Sequenced Treatment Making Inroads in HER2-Positive Early Breast Cancer

Denise Yardley, MD

The introduction of targeted therapies has transformed HER2-positive breast cancer from an aggressive disease with poor outcomes to a highly manageable disease with potential for longterm survival. However, further research is needed to identify subgroups who would benefit from new treatment regimens, according to experts who participated in an OncLive^® Peer Exchange^® panel.

Adjuvant Therapy for Early-Stage Cancer

The panelists discussed the use of dual-targeted and extended adjuvant therapy for patients with early-stage HER2-positive breast cancer; the optimal sequence of chemotherapy, HER2-targeted therapy, and hormonal therapy for patients with HER2-positive, estrogen receptor (ER)—positive, and progesterone receptor–positive (ie, “triple-positive”) breast cancer; and management of patients with brain metastases. The panelists stated that patients at high risk for recurrence will likely benefit from dual and extended targeted therapy, although proactive management of adverse effects, namely diarrhea, is important to ensure tolerability of treatment. Additionally, they stated that sequencing of therapies for hormone receptor (HR)–positive/HER2-positive breast cancer may help minimize the cumulative toxicity while delivering the benefits of a multimodal approach. Finally, the panelists agreed on the urgent need for effective treatment of brain metastases that avoids whole-brain radiation therapy (WBRT).Previous studies have shown that dual HER2- targeted therapy with pertuzumab (Perjeta) and trastuzumab (Herceptin) plus docetaxel improves progression-free and overall survival in patients with metastatic HER2-positive breast cancer¹ and increases the rate of pathologic complete response (pCR) in patients with locally advanced or early HER2-positive breast cancer in the neoadjuvant setting.² Recent results from the APHINITY trial³ indicate that adjuvant therapy with pertuzumab, trastuzumab, and chemotherapy may also benefit select patients with HER2-positive early-stage breast cancer, according to the panelists. In the APHINITY trial, patients who received the pertuzumab-containing regimen had an invasive disease-free survival (iDFS) rate of 94.1% at 3-year follow-up versus 93.2% for those who received trastuzumab, chemotherapy, and placebo.

The benefits were particularly notable in patients with node-positive disease, whereas 3-year iDFS was not different between treatment groups in the subgroup with node-negative disease. Thus, the panelists agreed that they would most likely limit use of this treatment regimen in the adjuvant setting for patients with early-stage breast cancer at high risk for recurrence, although further studies are needed. “The discussion is not going to be on whether to use it…but rather in whom to use it,” said José Baselga, MD, PhD.

Denise A. Yardley, MD, also stated that the positive outcomes in the placebo groups indicate that adding pertuzumab may not be necessary for all patients with HER2-positive early breast cancer, who generally have good outcomes with current standards of care. “I think picking out those subgroups that are really most likely to derive the benefit are the ones that I’ll be looking at,” she said.

The panelists noted that although the APHINITY trial showed a higher incidence of severe diarrhea in the pertuzumab group of 9.8% versus 3.7% in the placebo group, concerns about toxicity are minimal. “We have seen a little bit more diarrhea, but it’s self-limited,” said Baselga.

Extended Adjuvant Therapy for Early-Stage Cancer

Kimberly L. Blackwell, MD, also pointed out that many factors can contribute to diarrhea, particularly with the TCHP regimen (docetaxel, carboplatin, trastuzumab, and pertuzumab), and that pertuzumab-induced diarrhea may continue for some time after discontinuation due to the long halflife of the drug. “I think you have to just be careful and understand that there are lots of things during this period that can cause diarrhea,” she said.The panelists also discussed data supporting neratinib (Nerlynx), a tyrosine kinase inhibitor, for extended adjuvant treatment of patients with earlystage HER2-positive breast cancer. The ExteNET trial⁴ demonstrated that neratinib given within 2 years of trastuzumab-based chemotherapy led to a higher rate of 2-year iDFS than placebo (94.2% vs 91.9%, respectively). According to Baselga, these results were enough for the FDA’s Oncologic Drug Advisory Committee to recommend FDA approval, even though the different sponsors and multiple amendments to the study protocol increased the complexity of assessing the true benefits of neratinib. On July 16, the FDA approved neratinib in the extended adjuvant setting.

