Survival, Pathologic Response, and Genomics in CALGB 40601 (Alliance), a Neoadjuvant Phase III Trial of Paclitaxel-Trastuzumab With or Without Lapatinib in HER2-Positive Breast Cancer

PURPOSE CALGB 40601 assessed whether dual versus single human epidermal growth factor receptor 2 (HER2) –targeting drugs added to neoadjuvant chemotherapy increased pathologic complete response (pCR). Here, we report relapse-free survival (RFS), overall survival (OS), and gene expression signatures that predict pCR and survival. PATIENTS AND METHODS Three hundred five women with untreated stage II and III HER2-positive breast cancer were randomly assigned to receive weekly paclitaxel combined with trastuzumab plus lapatinib (THL), trastuzumab (TH), or lapatinib (TL). The primary end point was pCR, and secondary end points included RFS, OS, and gene expression analyses. mRNA sequencing was performed on 264 pretreatment samples. RESULTS One hundred eighteen patients were randomly allocated to THL, 120 to TH, and 67 to TL. At more than 7 years of follow-up, THL had significantly better RFS and OS than did TH (RFS hazard ratio, 0.32; 95% CI, 0.14 to 0.71; P = .005; OS hazard ratio, 0.34; 95% CI, 0.12 to 0.94; P = .037), with no difference between TH and TL. Of 688 previously described gene expression signatures, significant associations were found in 215 with pCR, 45 with RFS, and only 22 with both pCR and RFS (3.2%). Specifically, eight immune signatures were significantly correlated with a higher pCR rate and better RFS. Among patients with residual disease, the immunoglobulin G signature was an independent, good prognostic factor, whereas the HER2-enriched signature, which was associated with a higher pCR rate, showed a significantly shorter RFS. CONCLUSION In CALGB 40601, dual HER2-targeting resulted in significant RFS and OS benefits. Integration of intrinsic subtype and immune signatures allowed for the prediction of pCR and RFS, both overall and within the residual disease group. These approaches may provide means for rational escalation and de-escalation treatment strategies in HER2-positive breast cancer.

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Gene expression signatures in pre- and post-therapy (Rx) specimens from CALGB 40601 (Alliance), a neoadjuvant phase III trial of weekly paclitaxel and trastuzumab with or without lapatinib for HER2-positive breast cancer (BrCa).

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.15_suppl.506 ◽

2014 ◽

Vol 32 (15_suppl) ◽

pp. 506-506 ◽

Cited By ~ 7

Author(s):

Lisa A. Carey ◽

William Thomas Barry ◽

Brandy Pitcher ◽

Katherine A. Hoadley ◽

Maggie Chon U. Cheang ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Phase Iii ◽

Weekly Paclitaxel ◽

Her2 Positive ◽

Phase Iii Trial ◽

Her2 Positive Breast Cancer ◽

Gene Expression Signatures ◽

Post Therapy ◽

Positive Breast Cancer

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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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SABCS 2020: update on triple-negative and metastatic HER2-positive breast cancer

memo - Magazine of European Medical Oncology ◽

10.1007/s12254-021-00722-4 ◽

2021 ◽

Author(s):

Rupert Bartsch

Keyword(s):

Breast Cancer ◽

Triple Negative ◽

Phase Iii ◽

Line Treatment ◽

First Line ◽

Her2 Positive ◽

Her2 Positive Breast Cancer ◽

Pretreated Patients ◽

First Line Treatment ◽

Positive Breast Cancer

SummaryOne year into the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) pandemic, the 2020 San Antonio Breast Cancer Symposium (SABCS) was another large congress held in a virtual format. Despite these circumstances, clinically relevant data were presented, and this short review focuses on developments in the fields of triple-negative breast cancer (TNBC) and metastatic HER2-positive breast cancer. A quality-of-life (QoL) analysis from IMPassion031 showed that adding atezolizumab to neoadjuvant chemotherapy was not associated with a detrimental effect on QoL, while the burden of treatment-induced side effects increased with each cycle of neoadjuvant therapy in both treatment arms. KEYNOTE-355 evaluated the addition of pembrolizumab to chemotherapy as first-line treatment in metastatic TNBC (mTNBC); a significant improvement of progression-free survival (PFS) was reported in the pembrolizumab arm. At the 2020 SABCS, results with respect to different chemotherapy backbones were reported and the benefit of pembrolizumab was maintained irrespective of the type of taxane. Disappointingly, the phase III IPATunity130 study could not confirm a PFS improvement with the AKT inhibitor ipatasertib when added to paclitaxel as first-line treatment in mTNBC. A biomarker analysis from the phase III ASCENT study showed that the antibody–drug conjugate sacituzumab govitecan was superior to chemotherapy by investigator’s choice independent of Trop‑2 expression and BRCA mutation status. In HER2-positive breast cancer, the PRECIOUS trial suggested a small albeit significant benefit with reinduction of pertuzumab in later treatment lines in patients progressing on prior dual HER2-blockade in the first- or second-line setting. The HER2-specific tyrosine kinase inhibitor tucatinib when added to trastuzumab and capecitabine was shown to improve PFS and overall survival (OS) over trastuzumab and capecitabine alone in pretreated patients in the randomized HER2CLIMB trial; this benefit was apparently independent of hormone-receptor expression. An update from the DESTINY-Breast01 trial reported a median PFS of 19.4 months with trastuzumab deruxtecan in heavily pretreated patients. Finally, an analysis from the PERTAIN trial with > 6 years median follow-up showed excellent OS in patients with luminal B/HER2-positive receiving first-line trastuzumab/pertuzumab in combination with endocrine therapy suggesting that chemotherapy-free treatment is an option in highly selected patients.

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