scholarly journals Survival Analysis After Neoadjuvant Chemotherapy With Trastuzumab or Lapatinib in Patients With Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer in the GeparQuinto (G5) Study (GBG 44)

2018 ◽  
Vol 36 (13) ◽  
pp. 1308-1316 ◽  
Author(s):  
Michael Untch ◽  
Gunter von Minckwitz ◽  
Bernd Gerber ◽  
Christian Schem ◽  
Mahdi Rezai ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Hormone Receptor ◽  
Growth Factor Receptor ◽  
Long Term Outcomes ◽  
Her2 Positive ◽  
Adjuvant Trastuzumab ◽  
Hormone Receptor Positive ◽  
Epidermal Growth ◽  
Positive Breast Cancer

Purpose The GeparQuinto phase III trial demonstrated a lower pathologic complete response (pCR; pT0 ypN0) rate when lapatinib was added to standard anthracycline–taxane chemotherapy compared with trastuzumab in patients with human epidermal growth factor receptor 2 (HER2) –positive breast cancer. Here, we report the long-term outcomes. Methods Patients with HER2-positive tumors (n = 615) received neoadjuvant treatment with epirubicin (E) plus cyclophosphamide (C), followed by docetaxel (T) in combination with either lapatinib (L) or trastuzumab (H; ECH-TH arm: n = 307; ECL-TL arm: n = 308). All patients received adjuvant trastuzumab for a total of 12 months and 18 months in the ECH-TH and ECL-TL arms, respectively. Median follow-up was 55 months. Results Three-year disease-free survival (DFS), distant DFS (DDFS), and overall survival (OS) were not significantly different between the two treatment arms. Long-term outcomes correlated with pCR (DFS: hazard ratio [HR], 0.63; P = .042; DDFS: HR, 0.55; P = .021; and OS: HR, 0.31; P = .004). A benefit only for OS was observed in patients who were treated with trastuzumab and achieved pCR versus no pCR (HR, 0.15; P = .010), whereas no difference was found in patients with pCR versus without pCR in the lapatinib arm. DFS and DDFS remained unchanged in both treatment arms according to hormone receptor status, whereas OS was significantly better in hormone receptor–positive patients who were treated with neoadjuvant lapatinib (HR, 0.32; P = .019), followed by adjuvant trastuzumab. No difference was observed in hormone receptor–negative patients; however, the small number of events limits this interpretation. Within the hormone receptor–negative cohort, pCR was significantly associated with DFS, DDFS, and OS ( P = .002, .005, and .002, respectively). Conclusion pCR correlated with long-term outcome. In patients with hormone receptor–positive tumors, prolonged anti-HER2 treatment—neoadjuvant lapatinib for 6 months, followed by adjuvant trastuzumab for 12 months—significantly improved survival compared with anti-HER2 treatment with trastuzumab alone.

scholarly journals Impact of Diabetes, Insulin, and Metformin Use on the Outcome of Patients With Human Epidermal Growth Factor Receptor 2–Positive Primary Breast Cancer: Analysis From the ALTTO Phase III Randomized Trial

2017 ◽  
Vol 35 (13) ◽  
pp. 1421-1429 ◽  
Author(s):  
Amir Sonnenblick ◽  
Dominique Agbor-Tarh ◽  
Ian Bradbury ◽  
Serena Di Cosimo ◽  
Hatem A. Azim ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Hormone Receptor ◽  
Growth Factor Receptor ◽  
Disease Free Survival ◽  
Phase Iii ◽  
Her2 Positive ◽  
Hormone Receptor Positive ◽  
Patients With Diabetes ◽  
Epidermal Growth ◽  
Positive Breast Cancer

Purpose Previous studies have suggested an association between metformin use and improved outcome in patients with diabetes and breast cancer. In the current study, we aimed to explore this association in human epidermal growth factor receptor 2 (HER2 ) –positive primary breast cancer in the context of a large, phase III adjuvant trial. Patients and Methods The ALTTO trial randomly assigned patients with HER2-positive breast cancer to receive 1 year of either trastuzumab alone, lapatinib alone, their sequence, or their combination. In this substudy, we evaluated whether patients with diabetes at study entry—with or without metformin treatment—were associated with different disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS) compared with patients without diabetes. Results A total of 8,381 patients were included in the current analysis: 7,935 patients (94.7%) had no history of diabetes at diagnosis, 186 patients (2.2%) had diabetes with no metformin treatment, and 260 patients (3.1%) were diabetic and had been treated with metformin. Median follow-up was 4.5 years (0.16 to 6.31 years), at which 1,205 (14.38%), 929 (11.08%), and 528 (6.3%) patients experienced DFS, DDFS, and OS events, respectively. Patients with diabetes who had not been treated with metformin experienced worse DFS (multivariable hazard ratio [HR], 1.40; 95% CI, 1.01 to 1.94; P = .043), DDFS (multivariable HR, 1.56; 95% CI, 1.10 to 2.22; P = .013), and OS (multivariable HR, 1.87; 95% CI, 1.23 to 2.85; P = .004). This effect was limited to hormone receptor–positive patients. Whereas insulin treatment was associated with a detrimental effect, metformin had a salutary effect in patients with diabetes who had HER2-positive and hormone receptor–positive breast cancer. Conclusion Metformin may improve the worse prognosis that is associated with diabetes and insulin treatment, mainly in patients with primary HER2-positive and hormone receptor–positive breast cancer.

scholarly journals CDK4/6 inhibitors in breast cancer: beyond hormone receptor-positive HER2-negative disease

