scholarly journals Resistance to Neoadjuvant Treatment in Breast Cancer: Clinicopathological and Molecular Predictors

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2012
Author(s):  
María Rosario Chica-Parrado ◽  
Ana Godoy-Ortiz ◽  
Begoña Jiménez ◽  
Nuria Ribelles ◽  
Isabel Barragan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Risk Model ◽  
Residual Disease ◽  
Neoadjuvant Treatment ◽  
Growth Factor Receptor ◽  
Complete Response ◽  
Tumor Burden ◽  
Response To Treatment ◽  
Tumor Evolution ◽  
The Impact

Neoadjuvant Chemotherapy (NAC) in Breast Cancer (BC) has proved useful for the reduction in tumor burden prior to surgery, allowing for a more extensive breast preservation and the eradication of subjacent micrometastases. However, the impact on prognosis is highly dependent on the establishment of Pathological Complete Response (pCR), in particular for Triple Negative (TN) and Hormonal Receptor negative/Human Epidermal growth factor Receptor 2 positive (HR−/HER2+) subtypes. Several pCR predictors, such as PAM50, Integrative Cluster (IntClust), mutations in PI3KCA, or the Trastuzumab Risk model (TRAR), are useful molecular tools for estimating response to treatment and are prognostic. Major evolution events during BC NAC that feature the Residual Disease (RD) are the loss of HR and HER2, which are prognostic of bad outcome, and stemness and immune depletion-related gene expression aberrations. This dynamic nature of the determinants of response to BC NAC, together with the extensive heterogeneity of BC, raises the need to discern the individual and subtype-specific determinants of resistance. Moreover, refining the current approaches for a comprehensive monitoring of tumor evolution during treatment, RD, and eventual recurrences is essential for identifying new actionable alterations and the integral best management of the disease.

scholarly journals The Breast Cancer Immune Microenvironment is Modified by Neoadjuvant Chemotherapy

2021 ◽  
Author(s):  
Claudia Urueña ◽  
Paola Lasso ◽  
David Bernal-Estevez ◽  
Diego Rubio ◽  
Ana Janeth Salazar ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Immune Response ◽  
T Cells ◽  
Neoadjuvant Chemotherapy ◽  
Complete Response ◽  
Tumor Burden ◽  
Response To Treatment ◽  
Activated T Cells ◽  
Metastatic Cells ◽  
The Impact

Abstract Neoadjuvant chemotherapy (NAT) in breast cancer (BC) has been used to reduce tumor burden prior to surgery. However, the impact on prognosis depends on the establishment of Pathological Complete Response (pCR), which is influenced by tumor-infiltrating lymphocyte levels and the activation of the antitumor immune response. Nonetheless, NAT can affect immune infiltration and the quality of the response. Here, we showed that NAT induces dynamic changes in the tumor microenvironment (TME). After NAT, an increase of regulatory T cells and a decrease of CD8 + T cells was found in tumor, correlated with the presence of metastatic cells in lymph nodes. In addition, an increase of polymorphonuclear myeloid-derived suppressor like cells was found in luminal patients post-NAT. pCR patients showed a balance between the immune populations, while non-pCR patients presented an inverse relationship in the frequency of CD68 + versus CD3 + , CD8 + , and CD20 + cells. Moreover, activated T cells were found in peripheral blood, as well as an increase in T cell clonality with a lower diversity post-NAT. Overall, these results shown that NAT induces an activation of immune response, however, a balance in the TME seems to be related to a better antigenic presentation and therefore a better response to treatment.

scholarly journals Circulating Tumor Cells and Bevacizumab Pharmacokinetics during Neoadjuvant Treatment Combining Chemotherapy and Bevacizumab for Early Breast Cancer: Ancillary Analysis of the AVASTEM Trial

Cancers ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 140
Author(s):  
Renaud Sabatier ◽  
Jean-Yves Pierga ◽  
Hervé Curé ◽  
Rakan Abulnaja ◽  
Eric Lambaudie ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Neoadjuvant Treatment ◽  
Complete Response ◽  
Rank Test ◽  
Significant Prognostic Factor ◽  
Log Rank Test ◽  
The Impact

