Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer in the APHINITY Trial: 6 Years' Follow-Up

PURPOSE APHINITY, at 45 months median follow-up, showed that pertuzumab added to adjuvant trastuzumab and chemotherapy significantly improved invasive disease–free survival (IDFS) (hazard ratio 0.81 [95% CI, 0.66 to 1.00], P = .045) for patients with early human epidermal growth factor receptor 2 (HER2)–positive breast cancer (BC), specifically those with node-positive or hormone receptor (HR)–negative disease. We now report the preplanned second interim overall survival (OS) and descriptive updated IDFS analysis with 74 months median follow-up. METHODS After surgery and central HER2-positive confirmation, 4,805 patients with node-positive or high-risk node-negative BC were randomly assigned (1:1) to either 1-year pertuzumab or placebo added to standard adjuvant chemotherapy and 1-year trastuzumab. RESULTS This interim OS analysis comparing pertuzumab versus placebo did not reach the P = .0012 level required for statistical significance ( P = .17, hazard ratio 0.85). Six-year OS were 95% versus 94% with 125 deaths (5.2%) versus 147 (6.1%), respectively. IDFS analysis based on 508 events (intent-to-treat population) showed a hazard ratio of 0.76 (95% CI, 0.64 to 0.91) and 6-year IDFS of 91% and 88% for pertuzumab and placebo groups, respectively. The node-positive cohort continues to derive clear IDFS benefit from pertuzumab (hazard ratio 0.72 [95% CI, 0.59 to 0.87]), 6-year IDFS being 88% and 83%, respectively. Benefit was not seen in the node-negative cohort. In a subset analysis, IDFS benefit from pertuzumab showed a hazard ratio of 0.73 (95% CI, 0.59 to 0.92) for HR-positive disease and a hazard ratio of 0.83 (95% CI, 0.63 to 1.10) for HR-negative disease. Primary cardiac events remain < 1% in both the treatment groups. No new safety signals were seen. CONCLUSION This analysis confirms the IDFS benefit from adding pertuzumab to standard adjuvant therapy for patients with node-positive HER2-positive early BC. Longer follow-up is needed to fully assess OS benefit.

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Real-World Outcomes of Adjuvant Chemotherapy for Node-Negative and Node-Positive HER2-Positive Breast Cancer

Journal of the National Comprehensive Cancer Network ◽

10.6004/jnccn.2018.7066 ◽

2019 ◽

Vol 17 (1) ◽

pp. 47-56 ◽

Cited By ~ 1

Author(s):

Zachary Veitch ◽

Omar F. Khan ◽

Derek Tilley ◽

Domek Ribnikar ◽

Xanthoula Kostaras ◽

...

Keyword(s):

Breast Cancer ◽

Adjuvant Chemotherapy ◽

Real World ◽

Her2 Positive ◽

Node Negative ◽

Node Positive ◽

Her2 Positive Breast Cancer ◽

Positive Breast Cancer

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Neoadjuvant Chemotherapy with Docetaxel, Carboplatin and Weekly Trastuzumab Is Active in HER2-Positive Early Breast Cancer: Results after a Median Follow-Up of over 4 Years

Breast Care ◽

10.1159/000452079 ◽

2016 ◽

Vol 11 (5) ◽

pp. 323-327 ◽

Cited By ~ 1

Author(s):

Hans-Christian Kolberg ◽

Leyla Akpolat-Basci ◽

Miltiades Stephanou ◽

Bahriye Aktas ◽

Carla Verena Hannig ◽

...

Keyword(s):

Breast Cancer ◽

Lymph Node ◽

Neoadjuvant Therapy ◽

Disease Free Survival ◽

Her2 Positive ◽

Free Survival ◽

Her2 Positive Breast Cancer ◽

Disease Free ◽

Positive Breast Cancer

Introduction: Most patients with HER2-positive breast cancer receive chemotherapy and trastuzumab. Data from adjuvant trials have shown that the combination of docetaxel, carboplatin and weekly trastuzumab (TCH) is well tolerated and as effective as anthracycline-containing regimes. Previous investigations on neoadjuvant treatment with taxanes, platinum salts and trastuzumab showed pathological complete remission (pCR) rates between 43.3 and 76%. To date, the longest published follow-up in this indication is 3 years. Here we present 4-year follow-up data for a cohort of 78 patients treated with neoadjuvant TCH. Methods: Between 2009 and 2014 we treated 78 patients with operable HER2-positive breast cancer with a neoadjuvant schedule of docetaxel (75 mg/m2) and carboplatin (AUC 6) every 3 weeks (q3w) and trastuzumab (4 mg/kg loading dose then 2 mg/kg) q1w. Lymph node involvement was verified by sentinel lymph node or core-cut biopsy. Patients were diagnosed at a mean age of 55.5 years; 65.4% had hormone receptor-positive tumors, 34.6% presented with grade 3 disease and 51.3% of patients were node positive. Patients were monitored every 2 cycles by ultrasound. After 6 cycles of chemotherapy all patients had surgery. Axillary dissection was performed in case of positive lymph node status prior to TCH. After surgery, trastuzumab was continued q3w up to 1 year. Results: No grade III/IV toxicities occurred and no case of congestive heart failure was observed. Neither dose modifications nor dose delays were necessary. 34 of the 78 patients (43.6%) achieved a pCR, 27 of the 40 node-positive patients (67.5%) experienced nodal conversion. After a median follow up of 48.5 months the disease-free survival (DFS) was 84.6%, the distant disease-free survival (DDFS) was 87.2% and the overall survival (OS) was 91%. Only T stage and nodal status at baseline were found to be significantly associated with survival estimates. Conclusion: The anthracycline-free regimen TCH is effective and safe in the neoadjuvant therapy of HER2-positive breast cancer, yielding DFS, DDFS and OS probabilities comparable to the results of adjuvant trials. Our data support the use of TCH as a neoadjuvant therapy regimen for patients with HER2-positive breast cancer. They also strongly encourage the use of taxanes and platinum salts as the chemotherapy backbone in studies investigating dual blockade with trastuzumab and pertuzumab in the neoadjuvant setting.

