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Adjuvant Therapy for HER+ EBC
Understanding Evolving Adjuvant Treatment Approaches for HER2-Positive Breast Cancer

Released: April 12, 2018

Expiration: April 11, 2019

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Case 1: ER-Positive, HER2-Positive, Node-Negative Early Breast Cancer (EBC)

A 44‑year-old premenopausal woman has a clinical T2N0M0 grade 3 breast cancer, which is strongly positive for ER and PgR expression, is definitively HER2 positive (IHC 3+), and has a highly proliferative Ki-67 score of 50%. Because she has a HER2-positive T2 lesion and high-grade aggressive disease, she received the current standard of care: preoperative docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP) and had a clinical CR.

At lumpectomy she has 1 cm of residual disease in her breast, but sentinel lymph nodes were negative and her Ki-67 score is now much lower at 10%. She is going to proceed to breast radiotherapy and IV zoledronic acid. I also would strongly favor using a luteinizing hormone-releasing hormone (LHRH) agonist plus exemestane instead of tamoxifen. At least in the beginning, she had aggressive, very highly proliferative breast cancer, which will benefit considerably more from an aromatase inhibitor than tamoxifen.

The Bigger Question Is: What Would Be Optimal Adjuvant Therapy?
There is no definitive answer for this type of patient. My choice would likely be trastuzumab alone, although the FDA label for pertuzumab states that if patients receive pertuzumab and trastuzumab as part of neoadjuvant treatment, they should continue both trastuzumab and pertuzumab following surgery as part of adjuvant therapy for a total of 1 year (or until disease progression or unmanageable toxicity).

That said, a subgroup analysis from the phase III APHINITY trial suggests that patients with node-negative HER2-positive EBC may not benefit from dual HER2-targeted therapy over standard trastuzumab. We do not know what the patient’s pathologic nodal status was at the time of diagnosis but, following neoadjuvant TCHP, at the time of definitive surgery, she was pathologically node negative. I would not treat her with adjuvant pertuzumab and instead would suggest continuing with adjuvant trastuzumab for a total of 1 year.

Case 2: ER-Negative, HER2-Positive, Node-Positive EBC

A 51‑year-old postmenopausal woman presents with a clinical T3N1M0, grade 3 breast cancer. Her tumor is negative for both ER and PgR, is positive for HER2 (FISH+), and has a very high Ki-67 score of 70%.

She is treated with 6 cycles of TCHP and achieves a PR. At mastectomy, she has residual disease in her breast as well as 3 positive axillary lymph nodes; the breast cancer remains ER/PgR negative and HER2 positive. Planned postmastectomy therapy includes comprehensive regional nodal irradiation and IV zoledronic acid.

Again, the Question Is: What Is Optimal Adjuvant Therapy?

For this patient, I would continue adjuvant trastuzumab with pertuzumab for a year. In the phase III APHINITY trial, the patients who benefited most from the addition of pertuzumab were those with node-positive, hormone receptor–negative disease.

Upon completion of the year of trastuzumab and pertuzumab, the next question for this patient is whether to start a year of adjuvant neratinib. The phase III ExteNET trial included patients with HER2-positive EBC and a high risk of recurrence—the majority had node-positive disease like this patient—and results showed an invasive disease-free survival benefit from the neratinib that was particularly meaningful and persistent for patients who were both HER2 positive and hormone receptor positive (ER positive and/or PgR positive). Patients with ER-negative disease had a more transient benefit, as the observed benefit while receiving neratinib dissipated after treatment was stopped. However, the ER subset analysis is hypothesis generating, there was not a statistically significant interaction between hormone receptor status and neratinib benefit, and the overall ExteNET trial results were positive. The FDA approved neratinib for the adjuvant treatment of patients with higher-risk HER2-positive EBC regardless of ER status.

To date, there is no level 1 evidence of definitive benefit from neratinib after finishing 1 year of adjuvant trastuzumab and pertuzumab; in the ExteNET trial, patients received neratinib after a year of adjuvant trastuzumab only. Nonetheless, I would consider neratinib for this patient because she does have very high-risk disease with 3 positive nodes after preoperative TCHP.

