Baseline Mutations and Up-Regulation of PI3K-AKT Pathway Serve as Potential Indicators of Lack of Response to Neoadjuvant Chemotherapy in Stage II/III Breast Cancer

Dong, Menghao; Shan, Baoen; Han, Xinghua; Zhao, Xiaotian; Wang, Fufeng; Zhu, Lei; Ou, Qiuxiang; Ma, Xiaopeng; Pan, Yueyin

doi:10.3389/fonc.2021.784985

Cited by 12 publications

(5 citation statements)

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“…RNA extraction and sequencing were performed as previously described 22 . Detailed descriptions were provided in Supplementary Methods (Supplemental Digital Content 3, http://links.lww.com/JS9/C113 ).…”

Section: Methodsmentioning

confidence: 99%

Genomic and immune microenvironment features influencing chemoimmunotherapy response in gastric cancer with peritoneal metastasis: a retrospective cohort study

Yu,

Ding,

Huang

et al. 2024

International Journal of Surgery

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Background: Patients with peritoneal metastasis (PM) from gastric cancer (GC) exhibit poor prognosis. Chemoimmunotherapy offers promising clinical benefits; however, its efficacy and predictive biomarkers in a conversion therapy setting remain unclear. The authors aimed to retrospectively evaluate chemoimmunotherapy efficacy in a conversion therapy setting for GC patients with PM and establish a prediction model for assessing clinical benefits. Materials and methods: A retrospective evaluation of clinical outcomes encompassed 55 GC patients with PM who underwent chemoimmunotherapy in a conversion therapy setting. Baseline PM specimens were collected for genomic and transcriptomic profiling. Clinicopathological factors, gene signatures, and tumor immune microenvironment were evaluated to identify predictive markers and develop a prediction model. Results: Chemoimmunotherapy achieved a 41.8% objective response rate and 72.4% R0 resection rate in GC patients with PM. Patients with conversion surgery showed better overall survival (OS) than those without the surgery (median OS: not reached vs 7.82 m, P<0.0001). Responders to chemoimmunotherapy showed higher ERBB2 and ERBB3 mutation frequencies, CTLA4 and HLA-DQB1 expression, and CD8+ T cell infiltration, but lower CDH1 mutation and naïve CD4+ T cell infiltration, compared to nonresponders. A prediction model was established integrating CDH1 and ERBB3 mutations, HLA-DQB1 expression, and naïve CD4+ T cell infiltration (AUC=0.918), which were further tested using an independent external cohort (AUC=0.785). Conclusion: This exploratory study comprehensively evaluated clinicopathological, genomic, and immune features and developed a novel prediction model, providing a rational basis for the selection of GC patients with PM for chemoimmunotherapy-involved conversion therapy.

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Section: Methodsmentioning

confidence: 99%

Genomic and immune microenvironment features influencing chemoimmunotherapy response in gastric cancer with peritoneal metastasis: a retrospective cohort study

Yu,

Ding,

Huang

et al. 2024

International Journal of Surgery

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“…Представленное исследование показало отсутствие эффективности НАПХТ при ГР+ HER2-PIK3CAмутированном РМЖ. Это согласуется с данными литературы, согласно которым люминальный РМЖ в целом демонстрирует низкую частоту полного регресса опухоли при проведении НАПХТ, что, вероятно, можно объяснить наличием мутации PIK3CA [12][13][14][15][16]. Неблагоприятное клиническое течение РМЖ при наличии мутации PIK3CA может быть связано с особенностями формирования локального иммунного ответа.…”

Section: Discussionunclassified

“…5,00 (1,(0)(1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)75) 5 (1,5) / 5 (1,(0)(1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)25) 0,013…”

Section: материалы и методыunclassified

Predictive and prognostic features of early and locally advanced <i>PIK3CA</i>-mutated luminal HER2-negative breast cancer

