Assessing the risk of recurrence in patients with early-stage HER2+ breast cancer
Baseline tumor size and nodal status impact long-term prognosis in HER2+ eBC, regardless of pCR
5-YEAR EFS BY pCR AND RISK FACTORS IN PATIENTS WITH HER2+ eBC (N=3710) IN 11 CLINICAL TRIALS TREATED WITH NEOADJUVANT CHEMOTHERAPY PLUS ANTI-HER2 THERAPY1,*:
- pCR was defined by the absence of residual invasive cancer in the resected breast specimen and all sampled ipsilateral lymph nodes but allowing for in situ cancer.1
- eBC: early-stage breast cancer; EFS: event-free survival; HER2-: human epidermal growth factor receptor 2–negative; HER2+: human epidermal growth factor receptor 2–positive; HR: hormone-receptor; N+: positive nodal involvement; N-: absence of cancer involvement in the regional lymph nodes; pCR: pathologic complete response; T1-2: tumor up to 5 cm; T3-4: tumor larger than 5 cm or with more advanced local spread.
Incidence of brain metastases in HER2+ eBC is not associated with achieving a pCR3
REAL-WORLD-EVIDENCE STUDY OF 526 PATIENTS WITH HER2+ eBC WHO RECEIVED NEOADJUVANT CHEMO WITH TRASTUZUMAB AND PERTUZUMAB3
Cumulative incidence of CNS recurrence events stratified by pCR vs non-pCR
- BM: brain metastases; CNS: central nervous system; eBC: early-stage breast cancer; HER2+: human epidermal growth factor receptor 2–positive; met: metastasis; pCR: pathologic complete response.
Despite advances in the treatment of HER2+ eBC, the risk of recurrence remains4
APHINITY: PHASE 3 STUDY OF PERTUZUMAB (N=2400) VS PLACEBO (N=2404) ADDED TO ADJUVANT CHEMOTHERAPY FOLLOWED BY TRASTUZUMAB IN PATIENTS WITH LN+ OR HIGH-RISK LN- HER2+ OPERABLE eBC4
- CNS: central nervous system; eBC: early-stage breast cancer; HER2+: human epidermal growth factor receptor 2–positive; iDFS: invasive disease–free survival; ITT: intent to treat; LN: lymph node; LN-: lymph node negative; LN+: lymph node positive.
KATHERINE: PHASE 3 STUDY OF T-DM1 (n=743) VS TRASTUZUMAB (n=743) IN PATIENTS WITH HER2+ eBC WITH NO pCR AFTER NEOADJUVANT TREATMENT5,6
RECURRENCE AT 7 YEARS WITH T-DM1 IN KATHERINE5,8,*
OVERALL SURVIVAL AT 7 YEARS IN THE ITT POPULATION IN KATHERINE5,8,†
89.1%
(89 events in 743 patients) with T-DM1
VS
84.4%
(126 events in 743 patients) with trastuzumab
- "Recurrence" was defined as the first occurrence of one of the following events: recurrence of ipsilateral locoregional invasive breast cancer, contralateral invasive breast cancer, a distant disease recurrence, or death from any cause.6
- (HR=0.66; 95% CI: 0.51-0.87; P=0.0027).
- CI: confidence interval; eBC: early-stage breast cancer; HER2+: human epidermal growth factor receptor 2–positive; HR: hazard ratio; ITT: intent to treat; pCR: pathologic complete response; T-DM1: trastuzumab emtansine.
The risk of recurrence in HER2+ eBC may increase over time5-8
KATHERINE: PHASE 3 STUDY OF T-DM1 (n=743) VS TRASTUZUMAB (n=743) IN PATIENTS WITH HER2+ eBC WITH NO pCR AFTER NEOADJUVANT TREATMENT5
RECURRENCE AT 3 YEARS AND AT 7 YEARS IN KATHERINE5-8,*
- "Recurrence" was defined as the first occurrence of one of the following events: recurrence of ipsilateral locoregional invasive breast cancer, contralateral invasive breast cancer, a distant disease recurrence, or death from any cause.6
- These data are for CNS recurrence as a site of first occurrence of an iDFS event.6,7
- CNS: central nervous system; eBC: early-stage breast cancer; HER2+: human epidermal growth factor receptor 2–positive; iDFS: invasive disease–free survival; ITT: intent to treat; pCR: pathologic complete response; T-DM1: trastuzumab emtansine.
Importance of assessing the risk of recurrence in patients with HER2+ eBC
JUST 1 RISK FACTOR AT INITIAL PRESENTATION IS ENOUGH TO INCREASE THE RISK OF RECURRENCE1,9,10
Tumor Size1,9,10
High BMI9,10
Young age at diagnosis9,10
- Individual data from 3,710 patients who were randomly assigned to 11 neoadjuvant trials for HER2-positive eBC, with ≥100 patients enrolled and a follow-up of ≥3 years.
- BMI: body mass index; CNS: central nervous system; eBC: early-stage breast cancer; HER2+: human epidermal growth factor receptor 2–positive; N+: positive nodal involvement; pCR: pathologic complete response.