Case 3: ER-Positive, HER2-Positive, Node-Positive EBC

A 55‑year-old postmenopausal woman presents with a clinical T1N1 grade 2 breast cancer that is positive for both ER and PgR, is HER2 positive (IHC 3+), and has a Ki-67 score of 25%. An MRI scan of her breast confirms 2 enlarged axillary lymph nodes with effacement of a fatty hila, suggesting metastatic disease.

She is treated with preoperative dose-dense doxorubicin and cyclophosphamide followed by weekly paclitaxel, trastuzumab, and pertuzumab. She achieves a clinical CR and, at mastectomy, has a pathologic CR in her breast, and of 3 sentinel lymph nodes, 2 have evidence of diffuse fibrosis, suggesting regression of initial metastases. She is started on adjuvant letrozole and IV zoledronic acid, and postmastectomy radiation therapy is planned.

What Would Be Optimal Adjuvant Therapy for This Patient?

In this particular case, I would continue both adjuvant trastuzumab and pertuzumab for a year based on her original node-positive status, even though she achieved a pathologic CR. In the APHINITY trial, 1 year of adjuvant trastuzumab and pertuzumab significantly improved invasive disease-free survival for patients with node-positive disease. As mentioned, patients with node-positive, ER-positive breast cancer in the ExteNET trial benefited greatly from a year of adjuvant neratinib. Although this patient has ER-positive (and HER2-positive) disease, she did achieved a pathologic CR to neoadjuvant therapy. I would suggest that she finishes the year of trastuzumab and pertuzumab, along with the letrozole and zoledronic acid, but I would not recommend a year of neratinib to her. If she had residual disease in her breast or axillary lymph nodes, I would have recommended 1 year of neratinib.

Discussing Treatment Options With Patients With EBC

From a patient’s standpoint, it is usually preferable to know what to expect for the whole treatment plan from the beginning. When deciding on additional therapy, whether 2 HER2-targeted agents or extended therapy with neratinib, it can be difficult for patients to have an unexpected extra therapy. It is much better, if you can, to have a conversation with your patient at the beginning of treatment and describe the potential benefits and risks of the treatment approaches as well as explain the rationale for whichever treatment is most appropriate based on her biomarker and nodal status.

In general, I try to plan all treatment at the beginning, particularly for patients with definitively high-risk EBC. For patients with hormone receptor–positive, node-positive disease, it is important to discuss the benefits of extended treatment with 1 year of neratinib. For these higher-risk, node-positive patients, particularly those who have residual disease in the axilla after neoadjuvant therapy, I certainly would recommend neratinib. Even in patients with ER-negative, node-positive disease who have considerable disease and a poor prognosis after a year of adjuvant therapy, I would recommend neratinib if only to not withhold potential benefits from these high-risk patients.

For patients who are clinically node negative, I try to explain that we will not have a full understanding of their nodal status until surgery following their preoperative systemic therapy. For these patients, I suggest waiting until we know the pathologic nodal status before making a final adjuvant treatment recommendation. Patients who are node negative at diagnosis and continue to be node negative at surgery following neoadjuvant treatment have an excellent prognosis, and I do not recommend neratinib.

While discussing the potential for neratinib therapy, it is also important to discuss the management of potential diarrhea associated with this agent. Proactive management and patient education can help mitigate this adverse events, particularly in the first month of therapy. From the first day of neratinib, prophylactic loperamide is recommended, either 4 times per day to start or 2 doses after the first loose stool each day followed by 1 dose after every subsequent loose stool. Women who are refractory to loperamide may be able to add a second agent such as colestipol or budesonide, as early data from the phase II CONTROL trial suggest this can attenuate diarrhea and improve neratinib tolerability. After the first 30 days or so, the diarrhea abates to where patients only have an occasional loose stool and can take the loperamide as needed.

After the first 30 days, I see patients monthly, to make sure they are doing okay and to identify any problems. Once they become comfortable with their treatment, I might decrease the frequency of visits to every 2 months but still keep an eye on overall toxicity, including liver function. Once they are doing very well, I see them every 3 months.

What challenges have you experienced in treating patients with HER2-positive EBC? Share your thoughts in the comment box below!

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