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Tumor Cellularity and Infiltrating Lymphocytes (CelTIL) as a Survival Surrogate in HER2-Positive Breast Cancer

JNCI Journal of the National Cancer Institute ◽

10.1093/jnci/djab057 ◽

2021 ◽

Author(s):

Nuria Chic ◽

Stephen J Luen ◽

Paolo Nuciforo ◽

Roberto Salgado ◽

Debora Fumagalli ◽

...

Keyword(s):

Breast Cancer ◽

Systemic Therapy ◽

Early Stage ◽

Statistical Significance ◽

Hazard Ratio ◽

Phase Iii ◽

Her2 Positive ◽

Her2 Positive Breast Cancer ◽

Infiltrating Lymphocytes ◽

Positive Breast Cancer

Abstract In early-stage HER2-positive breast cancer, biomarkers that guide de-escalation and/or escalation of systemic therapy are needed. CelTIL score is a novel, combined biomarker based on stromal tumor-infiltrating lymphocytes and tumor cellularity and determined in tumor biopsies at week 2 of anti-HER2 therapy only. We evaluated the prognostic value of CelTIL in 196 patients with early-stage HER2-positive disease treated with standard trastuzumab-based chemotherapy in the NeoALTTO phase III trial. Using a pre-specified CelTIL cutoff, a better 5-year event-free survival and overall survival was observed between CelTIL-high and CelTIL-low score with a 76.4% (95% confidence interval [CI] = 68.0%–85.0%) versus 59.7% (95% CI = 50.0%–72.0%) (hazard ratio = 0.40; 95% CI = 0.17 to 0.94), and 86.4% (95% CI = 80.0%–94.0%) vs 73.5% (95% CI = 64.0%–84.0%) (hazard ratio = 0.43; 95% CI = 0.20 to 0.92), respectively. Statistical significance was maintained after adjusting for baseline TILs, hormone receptor status, pre-treatment tumor size and nodal status, type of surgery, treatment arm, and pathological complete response. Further studies to support CelTIL as an early read-out biomarker to help de-escalate/escalate systemic therapy in HER2-positive breast cancer seem warranted.

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Longer follow-up on cardiac safety and distant disease free survival of dose-dense doxorubicin and cyclophosphamide followed by paclitaxel and trastuzumab in patients with early-stage HER2-positive breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.540 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 540-540

Author(s):

Rui Wang ◽

Anthony Francis Yu ◽

Richard Steingart ◽

Sujata Patil ◽

Jose Baselga ◽

...

Keyword(s):

Breast Cancer ◽

Early Stage ◽

Disease Free Survival ◽

Her2 Positive ◽

Distant Disease ◽

Free Survival ◽

Her2 Positive Breast Cancer ◽

Dose Dense ◽

Positive Breast Cancer

540 Background: We previously reported the cardiac safety results and distant disease-free survival (DDFS) on a phase 2 trial of dose-dense (dd) doxorubicin and cyclophosphamide (AC) followed by paclitaxel (T) and trastuzumab (H) in patients with early stage, human epidermal growth factor receptor 2 (HER2)-positive breast cancer. The incidence of congestive heart failure (CHF) was 1.4% both at a median follow-up of 2 and 7 years. Here, we report updated CHF and DDFS rates with longer follow-up. Methods: Patients were enrolled with HER2 overexpressed (immunohistochemistry 3+) or amplified (fluorescent in situ hybridization ratio > 2.0) disease, regardless of size or nodal status, and baseline left ventricular ejection fraction (LVEF) of > 55%. Patients (pts) received dd AC (60/600 mg/m2) q 2 weeks (w) x 4 →T (175 mg/m2) q 2 w x 4 with H (loading dose 4 mg/kg → 2 mg/kg q w during T → 6 mg/kg q 3 w for rest of 1 year); pegfilgrastim was administered after each chemotherapy cycle. LVEF monitoring with multigated acquisition scan occurred at baseline, months 2 (after AC), 6, 9, and 18 (after therapy completion). Results: From January 2005 to November 2005, 70 pts were enrolled; 2 (3%) and 68 (97%) were treated in neoadjuvant and adjuvant settings, respectively. In 68 pts treated in adjuvant setting, 40 (60%) and 27 (40%) had node-positive and node-negative disease, respectively. The median age was 49 years old (range 27-72); 55 (79%) had hormone-receptor positive disease, 11 (16%) had hypertension, and 21 (30%) had left sided radiation. The median baseline LVEF was 68% [range, 55%-81%]). With a median follow-up of 10.9 yrs, there was no additional CHF event. Therefore, the cumulative incidence of CHF remains to be 1.4% (95% confidence interval [95% CI], 1.36%- 7.7%). The 9 and 10 year DDFS rates were 89% (95% CI, 78%-94%) and 87% (95% CI 75%-93%), respectively. Conclusions: Longer follow-up of this study has demonstrated that ddAC →TH is associated with a low risk of CHF and promising DDFS in patients with early-stage HER2-positive breast cancer.

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