HER2-enriched subtype and pathological complete response in HER2-positive breast cancer: A systematic review and meta-analysis

Schettini, Francesco; Pascual, Tomás; Conte, Benedetta; Chic, Núria; Brasó-Maristany, Fara; Galván, Patricia; Martínez, Olga; Adamo, Bárbara; Vidal, María; Muñoz, Montserrat; Fernández-Martínez, Aranzazu; Rognoni, Carla; Griguolo, Gaia; Guarneri, Valentina; Conte, Pier Franco; Locci, Mariavittoria; Brase, Jan C.; González-Farré, Blanca; Villagrasa, Patricia; Placido, Sabino De; Schiff, Rachel; Veeraraghavan, Jamunarani; Rimawi, Mothaffar F.; Osborne, C. Kent; Pernas, Sònia; Perou, Charles M.; Carey, Lisa A.

doi:10.1016/j.ctrv.2020.101965

Cited by 116 publications

(81 citation statements)

References 62 publications

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“…Some variables beyond the tumour-node-metastasis classification have been associated with prognosis in early-stage, HER2-positive breast cancer-eg, staging before and after neoadjuvant therapy, hormone receptor status, number of stromal tumour-infiltrating lymphocytes, 14,17,18 and PAM50 intrinsic subtypes. 2,18,19 Similarly, these biomarkers and PIK3CA mutations 20 have been associated with the probability of achieving a pathological complete response, 20,21 which is also associated with a positive long-term outcome. 22 However, decisions about escalation or de-escalation of systemic therapies are…”

Section: Introductionmentioning

confidence: 96%

A multivariable prognostic score to guide systemic therapy in early-stage HER2-positive breast cancer: a retrospective study with an external evaluation

Prat

Guarneri

Paré³

et al. 2020

The Lancet Oncology

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Section: Introductionmentioning

confidence: 96%

A multivariable prognostic score to guide systemic therapy in early-stage HER2-positive breast cancer: a retrospective study with an external evaluation

Prat

Guarneri

Paré³

et al. 2020

The Lancet Oncology

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“…Among them, the HER2-Enriched subtype has been systematically associated with higher pCR rates to anti-HER2 targeted therapies across multiple neoadjuvant clinical trials. 3,6,[10][11][12][13][14][15][16][17] At a DNA level, PIK3CA mutations have also been associated with lower treatment response. 18,19 Apart from intrinsic tumor characteristics, different immune system features have been correlated with a higher pCR rate in HER2-positive breast cancer, including the presence of tumor-infiltrating lymphocytes (TILs), 14,[20][21][22][23][24] programmed death ligand-1 protein expression, 23 T-cell receptor diversity metrics, 25 and immune gene-expression signatures.…”

Section: Introductionmentioning

confidence: 99%

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

Fernández-Martínez

Krop

Hillman

et al. 2020

JCO

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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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“…Human epidermal growth factor receptor 2 (HER2)-positive (+) breast cancer, irrespective of hormone receptor status, accounts for 11%-30% of all breast tumors. 1 Survival for metastatic disease has risen from a median of ∼20 months before the introduction of anti-HER2 targeted agents, to ∼45 months. 2 , 3 Current first- and second-line therapeutic standards are, respectively, the combination of pertuzumab + trastuzumab (P + T) + docetaxel/paclitaxel and the antibody–drug conjugate ado-trastuzumab-emtansine (T-DM1).…”

Section: Introductionmentioning

confidence: 99%

T-DM1 versus pertuzumab, trastuzumab and a taxane as first-line therapy of early-relapsed HER2-positive metastatic breast cancer: an Italian multicenter observational study

Schettini

Conte

Buono³

et al. 2021

ESMO Open

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Background The current standard first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive (+) metastatic breast cancer is the combination of pertuzumab, trastuzumab and a taxane (P + T + taxane), while standard second-line is ado-trastuzumab-emtansine (T-DM1). The registration trial of pertuzumab, however, did not include early-relapsing patients, defined as patients experiencing tumor relapse ≤12 months from the end of (neo)adjuvant anti-HER2 therapy. Conversely, the pivotal trial of T-DM1 included some patients relapsing ≤6 months after the end of (neo)adjuvant trastuzumab. Thus, a proportion of early-relapsing patients are currently eligible to receive T-DM1 as first-line treatment. Nevertheless, no direct comparison exists between the two regimens in this clinical setting. Patients and methods We retrospectively compared T-DM1 versus P + T + taxane as first-line treatment in two cohorts of early-relapsing patients in an Italian ‘real-world’ setting, involving 14 public health care institutions. The primary endpoint was progression-free survival. Secondary endpoints included patients' characterization, overall survival and post-progression survival. Univariate and multivariate analyses were carried out. All tests were two-sided and a P ≤ 0.05 was considered statistically significant. Results Among 1252 screened patients, 75 met the inclusion criteria. Forty-four (58.7%) received P + T + taxane and 31 (41.3%) received T-DM1. The two cohorts showed similar characteristics of aggressiveness and no significant differences in treatment history. T-DM1, compared with P + T + taxane was associated with worse progression-free survival (adjusted hazard ratio: 2.26, 95% confidence interval: 1.13-4.52, P = 0.021) and overall survival (adjusted hazard ratio: 3.95, 95% confidence interval: 1.38-11.32, P = 0.010), irrespective of previous (neo)adjuvant treatment, age, hormone receptors status, time-to-relapse (≤6 months or within 6-12 months) and presence of visceral/brain metastases. No differences were observed in post-progression survival ( P = 0.095). Conclusions Our study suggests superiority for P + T + taxane over T-DM1 as up-front treatment of early-relapsing HER2+ metastatic breast cancer, which merits further assessment in larger and prospective trials.

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HER2-enriched subtype and pathological complete response in HER2-positive breast cancer: A systematic review and meta-analysis

Cited by 116 publications

References 62 publications

A multivariable prognostic score to guide systemic therapy in early-stage HER2-positive breast cancer: a retrospective study with an external evaluation

A multivariable prognostic score to guide systemic therapy in early-stage HER2-positive breast cancer: a retrospective study with an external evaluation

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

T-DM1 versus pertuzumab, trastuzumab and a taxane as first-line therapy of early-relapsed HER2-positive metastatic breast cancer: an Italian multicenter observational study

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