Use of HER2-Targeted Therapy in Breast Cancer

Ruth O’Regan, MD:This is a 49-year-old lady who presented with a left breast mass. The mass was found on examination, so she was worked up and had imaging that showed suspicious findings. She then went ahead and had a biopsy of both the breast and the axilla lymph nodes, both of which showed high-grade invasive ductal cancer. The receptors were estrogen receptor-negative, progesterone receptor-negative, andHER2-positive. She then proceeded to mastectomy, and her N stage was T2N3, so she had fairly substantial disease. And she has now been recommended adjuvant chemotherapy withHER2-directed therapy. So, I think the key thing about this case is that if she had perhaps been seen in a multidisciplinary clinic, she might have been recommended preoperative chemotherapy withHER2-directed therapy, which is something that we use routinely for these larger cancers, particularly when they’re node positive.

As far as this lady’s prognosis, it’s a little bit hard to know. In general,HER2-positive cancer is very aggressive. They do have a propensity to metastasize fairly early following diagnosis. However, with the use of chemotherapy in combination with trastuzumab and now more recently with pertuzumab, many of these patients are being cured of their disease even though they have positive lymph nodes and large cancer. So, in this lady, it’s hard to know. If we had given her preoperative treatment with chemotherapy andHER2-directed therapy, we could have used her response to that therapy as a marker for prognosis because we know—particularly with estrogen receptor-negative,HER2-positive cancers—they tend to respond in a high percentage of cases. And patients who have a complete response to the preoperative treatment actually have a very favorable outcome. So, in this lady, it’s a little bit hard to know, but I think with aggressive adjuvant systemic therapy, she actually could be fine and not have any evidence of recurrence. If she does have a recurrence, it would be likely to occur within the next 4 to 5 years. So, once she gets to 5 years, she’ll be pretty unlikely to have a recurrence of this cancer.

As far as the story ofHER2-targeted therapy, the HER2 receptor was actually discovered back in the 1990s and was associated with very aggressive cancers with a high metastatic potential. However, just shortly after the HER2 receptor was discovered, the antibody trastuzumab was developed to basically target the HER2 receptors on these cancer cells. Now, interestingly, trastuzumab has very little activity on its own as a single agent, but when you give it with chemotherapy, there’s quite marked synergy between trastuzumab and the chemotherapy. So, the pivotal trial that was done was the trial for patients with metastaticHER2-positive breast cancer who were treated with chemotherapy alone or chemotherapy/trastuzumab. And the addition of trastuzumab markedly improved the outcome for these patients and really has been the standard of care not just for metastatic breast cancer, but also in the early-stage setting since that time point.

Now, one of the interesting things about theHER2story was that at the time that trastuzumab was developed, we really weren’t very savvy about the idea of targeted therapies. So, when a new drug came along, we would use it on every type of breast cancer regardless of what subtype the patient had. However, Dennis Slamon, who discovered trastuzumab, spoke to the FDA and basically said that this drug would only work inHER2-positive cancers. It’s good that he did because we subsequently did a trial in patients withHER2-normal metastatic breast cancer where trastuzumab didn’t improve outcome at all.

Since that time, we’ve had a number of agents come down the pipeline. So, pertuzumab is another antibody that targetsHER2, but it’s a slightly different domain of the HER2 receptor compared to trastuzumab. And what we know in the metastatic setting is that the combination of trastuzumab and pertuzumab with chemotherapy has had very a profound impact on outcome, such that women who get that regimen can actually expect to live for a median of almost 5 years, which is a huge move forward from where we were before.

Pertuzumab has also been shown to increase the likelihood of getting a complete response to trastuzumab and chemotherapy in the preoperative setting, and it’s very commonly used in that area. We also have trastuzumab DM1—which is a conjugate of trastuzumab with chemotherapy moiety—which has been shown to be effective in metastatic breast cancer for patients who’ve had prior trastuzumab. Now, the most recent drug is called neratinib, which is a tyrosine kinase inhibitor that targets HER2 and the other HER receptors and has been just recently approved for extended adjuvant therapy for patients withHER2-positive breast cancer.

Obviously, we now know that there are a number of different subtypes of breast cancer. So, it’s very important that we determine what type of subtype of breast cancer a patient has, and the way we do that is by measuring the estrogen receptor inHER2/neu.HER2is measured either by immunohistochemistry or by in situ hybridization; either method is reasonable. Sometimes in the event when equivocal, an immunohistochemical test will use in situ hybridization to determine whether the cancer isHER2-positive or not. So, that’s a very, very important thing to find out for your patients because it really gives them the opportunity of having the option, with these life-savingHER2-directed therapies, to improve their outcome.

Transcript edited for clarity.

• A 49-year-old women was referred for biopsy after routine mammography showed a 2.4-cm diameter spiculated mass in the left breast
• PE: revealed a well-circumscribed, non-tender firm mass in the lower-outer quadrant of the left breast; singular palpable nodal enlargement in the left axilla
• Excisional biopsy of the breast and axillary lymph nodes showed high grade lobular carcinoma
  • ER-/PR-; HER2 IHC 3+; Ki-67, 89%
  • Staging, pT2N3M0
• She underwent right mastectomy and lymph node dissection
• The patient was started on adjuvant chemotherapy with docetaxel + carboplatin with 12 months of trastuzumab + pertuzumab