The phase II AVASTEM trial explored the impact of chemotherapy-bevacizumab combination on breast cancer stem cells in the neoadjuvant setting. We aimed to identify biological features associated with preoperative chemotherapy efficacy and prognosis by analyses of circulating tumor cells (CTCs) and bevacizumab pharmacokinetics (PK). The main objective was to assess the prognostic (relapse-free survival and overall survival) and predictive (pathological complete response, pCR) values of CTCs (CellSearch technology) and bevacizumab PK (ELISA). Seventy-five patients were included. Out of them 50 received bevacizumab-chemotherapy and 25 received chemotherapy alone. CTC results were available for 60 patients and PK data for 29 patients in the experimental arm. The absence of CTC at inclusion was correlated to better outcome. Five-years overall survival (OS) was 91% for CTC-negative patients vs. 54% for CTC-positive cases (HR = 6.21; 95%CI (1.75–22.06), p = 0.001, log-rank test). Similar results were observed for RFS with 5 y-RFS of 78% vs. 44% (HR = 3.51; 95%CI (1.17–10.52), p = 0.017, log-rank test). However, CTC status at baseline was not predictive of pCR (p = 0.74). CTC status after one cycle was not a significant prognostic factor (HR = 1.56; 95%CI (0.19–12.67); p = 0.68 for OS and HR = 2.76; 95%CI (0.60–12.61); p = 0.17 for RFS, log-rank test). Bevacizumab serum levels could not predict pCR and survival. PK values were not associated with treatment-related toxicities. In conclusion, CTCs detection at baseline is a prognostic marker for breast cancer receiving a neoadjuvant chemotherapy-bevacizumab combination independently of tumor response.

scholarly journals Antitumor activity and efficacy of shorter versus longer duration of anthracycline-taxane neoadjuvant chemotherapy in stage II–III HER2-negative breast cancer: a 10-year, retrospective analysis

2020 ◽  
Vol 12 ◽  
pp. 175883592097008
Author(s):  
Riccardo Lobefaro ◽  
Emma Zattarin ◽  
Federico Nichetti ◽  
Michele Prisciandaro ◽  
Francesca Ligorio ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Outcomes ◽  
Statistical Significance ◽  
Growth Factor Receptor ◽  
Disease Free Survival ◽  
Standard Of Care ◽  
Complete Response ◽  
Stage Ii ◽  
Specific Patient ◽  
The Impact

Background: Neoadjuvant anthracycline-taxane-based chemotherapy (ChT) is a standard of care treatment option for stage II–III breast cancer (BC) patients. However, the optimal duration of neoadjuvant ChT has been poorly investigated so far. Material and methods: We retrospectively retrieved clinical data of patients with stage II–III human epidermal growth factor receptor 2-negative (HER2–) BC who were treated between October 2007 and January 2018 with neoadjuvant AT (doxorubicin-paclitaxel) for three cycles followed by CMF (cyclophosphamide-methotrexate-5-fluorouracil) for three cycles (cohort A) or with four AT cycles followed by four CMF cycles (cohort B). The aim of our study was to investigate the impact of neoadjuvant ChT duration (cohort A versus cohort B) on pathological complete response (pCR) rates, disease-free survival (DFS) and overall survival (OS). Results: Of 209 HER2– BC patients included, 62 had triple-negative breast cancer (TNBC) and 147 had hormone receptor-positive (HR+) BC. Median age was 48 years (range 30–74 years). A total of 111 patients belonged to cohort A and 98 patients belonged to cohort B. pCR was detected in 29 (13.9%) patients, 25 (40.3%) of whom had TNBC and four (2.7%) had HR+ HER2– BC. Patients achieving pCR had significantly longer DFS and OS, with statistical significance reached only in patients with TNBC. We found no differences between cohort A and cohort B in terms of pCR rates (15.3% versus 12.2%; p = 0.55), DFS ( p = 0.49) or OS ( p = 0.94). The incidence of grade 3/4 adverse events was similar in cohort A versus cohort B as well (22.5% versus 19.4%; p = 0.54). Conclusion: Shorter duration of neoadjuvant anthracycline-taxane ChT was not associated with worse clinical outcomes in patients with stage II–III BC. Prospective studies are needed to evaluate whether the duration of neoadjuvant anthracycline-taxane-based ChT can be reduced in specific patient subgroups without negatively affecting clinical outcomes.

scholarly journals Post-neoadjuvant treatment and the management of residual disease in breast cancer: state of the art and perspectives