Stukan,

Semiglazova,

Kutukova

et al. 2024

Opuholi ženskoj reproduktivnoj sistemy

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Background. Data on the prognostic role of the PIK3CA mutation in hormone receptor-positive (HR+) HER2-negative (HER2–) breast cancer (BC) are contradictory; nevertheless, there are indications of its negative predictive and prognostic significance. This dictates the need for early genetic testing of BC to predict the clinical course, select a primary therapy option and individualize systemic treatment with disease progression. Investigation of regulation of the tumor cell cycle, as well as the relationship between genetic markers, infiltration of tumor-infiltrating lymphocytes (TILs) and subpopulations of immune cells is strategically important for the search for drug therapy targets.Aim. To search for predictive and prognostic markers of the clinical course of PIK3CA-associated HR+ HER2– BC.Materials and methods. The clinical, morphological and molecular features of the tumor of 101 BC patients with PIK3CA mutations (100 women and 1 man) were analyzed. Early and locally advanced HR+ HER2– BC is present in 81 % of cases, where neoadjuvant chemotherapy (NAPCT) was performed in 28 % of patients. Primary metastatic disease was detected in 17 % of cases. An immunohistochemical evaluation was performed on sections from paraffin blocks using monoclonal antibodies to estrogen receptors, progesterone receptors, HER2, Ki-67, CD8, CD4, CD68, CD163, Bcl-2, p53, cyclin D1. TILs were evaluated when stained with hematoxylin and eosin. TILs were evaluated in the stromal component of the tumor. The correlation of clinical and morphological parameters with the type of mutation and clinical outcomes of treatment of patients with early and locally advanced HR+ HER2– BC was evaluated. The statistical analysis was performed using the IBM SPSS Statistics v. 22 statistical package.Results. In BC with the PIK3CA mutation, a low level of TILs infiltration was detected (1 point), which does not differ depending on the presence of mutations in exon 20 and exon 9 (p >0.05). However, the E545K mutation is characterized by a higher TILs level (2 points) (p = 0.05). CD4+ T-TILs and CD8+ T-TILs levels are statistically significantly higher with mutations in exon 20 compared to exon 9 of the PIK3CA gene (p = 0.017 and 0.013, respectively). At the same time, in comparison with other mutations, tumors with H1047R and E545K mutations (p = 0.05) were characterized by a higher level of CD4 and CD8 expression. Regardless of the mutated exon, a high level of CD68+ tumor-associated macrophages (Me = 80 %), was detected due to the CD163+ fraction of immunosuppressive M2-polarized tumor-associated macrophages (Me = 70 %). A feature of the regulation of the PIK3CA-mutated BC cell cycle is the high level of cyclin D1 expression, the absence of p53 expression and the positive expression of the antiapoptotic marker Bcl-2. The median disease-free survival in early and locally advanced HR+ HER2– BC with the PIK3CA mutation was 36 months (95 % confidence interval (CI) 24.720–47.280). The risk of progression was increased by NAPCT (hazard ratio 3.389; 95 % CI 1.530–7.504; p = 0.003). The risk of progression was reduced by age younger than 49 years (hazard ratio 0.54; 95 % CI 0.30–0.96, p = 0.0359) and the absence of expression of the antiapoptotic marker Bcl-2 (hazard ratio 0.36; 95 % CI 0.14–0.97; p = 0.0425).Conclusion. The data obtained indicate that BC with the PIK3CA mutation is a kind of biological subtype of HR+ HER2– BC, which shows the lack of significant efficacy of NAPCT, probably due to the immunosuppressive microenvironment and low TILs levels. At the same time, the predominant population was M2-polarized tumor-associated macrophages. Moreover, the administration of NAPCT and the positive expression of Bcl-2 reduce disease-free survival, which can be explained by the possible effect of increasing the invasiveness and migration potential of the tumor cell. It is important to continue investigation of identified clinical and morphological prognostic markers when planning and developing new strategies for the treatment of early and metastatic HR+ HER2– BC with the PIK3CA mutation, as well as the use of specific targeted therapy at early metastatic disease.

