy, but there is a logistic challenge. Whether that be for the surgeon's technical approach or for cosmesis, either one can be considered, because fortunately, HER2-positive breast cancer is very sensitive to HER2-targeted therapy. If a smaller surgical space would lead to better surgical outcomes, cosmetically or technically or both, that's a reasonable reason to do neoadjuvant therapy, and for discussion with the surgical oncologist as well.

Second, is the potential benefit of auxiliary lymph node down-staging. This patient did have a positive lymph node, but in the setting of neoadjuvant therapy, it's often the case, because of how sensitive HER2-positive breast cancer is, that upon surgery after neoadjuvant therapy, if there's auxiliary lymph node down-staging, patients may be able to undergo a sentinel lymph node biopsy. If that's negative for disease after neoadjuvant therapy, patients may be spared a full auxiliary dissection, which can certainly be beneficial, in terms of outcomes from a less involved surgical intervention, if possible.

The third is reflective of an advance within medical oncology that's just been tremendous. I think that momentum continues moving forward, and that's this idea of an adaptive approach based on the response of the tumor. As mentioned, fortunately, HER2-positive breast cancer tends to be very sensitive to HER2-targeted therapy. There are very high rates of pathologic complete response, particularly in hormone receptor-negative, HER2-positive breast cancer. It's typically well over 50% of patients will have a complete pathologic response, which is excellent.

In patients that haven't experienced a complete pathologic response, then the question is, well, do we continue the baseline HER2-targeted therapy, so trastuzumab and pertuzumab for a year? Is there another agent that we can use, also targeting HER2, that would have more efficacy in this patient population? That was really established by the KATHERINE trial, which looked at changing therapy in the setting of residual disease to T-DM1. T-DM1 is trastuzumab emtansine, it's an antibody drug conjugate. It's effectively taking the trastuzumab that's targeting the HER2 receptor, but that drug is also bound to a potent chemotherapy payload emtansine. It selectively delivers that to cancer cells.

Antibody drug conjugates are really having a moment within solid tumor oncology in general, and certainly in breast cancer. The KATHERINE trial established improved outcomes in patients with pathologic residual disease, changing to T-DM1 for 14 cycles of an every 21 day dose. That's helpful for thoughtful care in patients receiving targeted therapy.

The last reason we might want to do neoadjuvant therapy is if a patient is not a good candidate for surgery at that time. A classic example would be an extensive smoking history that might make upfront surgery challenging. Trying to give some time to stop smoking, and have other optimization, say for cardiac reasons, or for any sort of other reasons are all things to think about in the neoadjuvant space.

In the case of this patient, she ended up receiving 6 cycles of docetaxel, carboplatin, trastuzumab, and pertuzumab, which is commonly known as TCHP. That's the standard of care regimen in neoadjuvant therapy for HER2-positive breast cancer.

There are some deescalated measures that are currently under study as well and showing some promising results on trying to have a less, fewer medications in select patient populations with stage 2 or 3 disease.

Another important thing to think about is, after we talked about those principles of neoadjuvant therapy, is which patients would still benefit from an upfront surgery? This is where collaboration with our surgical colleagues is just so excellent. Because especially in the setting of T1 and 0 disease, there's the APT trial, which tells us that if we take the breast cancer out, that's quite a small tumor without lymph node positivity. The APT trial established that, subsequently treating with 12 weeks of concurrent paclitaxel weekly, and then every 3 weeks trastuzumab, and then continuing the trastuzumab subsequently, to finish out therapy, really has excellent outcomes, and is a nice de-escalation measure for patients who qualify.

All this is to say that there are a lot of options for patients in the neoadjuvant and in the upfront surgery setting, that really involves a collaborative effort with other providers, patients as well. Just making the right decision for the patient in front of us, so that we're working together to improve care.

In the case of this patient, after completing neoadjuvant therapy, she underwent lumpectomy, and was found to have a complete pathologic response, and the sentinel lymph node was negative. That's an excellent prognosis. It's very common to see responses like that, given how explicitly sensitive HER2-positive breast cancer can be. In this case, the patient continued trastuzumab and pertuzumab to complete a year of therapy. Pertuzumab is another HER2-targeted therapy that was established via the APHINITY trial to show improved outcomes with that regimen as well.

Other principles to just think about: This patient returned a year after her original diagnosis, mammogram was negative. You do need continued mammograms if there's residual breast tissue, as in the case of lumpectomy, or if there were unilateral mastectomy, it's important to continue breast cancer surveillance. Then while a patient is on trastuzumab, there's a rare risk of cardiac toxicity that we know can be mitigated by regular monitoring. Just know that if a patient is going to be going on a trastuzumab-based regimen, they do need a baseline echocardiogram. We'll typically do surveillance echocardiograms while on therapy every 3 months. In this patient's case, excellent cardiac function throughout and after the trastuzumab-based therapy.

To sum up, HER2-positive breast cancer is a very targetable breast cancer, and we have very thoughtful regimens that have been established through ongoing clinical trials. The momentum is to continue, to further refine the way that we're treating patients with this type of breast cancer. De-escalation is something we're always thinking about, about other regimens where patients are exposed to less therapies, as few therapies as they need, while maintaining efficacy. Pathologic complete response is something that is a favorable prognosis and is very common in HER2-positive breast cancer. Many patients, like this patient, will experience a similar course. Thank you for your time.

Source:

von Minckwitz G, Huang CS, Mano MS, et al. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med. 2019;380(7):617-628. doi:10.1056/NEJMoa1814017

Tolaney SM, Barry WT, Dang CT, et al. Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer. N Engl J Med. 2015 Jan;372(2):134-41. doi:10.1056/NEJMoa1406281

von Minckwitz G, Procter M, de Azambuja E, et al. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017;377(2):122-131. doi:10.1056/NEJMoa1703643