2018 ◽  
Vol 10 ◽  
pp. 175883591881834 ◽  
Author(s):  
Adriana Matutino ◽  
Carla Amaro ◽  
Sunil Verma
Keyword(s):  
Breast Cancer ◽  
Hormone Receptor ◽  
Growth Factor Receptor ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Breast Cancers ◽  
Cyclin Dependent Kinase ◽  
Her2 Positive ◽  
Hormone Receptor Positive ◽  
Epidermal Growth

The development of cyclin-dependent kinase (CDK) 4/6 inhibitors has been more prominent in hormone receptor (HR)-positive human epidermal growth factor receptor 2 (HER2)-negative breast cancers, with a significant improvement in progression-free survival (PFS) in first and later lines of metastatic breast cancer (MBC) therapy. Preclinical evidence suggests that there is activity of CDK4/6 inhibitors in nonluminal cell lines. Here, we present a review of the current preclinical and clinical data on the use of CDK inhibitors in HER2-positive and triple-negative breast cancer (TNBC).

scholarly journals Impact of PTEN Protein Expression on Benefit From Adjuvant Trastuzumab in Early-Stage Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer in the North Central Cancer Treatment Group N9831 Trial

2013 ◽  
Vol 31 (17) ◽  
pp. 2115-2122 ◽  
Author(s):  
Edith A. Perez ◽  
Amylou C. Dueck ◽  
Ann E. McCullough ◽  
Beiyun Chen ◽  
Xochiquetzal J. Geiger ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Early Stage ◽  
Growth Factor Receptor ◽  
Her2 Positive ◽  
Adjuvant Trastuzumab ◽  
Pten Protein ◽  
North Central ◽  
Epidermal Growth ◽  
Positive Breast Cancer

Purpose It has been suggested that PTEN, a negative regulator of PI3K/AKT signaling, is involved in tumor sensitivity to trastuzumab. We investigated the association between tumor PTEN protein expression and disease-free survival (DFS) of patients randomly assigned to receive chemotherapy alone (arm A) or chemotherapy with sequential (arm B) or concurrent trastuzumab (arm C) in the phase III early-stage human epidermal growth factor receptor 2 (HER2) –positive trial—North Central Cancer Treatment Group (NCCTG) N9831. Patients and Methods The intensity and percentage of invasive cells with cytoplasmic PTEN staining were determined in tissue microarray sections containing three cores per block (n = 1,286) or in whole tissue sections (WS; n = 516) by using standard immunohistochemistry (138G6 monoclonal antibody). Tumors were considered positive for PTEN (PTEN-positive) if any core or WS had any invasive cells with ≥ 1+ staining. Median follow-up was 6.0 years. Results Of 1,802 patients included in this analysis (of 3,505 patients registered to N9831), 1,342 (74%) had PTEN-positive tumors. PTEN positivity was associated with hormone receptor negativity (χ2 P < .001) and nodal positivity (χ2 P = .04). PTEN did not have an impact on DFS within the various arms. Comparing DFS of arm C to arm A, patients with PTEN-positive and PTEN-negative tumors had hazard ratios (HRs) of 0.65 (P = .003) and 0.47 (P = .005), respectively (interaction P = .16). For arm B versus arm A, patients with PTEN-positive and PTEN-negative tumors had HRs of 0.70 (P = .009) and 0.85 (P = .44), respectively (interaction P = .47). Conclusion In contrast to selected preclinical and limited clinical studies suggesting a decrease in trastuzumab sensitivity in patients with PTEN-negative tumors, our data show benefit of adjuvant trastuzumab for patients with HER2-positive breast cancer, independent of tumor PTEN status.

scholarly journals Management of Early-Stage Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer

2021 ◽  
Vol 17 (6) ◽  
pp. 320-330 ◽  
Author(s):  
Sonia Pernas ◽  
Sara M. Tolaney
Keyword(s):  
Breast Cancer ◽  
Early Stage ◽  
Growth Factor Receptor ◽  
Disease Free Survival ◽  
Invasive Disease ◽  
Her2 Positive ◽  
Free Survival ◽  
Epidermal Growth ◽  
Positive Breast Cancer

The addition of trastuzumab to chemotherapy dramatically improved the prognosis of early-stage human epidermal growth factor receptor 2 (HER2)–positive breast cancer. However, 15%-31% of patients still develop disease recurrence, on the basis of long-term follow-up of adjuvant pivotal trials. A better understanding of tumor biology has led to the development of optimized anti-HER2 drugs and add-on strategies to further improve survival outcomes. In the neoadjuvant setting, dual HER2 blockade with trastuzumab and pertuzumab plus chemotherapy has increased the rate of pathologic complete response, a surrogate marker of improved long-term outcome; yet, in the adjuvant setting, it has led to small benefits in invasive disease-free survival. Extended adjuvant therapy with the irreversible pan-HER2 inhibitor neratinib is an option for selected patients with HER2-positive and estrogen receptor–positive disease who have received neoadjuvant or adjuvant chemotherapy plus trastuzumab. Additionally, the use of the antibody-drug conjugate trastuzumab-emtansine has led to a significant improvement in invasive disease-free survival for patients with residual disease following neoadjuvant therapy and has taught us the importance of using preoperative therapy to adapt adjuvant treatment. Nevertheless, recurrences in the brain remain an important caveat, and not all patients benefit to the same extent from anti-HER2 therapies. Biologic heterogeneity within HER2-positive disease may modulate treatment response and prognosis. De-escalating treatment strategies to avoid unnecessary treatments and toxicities, without compromising outcomes, have become a crucial focus of research. To stratify patient risks and optimize treatment selection, other biomarkers including intrinsic subtype, level of HER2, and tumor-infiltrating lymphocytes should be further evaluated. We discuss the latest evidence on the current approach of early-stage, HER2-positive breast cancer and present future perspectives on its management.

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