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“…In this regard, the presence of double variants, especially in cis, seems to be associated with improved oncogenicity and sensitivity to PI3K inhibitors. To date, results regarding the association between PIK3CA mutations and clinical outcomes in a neoadjuvant setting are not entirely consistent, suggesting unfavorable clinical outcomes in terms of pCR rate and shorter DFS [ 17 , 18 , 19 , 41 , 44 , 45 , 46 , 47 , 48 ], favorable clinical outcomes [ 20 , 22 ] or no clinical impact [ 21 , 22 , 23 , 24 , 25 , 26 , 49 ].…”

Section: Discussionmentioning

confidence: 99%

Anthracycline-Free Neoadjuvant Treatment in Patients with HER2-Positive Breast Cancer: Real-Life Use of Pertuzumab, Trastuzumab and Taxanes Association with an Exploratory Analysis of PIK3CA Mutational Status

Irelli

Parisi

D’Orazio

et al. 2022

Cancers

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HER2 is considered one of the most traditional prognostic and predictive biomarkers in breast cancer. Literature data confirmed that the addition of pertuzumab to a standard neoadjuvant chemotherapy backbone (either with or without anthracyclines), in patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (EBC), leads to a higher pathological complete response (pCR) rate, which is known to correlate with a better prognosis. In this retrospective analysis, 47 consecutive patients with HER2-positive EBC received sequential anthracyclines and taxanes plus trastuzumab (ATH) or pertuzumab, trastuzumab and docetaxel (THP). Despite the limited sample size, this monocentric experience highlights the efficacy (in terms of pCR) and safety of THP in the neoadjuvant setting of HER2-positive EBC as an anthracycline-free approach. Given the role of PIK3CA as a prognostic and therapeutic target in breast cancer, tumors were also analyzed to assess the PIK3CA mutational status. Thirty-eight out of forty-seven patients were evaluated, and PIK3CA variants were identified in 21% of tumor samples: overall, one mutation was detected in exon 4 (2.6%), two in exon 9 (5.3%) and four in exon 20 (10.5%). Of note, one sample showed concurrent mutations in exons 9 (codon 545) and 20 (codon 1047). Among patients reaching pCR (n = 13), 38.5% were PIK3CA mutants; on the other hand, among those lacking pCR (n = 25), just 12% showed PIK3CA variants. Regarding THP-treated mutant patients (n = 5), 80% reached pCR (three hormone-receptor-negative, one hormone-receptor-positive). Interestingly, the only patient not achieving pCR had a tumor with two co-occurring PIK3CA mutations. In conclusion, this study provides new evidence about the efficacy and good safety profile of THP, compared to the ATH regimen, as an anthracycline-free neoadjuvant treatment of HER2-positive EBC. Further studies on larger/multicentric cohorts are planned for more in-depth analysis to confirm our molecular and clinical results.

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Baseline Mutations and Up-Regulation of PI3K-AKT Pathway Serve as Potential Indicators of Lack of Response to Neoadjuvant Chemotherapy in Stage II/III Breast Cancer

Cited by 12 publications

References 64 publications

Genomic and immune microenvironment features influencing chemoimmunotherapy response in gastric cancer with peritoneal metastasis: a retrospective cohort study

Genomic and immune microenvironment features influencing chemoimmunotherapy response in gastric cancer with peritoneal metastasis: a retrospective cohort study

Predictive and prognostic features of early and locally advanced <i>PIK3CA</i>-mutated luminal HER2-negative breast cancer

Anthracycline-Free Neoadjuvant Treatment in Patients with HER2-Positive Breast Cancer: Real-Life Use of Pertuzumab, Trastuzumab and Taxanes Association with an Exploratory Analysis of PIK3CA Mutational Status

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