MANAGEMENT OF HER2-positive breast cancer changed after the introduction of trastuzumab (Herceptin), the first anti-HER2 therapy to be approved by the U.S. Food and Drug Administration (FDA) for this type of cancer. Recent studies have more clearly defined the role of pertuzumab (Perjeta) and neratinib (Nerlynx). A question currently on the table is the optimal duration of trastuzumab. A recent study (Persephone) demonstrated that 6 months of trastuzumab is noninferior to 1 year. This is a more attractive option because of reduced potential for side effects, lower cost, and patient convenience, but experts agree that shorter treatment duration has not been definitively established.
Chau T. Dang, MD
Chau T. Dang, MD, Medical Director of Memorial Sloan Kettering Cancer Center Westchester’s Medical Oncology Service, updated attendees on the optimal adjuvant and neoadjuvant management of HER2-positive breast cancer during the 2018 Annual Chemotherapy Foundation Symposium.1
“For most patients with stage I HER2-positive breast cancer, taxane plus trastuzumab remains the standard of care, with excellent 7-year disease-free survival rates of about 93%. For most stage II to III HER2-positive breast cancers, trastuzumab/pertuzumab-based therapy has become a standard option. Neratinib may be ‘considered’ in high-risk patients, after trastuzumab-based treatment, for patients who did not receive pertuzumab, but there are no data to support its use after trastuzumab/pertuzumab-based treatment,” she told listeners.
“More study is needed to define the optimal duration of trastuzumab. As of now, 1 year remains the standard,” Dr. Dang noted.
Trastuzumab Alone or With Pertuzumab
LONG-TERM follow-up of trastuzumab combined with standard chemotherapy shows excellent disease-free survival rates of about 70% to 75% at 10 years and overall survival rates ranging from 80% to 85%, depending on the study. Although these long-term rates are quite good, there is room for improvement.
“Follow-up of four large adjuvant studies show that our patients are doing very well on trastuzumab,” she said. “Symptomatic congestive heart failure risk is a concern, albeit low, with some of the regimens used with trastuzumab, but this occurs mainly during active therapy,” she added.
For example, she said, with anthracycline/cyclophosphamide followed by paclitaxel/trastuzumab, the rate of symptomatic heart failure was 2% to 4%; for docetaxel, carboplatin, plus trastuzumab, 0.5%. “Late [heart failure] events are rare with either regimen,” Dr. Dang stated.
Dr. Dang discussed neoadjuvant and adjuvant anti-HER2 therapy with trastuzumab/pertuzumab. The combination of docetaxel, trastuzumab, and pertuzumab significantly increased the rate of pathologic complete response compared with docetaxel/trastuzumab alone in the open-label, phase II NEOSPHERE trial: 45.8% with the addition of pertuzumab vs 16.8% for trastuzumab/pertuzumab, 24% for docetaxel/pertuzumab, and 29% for docetaxel/trastuzumab.2
A European regimen of 3 cycles of fluorouracil (5-FU), epirubicin, and cyclophosphamide with trastuzumab/pertuzumab followed by 3 cycles of docetaxel with trastuzumab/pertuzumab was associated with pathologic complete response rates of 61.6% in the TRYPHAENA trial, compared with 57.3% for 3 cycles of 5-FU, epirubicin, and cyclophosphamide followed by 3 cycles of docetaxel plus trastuzumab/pertuzumab vs 66.2% for docetaxel/carboplatin with trastuzumab/pertuzumab.3 In that study, low rates of symptomatic left-ventricular dysfunction were reported with all three regimens.