An exploratory subgroup analysis of the ExteNET trial also showed that neratinib reduced risk for recurrence by 51% in patients with HR-positive/ HER2-positive tumors but only 7% in patients with HR-negative tumors, suggesting that persistent blockade of the estrogen and HER2 receptors may be an important treatment paradigm for reducing relapse in HER2-postive/HR-positive breast cancer, according to Baselga. “You have those patients who are HER2-positive/ER-positive…They continue to relapse even after many years of having stopped therapy, and that’s where these extended therapies may play a role,” said Baselga.

The panelists were optimistic that the results of ExteNET indicate that neratinib may have a longterm effect on HER2-positive disease much like hormonal therapies do for HR-positive breast cancer. “What I found fascinating about this trial is that we’ve known from hormonal therapy that you can make an impact on the natural history with very late interventions, [for] 5 to 10 years,” said Debu Tripathy, MD. “Now we’re learning that the same is true in [HER2-positive] disease.”

Despite the promising efficacy of neratinib, diarrhea was a nearly universal adverse effect in the ExteNET trial, with incidences of all-grade and grade 3 diarrhea of 95% and 40%, respectively, and leading to discontinuation of treatment in 16.8% of participants. However, the panelists agreed that the duration of diarrhea is often short lived and occurs early in the treatment course and that loperamide or dose interruption may help reduce its incidence and severity. The phase II CONTROL trial⁵ showed that loperamide prophylaxis during the first two 28-day treatment cycles yielded numerically lower incidences of all-grade and grade 3 diarrhea (77% and 31%, respectively) in patients taking neratinib. Overall, the panelists agree that although proactive management of diarrhea is important, the potential benefits of neratinib for a high-risk patient usually outweigh the risk for this adverse effect.

Triple-Positive Metastatic Breast Cancer

However, the panelists differed on how they would implement neratinib into clinical practice. Carlos L. Arteaga, MD, stated that he would recommend neratinib for a minority of patients who have a particularly high risk of recurrence, such as those with a high number of positive lymph nodes and HR-positive tumors. By contrast, Blackwell stated that she would offer neratinib to most of her patients given the positive outcomes in long-term data. “I will offer it to my patients with the caveat that there is [an adverse] effect, just as I do with everything else I do, and we’ll try to minimize the [adverse] effect,” she said.Triple-positive breast cancer represents a distinct subset of patients with HR-positive/HER2- positive disease. Some experts believe that using chemotherapy in addition to HER2 blockade and endocrine therapy may lead to overtreatment of patients with this subtype, although others, including the panelists, argue that chemotherapy-free regimens lead to poorer outcomes.

Blackwell and Baselga said that they typically start with a regimen similar to the one used in the CLEOPATRA trial⁶ (pertuzumab, trastuzumab, and docetaxel or another taxane) and replace the taxane with an aromatase inhibitor (AI) after 12 weeks, which maximizes the benefits of each of the therapeutic components while reducing the toxicity burden. As further support of his regimen, Baselga cited the PERTAIN study,⁷ which showed that addition of pertuzumab to trastuzumab, followed by AI therapy, led to favorable progression-free survival of 18.9 months versus 15.8 months for trastuzumab plus an AI in patients with locally advanced or metastatic HR-positive/ HER2-positive breast cancer. (Some patients also received induction chemotherapy prior to AI therapy at the investigator’s discretion.)

The panelists agree that they would give chemotherapy up front to most patients with triple-positive disease based on the inferior performance of chemotherapy-free arms in recent trials. For example, the NeoSphere trial2 showed that patients who received pertuzumab, trastuzumab, and docetaxel in the neoadjuvant setting had a pCR of 45.8%, whereas the group who received pertuzumab and trastuzumab without chemotherapy had a pCR of 16.8%. Even in a hypothetical example of a patient who achieved a pCR after 3 cycles of neoadjuvant TCHP and surgical resection, Blackwell and Tripathy stated that they would still complete the chemotherapy regimen for that patient after surgery.

Management of Brain Metastases

“I just think when you see survival benefits, you have to do it, as much as you hate to do it,” said Blackwell. “You don’t want to skimp on something that’s pretty much curing the majority of these women.”Brain metastases are more common in patients with HER2-positive breast cancer than in those with HER2-negative breast cancer and are a major cause of mortality; thus, effective management strategies are urgently needed, according to Adam M. Brufsky, MD, PhD, moderator of the panel.