References:
- van Mackelenbergh MT, Loibl S, Untch M, et al. Pathologic complete response and individual patient prognosis after neoadjuvant chemotherapy plus anti-human epidermal growth factor receptor 2 therapy of human epidermal growth factor receptor 2-positive early breast cancer. J Clin Oncol. 2023;41(16):2998-3008. doi: 10.1200/JCO.22.02241
- Breast cancer stages. American Cancer Society. https://www.cancer.org/cancer/types/breast-cancer/understanding-a-breast-cancer-diagnosis/stages-of-breast-cancer.html. Accessed August 13, 2025.
- Ferraro E, Singh J, Patil S, et al. Incidence of brain metastases in patients with early HER2-positive breast cancer receiving neoadjuvant chemotherapy with trastuzumab and pertuzumab. NPJ Breast Cancer. 2022;8(1):37. doi: 10.1038/s41523-022-00380-7
- Loibl S, Jassem J, Sonnenblick A, Parlier D, et al. Adjuvant pertuzumab and trastuzumab in early human epidermal growth factor receptor 2-positive breast cancer in the APHINITY Trial: Third interim overall survival analysis with efficacy update. J Clin Oncol. 2024;42(31):3643-3651. doi: 10.1200/JCO.23.02505
- Geyer C, Untch M, Huang C-S, et al. Survival with Trastuzumab Emtansine in Residual HER2-Positive Breast Cancer. N Engl J Med. 2025;392(3):249-257. doi: 10.1056/NEJMoa2406070
- von Minckwitz G, Huang C-S, 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
- Data Supplement for: von Minckwitz G, Huang C-S, 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
- Data Supplement for: Geyer C, Untch M, Huang C-S, et al. Survival with trastuzumab emtansine in residual HER2-positive breast cancer. N Engl J Med. 2025;392(3):249-257. doi:10.1056/NEJMoa2406070
- O’Shaughnessy J, Gradishar W, O’Regan, et al. Risk of recurrence in patients with HER2+ early-stage breast cancer: literature analysis of patient and disease characteristics. Clin Breast Cancer. 2023;23(4):350-362.
- Recurrent breast cancer. Mayo Clinic. https://www.mayoclinic.org/diseasesconditions/recurrent-breast-cancer/symptoms-causes/syc-20377135. Accessed August 13, 2025.
Important Safety Information
Warnings and Precautions:
- Diarrhea: Manage diarrhea through either Nerlynx dose escalation or loperamide prophylaxis. If diarrhea occurs despite recommended prophylaxis, treat with additional antidiarrheals, fluids, and electrolytes as clinically indicated. Withhold Nerlynx in patients experiencing severe and/or persistent diarrhea. Permanently discontinue Nerlynx in patients experiencing Grade 4 diarrhea or Grade ≥2 diarrhea that occurs after maximal dose reduction.
Indications
Nerlynx® (neratinib) tablets, for oral use, is a kinase inhibitor indicated:
- As a single agent, for the extended adjuvant treatment of adult patients with early-stage HER2-positive breast cancer, to follow adjuvant trastuzumab-based therapy.
Important Safety Information
Warnings and Precautions:
Warnings and Precautions:
- Hepatotoxicity: Monitor liver function tests monthly for the first 3 months of treatment, then every 3 months while on treatment and as clinically indicated. Withhold Nerlynx in patients experiencing Grade 3 liver abnormalities and permanently discontinue Nerlynx in patients experiencing Grade 4 liver abnormalities.
- Embryo-Fetal Toxicity: Nerlynx can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception.
Adverse Reactions: The most common adverse reactions (reported in ≥5% of patients) were:
- Nerlynx as a single agent: diarrhea, nausea, abdominal pain, fatigue, vomiting, rash, stomatitis, decreased appetite, muscle spasms, dyspepsia, AST or ALT increased, nail disorder, dry skin, abdominal distention, epistaxis, weight decreased, and urinary tract infection.
- Nerlynx in combination with capecitabine: diarrhea, nausea, vomiting, decreased appetite, constipation, fatigue/asthenia, weight decreased, dizziness, back pain, arthralgia, urinary tract infection, upper respiratory tract infection, abdominal distention, renal impairment, and muscle spasms.
To report suspected adverse reactions, contact Puma Biotechnology, Inc. at 1-844-Nerlynx (1-844-637-5969) or FDA at 1-800-332-1088 or www.fda.gov/medwatch.
Drug Interactions:
- Gastric acid reducing agents: Avoid concomitant use with proton pump inhibitors. Separate Nerlynx by at least 2 hours before or 10 hours after H2-receptor antagonists. Or separate Nerlynx by at least 3 hours after antacids.
- Strong CYP3A4 inhibitors: Avoid concomitant use.
- P-gp and moderate CYP3A4 dual inhibitors: Avoid concomitant use.
- Strong or moderate CYP3A4 inducers: Avoid concomitant use.
- Certain P-gp substrates: Monitor for adverse reactions of P-gp substrates for which minimal concentration change may lead to serious adverse reactions when used concomitantly with Nerlynx.
Use In Specific Populations:
- Lactation: Advise women not to breastfeed.
Please see Full Prescribing Information.
Indications
Nerlynx® (neratinib) tablets, for oral use, is a kinase inhibitor indicated:
- In combination with capecitabine, for the treatment of adult patients with advanced or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2 based regimens in the metastatic setting.