The phase II BERENICE trial explored the cardiac safety of neoadjuvant and adjuvant trastuzumab/pertuzumab in patients with HER2-positive breast cancer and normal cardiac function at baseline. In that study, the rates of New York Heart Association class 3 or 4 heart failure were 1.5% when dose-dense doxorubicin/ cyclophosphamide was used with combined HER2-blockade and 0.5% when 5-FU, epirubicin, and cyclophosphamide was used with trastuzumab/pertuzumab.4
Neoadjuvant pertuzumab is now recommended as part of the treatment regimen for stage II to III HER2-positive breast tumors greater than 2 cm, or node-positive, locally advanced, and inflammatory cancers. “Adjuvant pertuzumab is recommended for patients at high risk of recurrence,” Dr. Dang added. A preplanned analysis of the APHINITY trial showed a significant improvement in 3-year disease-free survival in node-positive HER2-positive breast cancer. The addition of pertuzumab to trastuzumab plus chemotherapy achieved a 3-year invasive disease–free survival rate of 92% in the pertuzumab group and 90.2% in the placebo group in the node-positive cohort (P = .02).5
“Adjuvant pertuzumab is recommended for patients at high risk of recurrence.”— Chau T. Dang, MD
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Role of Neratinib
THE EXTENET trial found that in high-risk patients, treatment with neratinib reduced the rate of recurrence by an absolute 2.3% compared with placebo in patients with stage I to III HER2-positive breast cancer: 2-year invasive disease–free survival was 93.9% with neratinib vs 91.6% with placebo (P = .074).6
Neratinib is approved by the FDA and endorsed by the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (NCCN Guidelines®) as an option for patients with hormone receptor–positive, HER2-positive breast cancer at a “perceived” high risk for recurrence following trastuzumab-based adjuvant therapy, she continued. However, to date, “there are no data on the use of neratinib following trastuzumab/pertuzumab,” she emphasized.
SEVERAL STUDIES have explored shortening the duration of trastuzumab from the standard of care (12 months). The Persephone trial explored whether 6 months of trastuzumab was as effective as 12 months, and results suggest that the shorter trastuzumab regimen is noninferior to the longer one; 4-year disease-free survival was 89.8% for 12 months vs 89.4% for 6 months.7 Similar results were observed for overall survival.
“We have to take these positive results in the context of two other negative trials of shorter duration with 6 months of trastuzumab: PHARE and HORG. Furthermore, with more than 10 years of follow-up, in 4 large randomized controlled trials of more than 14,000 patients, 1 year of trastuzumab conferred sustained disease-free and overall survival benefits. Thus, more work is needed to determine if there is a subgroup of patients who may benefit from shorter-duration trastuzumab therapy. To date, 1 year remains the current standard of care,” Dr. Dang stated. ■
DISCLOSURE: Dr. Dang has received funding from Roche/Genentech and Puma.
1. Dang C: Optimizing neoadjuvant and adjuvant therapy for HER2-positive breast cancer. 2018 Annual Chemotherapy Foundation Symposium. Presented November 8, 2018.
2. Gianni L, Pienkowski T, Im Y-H, et al: 5-Year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer NeoSphere: A multicenter, open-label, phase 2 randomised trial. Lancet Oncol 17:791-800, 2016.
3. Schneeweiss A, Chia S, Hickish T, et al: Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: A randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol 9:2278-2284, 2013.
4. Swain S, Ewer MS, Viale G, et al: Pertuzumab, trastuzumab, and standard anthracycline- and taxane-based chemotherapy for the neoadjuvant treatment of patients with HER2-positive localized breast cancer (BERENICE): A phase II, open-label, multicenter, multinational cardiac safety study. Ann Oncol 29:646-653, 2018.
5. von Minckwitz G, Procter M, de Azambuja E, et al: Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med 377:122-131, 2017.
6. Chan A, Delaloge S, Homes FA, et al: Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): A multicentre, randomized, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 17:366-367, 2016.
7. Earl HM, Hiller L, Vallier A-L, et al: PERSEPHONE: 6 versus 12 months of adjuvant trastuzumab in patients with HER2-positive early breast cancer: Randomized phase 3 non-inferiority trial with definitive 4-year disease-free survival results. 2018 ASCO Annual Meeting. Abstract 506. Presented June 4, 2018.