Arteaga explained that the high susceptibility of HER2-positive breast cancer to brain metastases is attributed in part to the brain’s high content of heregulin, a ligand of HER3 that promotes its dimerization with HER2. The ligand-activated HER2/HER3 dimer supports survival and proliferation signals through the PI3K/AKT and ERK1/2 pathways.⁸ A phase II trial⁹ showed that neratinib plus capecitabine is active in patients with HER2-positive breast cancer and brain metastases and yielded a volumetric overall response rate in 49% of patients who underwent the entire regimen. Arteaga said that he currently uses dual therapy with capecitabine and lapatinib (Tykerb) in addition to stereotactic radiation for HER2-positive brain metastases, although he and the rest of the panelists noted neratinib may replace lapatinib because it provides stronger inhibition of HER2. However, the panelists agreed that more research is needed to introduce effective drug regimens for brain metastases in HER2-positive metastatic breast cancer.

The panelists also emphasized the importance of avoiding WBRT when possible. Brufsky pointed out that given the potential for long-term survival in patients with HER2-positive breast cancer and brain metastases, the long-term effects of WBRT are often worse than the effects of the disease. He and the other panelists agreed that localized stereotactic radiotherapy is the best option for the radiation portion of treatment to preserve brain function and maximize quality of life.

Keeping Up With Data: An Ongoing Challenge

“In this HER2 space where the disease is controlled so well from the neck down, we need to do everything we can to try to, when clinically safe, avoid [WBRT],” said Blackwell. She emphasized that communication with the radiation oncologist, who typically treats multiple types of tumors, is important because prognosis for patients with brain metastases can differ drastically depending on the type of primary cancer.The panelists concluded the session by stating that the plethora of new treatment options, while highlighting the immense progress in the field of HER2-positive breast cancer, can be overwhelmingly complex in terms of making clinical decisions. They agreed that increasing participation in clinical trials will be essential to refining treatment approaches and improving selection of patients who are most likely to benefit. “The menu [of treatment options] is getting broader and broader,” said Yardley. “The challenge is trying to keep up with all the changes in the landscape of oncology.”

References

1. Swain SM, Baselga J, Kim SB, et al; CLEOPATRA Study Group. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015;372(8):724-734. doi: 10.1056/NEJMoa1413513.
2. Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol 2012;13(1):25-32. doi: 10.1016/S1470-2045(11)70336-9.
3. von Minckwitz G, Procter MJ, De Azambuja E, et al. APHINITY trial (BIG 4-11): a randomized comparison of chemotherapy (C) plus trastuzumab (T) plus placebo (Pla) versus chemotherapy plus trastuzumab (T) plus pertuzumab (P) as adjuvant therapy in patients (pts) with HER2-positive early breast cancer (EBC) [ASCO abstract LBA500]. J Clin Oncol. 2017;35(suppl). abstracts.asco.org/199/AbstView_199_189357.html.
4. Chan A, Delaloge S, Holmes FA, et al; ExteNET Study Group. Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2016;17(3):367-377. doi: 10.1016/S1470-2045(15)00551-3.
5. Barcenas C, Olek E, Hunt D, et al. Incidence and severity of diarrhea with neratinib + intensive loperamide prophylaxis in patients (pts) with HER2+ early-stage breast cancer (EBC): interim analysis from the multicenter, open-label, phase II CONTROL trial [SABCS abstract P2-11-03]. abstracts2view.com/sabcs/view.php?nu=SABCS16L_989.
6. Baselga J, Cortés J, Kim SB, et al; CLEOPATRA Study group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366(2):109-19. doi: 10.1056/NEJMoa1113216.
7. Arpino G, Ferrero JM, de la Haba-Rodriguez J, Easton V, Schuhmacher C, Restuccia E. Primary analysis of PERTAIN: a randomized, two-arm, open-label, multicenter phase II trial assessing the efficacy and safety of pertuzumab given in combination with trastuzumab plus an aromatase inhibitor in first-line patients with HER2-positive and hormone receptor-positive metastatic or locally advanced breast cancer [SABCS abstract S3-04]. abstracts2view.com/sabcs/view.php?nu=SABCS16L_973.
8. Momeny M, Saunus JM, Marturana F, et al. Heregulin-HER3-HER2 signaling promotes matrix metalloproteinase-dependent blood-brain-barrier transendothelial migration of human breast cancer cell lines. Oncotarget. 2015;6(6):3932-3946. doi: 10.18632/oncotarget.2846.
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