Impact of neoadjuvant therapy on eligibility for and frequency of breast conservation in stage II–III HER2-positive breast cancer: surgical results of CALGB 40601 (Alliance)

Abstract Purpose This study aimed to investigate the possibility of UCP-2 inhibitor in reducing acquired resistance of trastuzumab to improve the outcome of patients receiving trastuzumab therapy by exploring the relationship between UCP-2 expression and HER2 signaling pathway and examining whether UCP-2 expression was modulated by trastuzumab treatment. Methods 32 women diagnosed with primary HER2-positive breast cancer were recruited in this study. Needle biopsy was obtained from patients before they received at least four cycles neoadjuvant therapy containing trastuzumab in combination with chemotherapy. Surgical tumor biopsy was obtained during surgical procedure after the neoadjuvant therapy. Levels of HER2 phosphorylation and UCP-2 expression were detected by immunohistochemistry (IHC) and compared between tumor needle biopsy tissue and surgical tumor samples of these patients, as well as in BT474 breast cancer cells before and after trastuzumab treatment. HER2-selective phosphorylation/kinase activity inhibitor ONT-380 was used to identify the correlation between HER2 phosphorylation level and UCP-2 expression. UCP-2 inhibitor Genipin was then used to evaluate the apoptosis index in BT474 cells treated with trastuzumab. Results UCP-2 expression was significantly elevated in surgical tumor samples from breast cancer patients receiving trastuzumab in a neoadjuvant setting. We further confirmed our findings in HER2-positive BT474 cell line and found that trastuzumab treatment induced phosphorylation of HER2 and the overexpression of UCP-2, and the latter can be reversed by HER2 selective kinase inhibitor ONT-380. Moreover, UCP-2 inhibitor Genipin significantly enhanced the proliferation suppression effects of trastuzumab and markedly promoted apoptosis. Conclusion Taken together, our study identified UCP-2 as a novel therapeutic target for HER2 positive breast cancer and UCP-2 inhibitor may have great potential to enhance the response rate and efficacy of trastuzumab therapy.

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Trastuzumab-based neoadjuvant therapy in patients with HER2-positive breast cancer

Cancer ◽

10.1002/cncr.25120 ◽

2010 ◽

Vol 116 (12) ◽

pp. 2856-2867 ◽

Cited By ~ 63

Author(s):

Helena R. Chang

Keyword(s):

Breast Cancer ◽

Neoadjuvant Therapy ◽

Her2 Positive ◽

Her2 Positive Breast Cancer ◽

Positive Breast Cancer

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Efficacy and safety of neoadjuvant docetaxel, carboplatin, trastuzumab, and pertuzumab (TCH-P) in HER2-positive breast cancer: An Indian experience.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e12619 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e12619-e12619

Author(s):

Ajay Gogia ◽

Shalabh Arora ◽

SVS Deo ◽

Sandeep Mathur ◽

Dayanand Sharma

Keyword(s):

Breast Cancer ◽

Locally Advanced ◽

Neoadjuvant Treatment ◽

Breast Conservation ◽

Radical Mastectomy ◽

Stage Ii ◽

Breast Conservation Surgery ◽

Secondary Outcome ◽

Her2 Positive ◽

Positive Breast Cancer

e12619 Background: Dual targeted therapy with chemotherapy is one of the therapeutic approaches as neoadjuvant treatment in HER2/neu positive breast cancer (BC). However the safety and efficacy data of dual-targeted, chemotherapy regimen (docetaxel, carboplatin, trastuzumab, & pertuzumab [TCH-P] is limited from the Indian subcontinent. Methods: This retrospective study aims to evaluate the efficacy and toxicity of neoadjuvant TCH-P regimen in early, locally advanced, and oligometastatic (OM) HER2-positive BC, at All India Institute of Medical Sciences, New Delhi, India, in between the period 2015-2020. Total 6 cycles of 3-weekly neoadjuvant chemotherapy (NACT) protocol containing docetaxel (75 mg/m2), carboplatin (AUC = 6), trastuzumab (8 mg/kg loading followed by 6 mg/kg) and pertuzumab ( 840 mg loading followed by 420 mg) were planned. Subcutaneous peg-filgrastim was prophylactically administered on day 2 of each cycle. The primary outcome was the pathological complete response (pCR), which was defined as an absence of invasive and noninvasive cancer in breast or lymph node and secondary outcome were clinical overall response rate (ORR), rate of breast conservation surgery( BCS) for patients for whom modified radical mastectomy( MRM)was planned and toxicity. Results: Forty-five patients with a median age of 48 years (31-65) were included in this study. The TNM (AJCC-7th edition) stage distribution was stage II, 14 (31.1%); stage III, 29 (64.5%); and stage IV (OM), 2 (4.4%). Clinical node positivity disease was found in 26 (57.8%) cases. Nineteen (42.2%) patients had hormone-positive and 26(57.8%) cases were premenopausal. The clinically ORR and CR were seen in 100% and 60% respectively. Overall pCR rate was observed in 25 (55.6%) patients (70% in stage II). BCS was performed in 23(51.1%) cases. In 12(26.6%) cases, planned MRM was changed to BCS following NACT. Grade 3 and 4 toxicities were diarrhea 7 cases, thrombocytopenia in 6, neutropenia in 4, febrile neutropenia in 1, and anemia in 2 cases. Ten patients required dose modification and interruption. No patient had congestive heart failure or induction death. Conclusions: This is the first study of the non-anthracycline-based neoadjuvant protocol in HER2 positive BC from India. The TCH-P is an effective, safe, and well-tolerated, protocol with a path CR rate of 55.6% and 26.6% BCS conversion rate from planned MRM.

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Role of Post-Neoadjuvant therapy with trastuzumab emtansine in HER2-positive breast cancer

Medical Council ◽

10.21518/2079-701x-2021-20-68-74 ◽

2021 ◽

pp. 68-74

Author(s):

E. V. Lubennikova ◽

Ya. V. Vishnevskaya

Keyword(s):

Breast Cancer ◽

Adjuvant Therapy ◽

Neoadjuvant Therapy ◽

Locally Advanced ◽

Residual Tumor ◽

Long Term Results ◽

Trastuzumab Emtansine ◽

Her2 Positive ◽

Her2 Positive Breast Cancer ◽

Positive Breast Cancer

The widespread introduction of anti-HER2 agents has changed the natural course of Her2-positive breast cancer. The use of trastuzumab, and later dual anti-HER2 blockade with pertuzumab, in neoadjuvant regimens significantly increased the chances of complete cure. However, among patients with early and locally advanced forms of Her2-positive cancer, there is a cohort with an extremely unfavorable prognosis – tumors that have not achieved complete pathomorphological regression after neoadjuvant chemotherapy.The presence of a residual tumor in Her2-positive breast cancer has long been only a prognostically unfavorable factor without the potential to influence disease outcome. The results of the international phase III study KATHERINE, which demonstrated the high efficacy of post-adjuvant therapy with trastuzumab emtansine (T-DM1) in this patient cohort, have established a new standard of care. Due to T-DM1 adjuvant therapy, the possibility to significantly improve long-term results determined the predictive characteristics of the morphological response to the choice of treatment tactics, which became an important argument in favor of neoadjuvant therapy in patients with not only locally advanced but also primarily resectable Her2-positive breast cancer, followed by personalization of therapy.This article presents our own experience with post-neoadjuvant therapy with trastuzumab emtansine in a young patient with a residual tumor. The data of the main studies in early Her2-positive breast cancer are summarized.

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