Abstract P3-06-22: Mechanisms behind trastuzumab resistance as neoadjuvant therapy in HER2-positive operable breast cancer

168 Background: Despite clinical usefulness of trastuzumab, intrinsic or acquired resistance to trastuzumab is a common clinical phenomenon. However, the mechanisms of resistance to trastuzumab have not been fully elucidated. The objective of this study was to determine the possible mechanisms of resistance to trastuzumab as neoadjuvant therapy in women with HER2-overexpressing operable breast cancer. Methods: Patients with operable breast cancer received 12 cycles of weekly paclitaxel plus weekly trastuzumab before surgery. All tumors were HER2-positive by immunohistochemistry (IHC) or fluorescence in situ hybridization. Expressions of ER, PgR, Ki67, PTEN, phosphorylated IGF-1R (pIGF-1R) and MUC4 were performed by IHC in core needle biopsy samples at baseline. PIK3CA mutation status was evaluated by sequencing of PIK3CA exons 9 and 20 using PCR amplification and direct sequencing. Results: Thirty-seven patients were enrolled and assessable for clinical and pathologic responses. The pCR rate was 48.6% (18/37). Negative, moderate and strong membranous expression of MUC4 was observed in 3 (8.1%), 18 (48.6%) and 12 (32.4%) patients, respectively. Membranous staining for pIGF1-R was negative in 24 (64.9%) patients. PTEN loss was observed in 33.3% (8/24) of the tumor examined. PIK3CA sequence analysis of the 13 tumors identified 2 mutations in exon 20 and 2 mutations in exon 9, corresponding to a PIK3CA mutation frequency of 30.8%. MUC4 status did not affect the pCR rate. Although membranous pIGF1-R expression did not affect pCR rate in hormone receptor-positive patients (66.7% vs. 50.0%), hormone receptor-positive patients with positive membranous pIGF1-R tended to show higher pCR rate compared with negative pIGF1-R (41.2% vs. 0%). PTEN loss and/or PIK3CA mutation were not significantly associated with pCR rate. Conclusions: These data indicate that aberrant downstream signaling caused by loss of PTEN and/or PIK3CA mutation, alternative signaling from IGF-1R and masking with MUC4 were not important mechanisms of resistance to trastuzumab.

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Faculty Opinions recommendation of Lapatinib as a component of neoadjuvant therapy for HER2-positive operable breast cancer (NSABP protocol B-41): an open-label, randomised phase 3 trial.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718133752.793486396 ◽

2013 ◽

Author(s):

Ana Maria Gonzalez-Angulo

Keyword(s):

Breast Cancer ◽

Neoadjuvant Therapy ◽

Operable Breast Cancer ◽

Her2 Positive ◽

Open Label ◽

Phase 3 ◽

B 41

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Neoadjuvant therapy with FEC followed by weekly paclitaxel and concurrent trastuzumab in Her2 positive non operable breast cancer: a phase II study

Annals of Oncology ◽

10.1093/annonc/mdw337.37 ◽

2016 ◽

Vol 27 ◽

pp. iv70

Author(s):

A. Levaggi ◽

F. Poggio ◽

M. Lambertini ◽

A. D'Alonzo ◽

S. Giraudi ◽

...

Keyword(s):

Breast Cancer ◽

Neoadjuvant Therapy ◽

Phase Ii ◽

Phase Ii Study ◽

Operable Breast Cancer ◽

Weekly Paclitaxel ◽

Her2 Positive

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Lapatinib as a component of neoadjuvant therapy for HER2-positive operable breast cancer (NSABP protocol B-41): an open-label, randomised phase 3 trial

The Lancet Oncology ◽

10.1016/s1470-2045(13)70411-x ◽

2013 ◽

Vol 14 (12) ◽

pp. 1183-1192 ◽

Cited By ~ 208

Author(s):

André Robidoux ◽

Gong Tang ◽

Priya Rastogi ◽

Charles E Geyer ◽

Catherine A Azar ◽

...

Keyword(s):

Breast Cancer ◽

Neoadjuvant Therapy ◽

Operable Breast Cancer ◽

Her2 Positive ◽

Open Label ◽

Phase 3 ◽

B 41

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Efficacy and safety of neoadjuvant therapy for HER2-positive early breast cancer: a network meta-analysis

Therapeutic Advances in Medical Oncology ◽

10.1177/17588359211006948 ◽

2021 ◽

Vol 13 ◽

pp. 175883592110069

Author(s):

Jie Zhang ◽

Yushuai Yu ◽

Yuxiang Lin ◽

Shaohong Kang ◽

Xinyin Lv ◽

...

Keyword(s):

Breast Cancer ◽

Neoadjuvant Therapy ◽

Combination Chemotherapy ◽

Target Therapy ◽

Meta Analysis ◽

Her2 Positive ◽

Single Target ◽

Dual Target ◽

Better Than ◽

Positive Breast Cancer

Aims: Currently, there are many approaches available for neoadjuvant therapy for human epidermal growth factor receptor 2 (HER2)-positive breast cancer that improve therapeutic efficacy but are also controversial. We conducted a two-step Bayesian network meta-analysis (NMA) to compare odds ratios (ORs) for pathologic complete response (PCR) and safety endpoints. Methods: The Cochrane Central Register of Controlled Trials, PubMed, Embase, and online abstracts from the American Society of Clinical Oncology and San Antonio Breast Cancer Symposium were searched comprehensively and systematically. Phase II/III randomised clinical trials for targeted therapy in at least one arm were included. Results: A total of 9779 published manuscripts were identified, and 36 studies including 10,379 patients were finally included in our analysis. The NMA of PCR showed that dual-target therapy is better than single-target therapy and combination chemotherapy is better than monochemotherapy. However, anthracycline did not bring extra benefits, whether combined with dual-target therapy or single-target therapy. On the other hand, the addition of endocrine therapy in the HER2-positive, hormone receptor (HR)-positive subgroup might have additional beneficial effects but without significant statistical difference. By performing a conjoint analysis of the PCR rate and safety endpoints, we found that ‘trastuzumab plus pertuzumab’ and ‘T-DM1 containing regimens’ were well balanced in terms of efficacy and toxicity in all target regimens. Conclusion: In summary, trastuzumab plus pertuzumab-based dual-target therapy with combination chemotherapy regimens showed the highest efficacy of all optional regimens. They also achieved the best balance between efficacy and toxicity. As our study showed that anthracycline could be replaced by carboplatin, we strongly recommended TCbHP as the preferred choice for neoadjuvant treatment of HER2-positive breast cancer. We also look forward to the potential value of T-DM1 in improving outcomes, which needs further study in future trials.

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UCP-2 inhibitor enhanced the efficacy of trastuzumab against HER2 positive breast cancer cells

Cancer Chemotherapy and Pharmacology ◽

10.1007/s00280-021-04303-4 ◽

2021 ◽

Author(s):

Jun Hua ◽

Zhe Zhang ◽

Lili Zhang ◽

Yan Sun ◽

Yuan Yuan

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Neoadjuvant Therapy ◽

Needle Biopsy ◽

Breast Cancer Cells ◽

Her2 Positive ◽

Trastuzumab Treatment ◽

Her2 Positive Breast Cancer ◽

Trastuzumab Therapy ◽

Positive Breast Cancer

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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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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