2019 ◽  
Vol 11 ◽  
pp. 175883591982771 ◽  
Author(s):  
Rafael Caparica ◽  
Matteo Lambertini ◽  
Noam Pondé ◽  
Debora Fumagalli ◽  
Evandro de Azambuja ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Residual Disease ◽  
Checkpoint Inhibitors ◽  
Expression Profiles ◽  
Pathologic Complete Response ◽  
Neoadjuvant Treatment ◽  
Metastatic Breast ◽  
Complete Response ◽  
Her2 Positive ◽  
Potential Biomarker

Achieving a pathologic complete response after neoadjuvant treatment is associated with improved prognosis in breast cancer. The CREATE-X trial demonstrated a significant survival improvement with capecitabine in patients with residual invasive disease after neoadjuvant chemotherapy, and the KATHERINE trial showed a significant benefit of trastuzumab-emtansine (TDM1) in human epidermal growth factor receptor 2 (HER2)-positive patients who did not achieve a pathologic complete response after neoadjuvant treatment, creating interesting alternatives of post-neoadjuvant treatments for high-risk patients. New agents are arising as therapeutic options for metastatic breast cancer such as the cyclin-dependent kinase inhibitors and the immune-checkpoint inhibitors, but none has been incorporated into the post-neoadjuvant setting so far. Evolving techniques such as next-generation sequencing and gene expression profiles have improved our knowledge regarding the biology of residual disease, and also on the mechanisms involved in treatment resistance. The present manuscript reviews the current available strategies, the ongoing trials, the potential biomarker-guided approaches and the perspectives for the post-neoadjuvant treatment and the management of residual disease after neoadjuvant treatment in breast cancer.

Tumor mutation burden and PIK3CA mutations are associated with pathological complete response in human epidermal growth factor receptor 2-positive breast cancer patients receiving pyrotinib combined with trastuzumab neoadjuvant treatment.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e12610-e12610
Author(s):  
Qiyun Shi ◽  
Juncheng Xuhong ◽  
Jia Ge ◽  
Feng Liu ◽  
Yang Lan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Neoadjuvant Treatment ◽  
Growth Factor Receptor ◽  
Complete Response ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Mutation Burden ◽  
Positive Breast Cancer

e12610 Background: Our previous study reported a good efficacy and safety of pyrotinib combined with trastuzumab neoadjuvant treatment in human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients. We further explored the potential biomarkers for the efficacy of pyrotinib combined with trastuzumab neoadjuvant treatment in HER2-positive breast cancer patients. Methods: To date, a total of 96 patients with early-stage breast cancer were enrolled for the neoadjuvant pyrotinib combined with trastuzumab treatment clinical trial (ChiCTR1900022293). By the method of 425 genes next-generation sequencing (NGS), the genomic characteristics of them were evaluated for the potential correlation with postoperative pathological complete response (pCR). Results: Among the cohort of 96 cases, a total of 32 patients have completed the whole therapy as well as final surgery and acquired qualified sequencing analysis report, and 18 of them achieved total pCR. The most frequently mutated driver genes were TP53 (75%), PIK3CA (44%), NBN (9%), RUNX1 (9%), FANCD2 (9%), ATRX (9%), MAP3K1 (9%) and NF1 (9%), respectively. In terms of somatic copy number alterations, the most frequent alterations are gain or amplification of ERBB2 (63%), MYC (22%), CCND1 (19%), CDK12 (16%) and FGF19 (16%), respectively. The median tumor mutation burden (TMB) of the 36 patients was 4.23 mut/Mb (0.00-29.61). Compared with pCR populations, non-pCR populations had significantly higher median TMB (5.29 vs 3.17 mut/Mb, P = 0.025). In addition, the pCR rate of patients with wild-type PIK3CA is significantly higher than that of patients with mutated PIK3CA (88.9% vs 14.3%, P < 0.001). Conclusions: Preliminary results suggested that HER2-positive breast cancer patients with higher TMB and activating mutations in PIK3CA are less likely to benefit from pyrotinib combined with trastuzumab neoadjuvant therapy, which need larger sample size to validate. *Qiyun Shi and Juncheng Xuhong contributed equally. #Co-corresponding author (Dr. Jun Jiang, [email protected]; Dr. Xiaowei Qi, [email protected]). Clinical trial information: ChiCTR1900022293.

IDH Mutations Identify a Subgroup of NPM1 Patients with a More Favorable Prognosis. a Retrospective Multicenter Study of the Filo Group

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 39-40
Author(s):  
Sylvain Garciaz ◽  
Marie Anne Hospital ◽  
Colombe Saillard ◽  
Yosr Hicheri ◽  
Evelyne D'Incan ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Residual Disease ◽  
Complete Response ◽  
Response To Treatment ◽  
P Value ◽  
High Dose ◽  
Idh Mutation ◽  
Npm1 Mutation ◽  
Idh Mutations ◽  
The Impact

IDH mutations are strongly enriched in cytogenetically normal AML harboring NPM1 mutation (CN-NPM1mut-AML). The impact of these mutations on response to treatment is still a matter of debate. In the ELN 2017 classification, NPM1mut/FLT3-ITD allelic ratio &gt;0.5 (FLT3-high) are considered intermediate-risk AML, whereas NPM1mut/ FLT3-ITD neg or &lt;0.5 (FLT3-low) are low-risk. We aimed to evaluate the impact of IDH mutation in CN-NPM1mut-AML patients (pts) treated intensively. For this purpose, we retrospectively analyzed 177 CN-NPM1-AML pts from the Paoli-Calmettes Institute and from the French Innovative leukemia organization (FILO) databases who had received conventional intensive chemotherapy according to the FILO protocols (anthracycline-cytarabine based regimen for induction and High-intermediate dose cytarabine (HIDAC) for consolidation. Forty-seven (26%) AML pts had an IDH mutation -18 IDH1-R132 (10%), 27 IDH2-R140 (15%) and 2 IDH2-R172 (1%) - while 130 AML pts were IDHwt. Pts characteristics are presented in the Table.The complete response rate after one or two courses of chemotherapy (CR1) was 100% and 90% (p-value=.03) in the IDHmut and IDHwt groups, respectively. For pts in CR1, NPM1 molecular residual disease after the first consolidation (MRD2) was negative (&gt;4 Log reduction) in 86% vs 53% of pts (p-value=.04). Nine (19%) and 24 (18%) pts received an allogeneic transplantation in CR1. The median time between CR1 and relapse was 11 months and 8 months, in IDHmut and IDHwt pts, respectively (p-value=.008). Day-100 non-relapse mortality was 8% and 12% respectively (p-value=ns). Median follow-up is 45 months (range, 2.4-115). Median EFS and OS are 21 months vs 12 months (p-value=.01) and 112 vs 23 months (p-value=.02), in the IDHmut vs IDHwt groups respectively (Figure). No survival differences were observed between IDH1mut and IDH2mut AML patients. Multivariate analyses with age&gt;65, FLT3-high and IDHmut as covariates showed that IDHmut was independently associated with a higher EFS (HR=1.7, ranges 1.1-2.6) and OS (HR=1.7, ranges 1.1-2.7). Our results suggest that IDHmut is associated with a better response and a good disease control with high-dose chemotherapy. Nevertheless, some relapses still occur justifying the use of an IDH inhibitor combined with first-line chemotherapy or in a post-remission maintenance setting. Figure Disclosures No relevant conflicts of interest to declare.

scholarly journals The Impact of Post-Mastectomy Radiotherapy on Survival Outcomes in Breast Cancer Patients Who Underwent Neoadjuvant Chemotherapy

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6205
Author(s):  
Janghee Lee ◽  
Jee-Ye Kim ◽  
Soong-June Bae ◽  
Yeona Cho ◽  
Jung-Hwan Ji ◽  
...  
Keyword(s):  
Neoadjuvant Chemotherapy ◽  
Residual Disease ◽  
Pathologic Complete Response ◽  
Residual Tumor ◽  
Complete Response ◽  
Tumor Burden ◽  
Breast Cancer Patients ◽  
Free Survival ◽  
Kaplan Meier ◽  
The Impact

This study aimed to determine whether post-mastectomy radiotherapy (PMRT) is beneficial for the prognosis of patients who achieved pathologic complete response (pCR), or who had minimal residual disease, after undergoing neoadjuvant chemotherapy (NAC). Patients who underwent a total mastectomy between 2006 and 2018, after NAC, were included. Patients who did not receive PMRT were matched using 1:3 propensity score matching (PSM). Kaplan–Meier survival curves were used to compare locoregional recurrence-free survival (LRRFS) and overall survival (OS). A total of 368 patients were included after 1:3 PSM. PMRT improved the LRRFS (p = 0.016) and OS (p = 0.017) rates of patients who underwent NAC. However, PMRT did not affect the prognosis of patients with pCR (LRRFS: p = 0.999; OS: p = 0.453). In addition, PMRT had a limited effect on LRRFS and OS in patients who responded well to NAC, with a neoadjuvant response index (NRI) value of 0.7–1.0 (LRRFS: p = 0.568; OS: p = 0.875). PMRT improved the OS of patients with a large residual tumor burden, such as nodal metastases or pathologic stage II/III. The benefits of PMRT vary depending on the patients’ response to NAC, although PMRT is useful for treating patients who underwent NAC. PMRT can be omitted, not only in patients with pCR, but also in good responders with an NRI value of 0.7–1.0.

scholarly journals Ganitumab and metformin plus standard neoadjuvant therapy in stage 2/3 breast cancer

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Douglas Yee ◽  
Claudine Isaacs ◽  
Denise M. Wolf ◽  
Christina Yau ◽  
Paul Haluska ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Pathologic Complete Response ◽  
Neoadjuvant Treatment ◽  
Growth Factor Receptor ◽  
Predictive Biomarkers ◽  
Standard Of Care ◽  
Complete Response ◽  
Type I ◽  
Drug Induced ◽  
Phase 2 Clinical Trial

AbstractI-SPY2 is an adaptively randomized phase 2 clinical trial evaluating novel agents in combination with standard-of-care paclitaxel followed by doxorubicin and cyclophosphamide in the neoadjuvant treatment of breast cancer. Ganitumab is a monoclonal antibody designed to bind and inhibit function of the type I insulin-like growth factor receptor (IGF-1R). Ganitumab was tested in combination with metformin and paclitaxel (PGM) followed by AC compared to standard-of-care alone. While pathologic complete response (pCR) rates were numerically higher in the PGM treatment arm for hormone receptor-negative, HER2-negative breast cancer (32% versus 21%), this small increase did not meet I-SPY’s prespecified threshold for graduation. PGM was associated with increased hyperglycemia and elevated hemoglobin A1c (HbA1c), despite the use of metformin in combination with ganitumab. We evaluated several putative predictive biomarkers of ganitumab response (e.g., IGF-1 ligand score, IGF-1R signature, IGFBP5 expression, baseline HbA1c). None were specific predictors of response to PGM, although several signatures were associated with pCR in both arms. Any further development of anti-IGF-1R therapy will require better control of anti-IGF-1R drug-induced hyperglycemia and the development of more predictive biomarkers.

scholarly journals Impact of hormone receptor status on the efficacy of HER2-targeted treatment

2018 ◽  
Vol 25 (6) ◽  
pp. 687-697 ◽  
Author(s):  
Bin Zhao ◽  
Hong Zhao ◽  
Jiaxin Zhao
Keyword(s):  
Neoadjuvant Therapy ◽  
Hormone Receptor ◽  
Meta Analysis ◽  
Neoadjuvant Treatment ◽  
Growth Factor Receptor ◽  
Disease Free Survival ◽  
Complete Response ◽  
Targeted Treatment ◽  
Her2 Positive ◽  
The Impact

The introduction of human epidermal growth factor receptor 2 (HER2)–targeted drugs into routine clinical practice has a dramatic effect on the outlook for patients with HER2-positive breast cancer (BC). However, the association between efficacy of HER2-targeted therapy and hormone receptor (HR) status is still unclear. Here we conducted a meta-analysis of randomized controlled trials (RCTs) to address this issue in both neoadjuvant and adjuvant settings. PubMed and EMBASE were searched from inception to October 2017 for studies involving trastuzumab, lapatinib, pertuzumab, trastuzumab emtansine and neratinib. Efficacy endpoints were pathological complete response (pCR) for neoadjuvant therapy and disease-free survival (DFS) for adjuvant therapy. In neoadjuvant setting, pCR was reported in 7 trials with 2868 subjects. Hormone receptor (HR)–negative women derived substantially greater benefit from HER2-targeted agents than did HR-positive patients (odds ratio (OR), 2.34; 95% confidence interval (CI), 1.99–2.75). Additionally, the impact of HR status on pCR was independent of anti-HER2 agents. In adjuvant setting, DFS was investigated in 7 studies with 12,768 patients. HR-positive patients benefit more from anti-HER2 treatment than did HR-negative subjects (OR, 0.81; 95% CI, 0.74–0.89). Moreover, patients who did not receive any endocrine or anti-HER2 neoadjuvant treatment showed similar outcome but with a smaller effect (OR, 0.88; 95% CI, 0.78–0.99). In summary, compared with HER2-positive/HR-negative subjects, HER2-positive/HR-positive patients achieved greater benefit from HER2-targeted treatment although the efficacy from neoadjuvant therapy was relatively poor.

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