Tumor Microenvironment Modulation by Neoadjuvant Erlotinib Therapy and Its Clinical Impact on Operable EGFR-Mutant NSCLC

안병철,박찬이,김문수,이종목,최진호,김혜영,이건국,유남희,이영주,한지연 대한암학회 2024 Cancer Research and Treatment Vol.56 No.1

Purpose Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors have greatly improved survival in EGFR-mutant (EGFRm) non–small cell lung cancer (NSCLC); however, their effects on the tumor microenvironment (TME) are unknown. We assessed the changes induced by neoadjuvant erlotinib therapy (NE) in the TME of operable EGFRm NSCLC. Materials and Methods This was a single-arm phase II trial for neoadjuvant/adjuvant erlotinib therapy in patients with stage II/IIIA EGFRm NSCLC (EGFR exon 19 deletion or L858R mutations). Patients received up to 2 cycles of NE (150 mg/day) for 4 weeks, followed by surgery and adjuvant erlotinib or vinorelbine plus cisplatin therapy depending on observed NE response. TME changes were assessed based on gene expression analysis and mutation profiling. Results A total of 26 patients were enrolled; the median age was 61, 69% were female, 88% were stage IIIA, and 62% had L858R mutation. Among 25 patients who received NE, the objective response rate was 72% (95% confidence interval [CI], 52.4 to 85.7). The median disease-free and overall survival (OS) were 17.9 (95% CI, 10.5 to 25.4) and 84.7 months (95% CI, 49.7 to 119.8), respectively. Gene set enrichment analysis in resected tissues revealed upregulation of interleukin, complement, cytokine, transforming growth factor β, and hedgehog pathways. Patients with upregulated pathogen defense, interleukins, and T-cell function pathways at baseline exhibited partial response to NE and longer OS. Patients with upregulated cell cycle pathways at baseline exhibited stable/progressive disease after NE and shorter OS. Conclusion NE modulated the TME in EGFRm NSCLC. Upregulation of immune-related pathways was associated with better outcomes.

국소적으로 진행된 자궁경부암에서 동시 항암화학방사선요법과 선행보조항암화학요법 후 근치적 수술의 치료효과 및 생존율 비교

전섭,문성택,김윤숙,송은석,선우재근,최승도,배동한,김은석,남계현 순천향대학교 순천향의학연구소 2009 Journal of Soonchunhyang Medical Science Vol.15 No.2

Background : To compare of toxicity and survival in two treatment groups ; neoadjuvant chemotherapy followed by radical surgery versus standard cisplatin based chemoradiation therapy in the treatment of locally advanced cervical cancers. Methods : From 2004 to 2007, Among 31 patients with locally advanced cervical carcinoma stages IB2-IIIB, 17 patients were treated with pelvic radiation plus 6 weekly course of cisplatin 40mg/m2 followed by brachytherapy (CCRT group) and 14 patients were treated with three 21 day course of neoadjuvant chemotherapy(paclitaxel 135 mg/m2 plus cisplatin 75 mg/m2) followed by radical hysterectomy (NACT group). Results : In the CCRT group, complete remission occurred in 14 out of 17 patients, 3 patients recurred. Overall and disease free survival rates were 81.2% and 62.5% respectively. In the NACT group, overall clinical response rate to chemotherapy is 78.5% (CR, 50.0% PR 28.5%), pathologic response rate is 14.2%, and toxicity of chemotherapy was well tolerable. 3 patients recurred and overall and disease free survival rates were 92.8% and 71.4% respectively. At median follow up of 24 (range12-39) and 18 (range4-53)months in the CCRT and NACT groups respectively, there were no differences in overall survival and disease free survival rates. Conclusions : The combination of paclitaxel and cisplatin seems to be tolerated and active in the locally advanced cervical cancer. The results of our comparison study suggest that neoadjuvant chemotherapy at least as effective in terms of overall and disease free survival as standard cisplatin based chemoradiation therapy. Large sample of randomized study is needed to confirm these findings.

Lymphocyte-Activation Gene-3 Expression and Prognostic Value in Neoadjuvant-Treated Triple-Negative Breast Cancer

Yunxuan Wang,Tieying Dong,Qijia Xuan,Hong Zhao,Ling Qin,Qingyuan Zhang 한국유방암학회 2018 Journal of breast cancer Vol.21 No.2

Purpose: In this study, we aimed to evaluate lymphocyte-activation gene-3 (LAG-3) expression and its prognostic value in neoadjuvant- treated triple-negative breast cancer (TNBC). Methods: LAG-3, programmed death-1 (PD-1), programmed death ligand- 1 (PD-L1), and CD8+ tumor-infiltrating lymphocyte (TILs) levels were examined using immunohistochemistry in 148 preand 114 post-neoadjuvant chemotherapy (NACT) specimens of human TNBC tissue. Correlations between expression levels and clinicopathological features were analyzed. Prognostic values for combined detection in TNBC following NACT were evaluated. Results: In pre-NACT specimens, LAG-3 expression showed a significant association with pathological complete response (pCR, p=0.038) and was correlated with PD-1 (p<0.001) and PD-L1 (p=0.008). In post-NACT specimens, high expression of LAG-3 showed significant effects on nodal status (p=0.023) and PD-1 (p<0.001). The expression of immune markers on TILs significantly increased following NACT. Multivariate analysis indicated that only nodal status (odds ratio [OR], 0.226; 95% confidence interval [CI], 0.079–0.644; p=0.005) and high quantities of CD8+TILs (OR, 3.186; 95% CI, 1.314–7.721; p=0.010) are independent predictors of pCR. Nodal status (hazard ratio [HR], 2.666; 95% CI, 1.271–5.594; p=0.010), CD8+TILs (HR, 0.313; 95% CI, 0.139–0.705; p=0.005), and the LAG-3- high/PD-L1-high group (HR, 2.829; 95% CI, 1.050–7.623; p=0.040) provided prognostic values for patients with TNBC following NACT. Conclusion: CD8+TILs were sensitive predictive markers in response to NACT. High expression of LAG-3 in residual tissues, especially in combination with PD-L1, was associated with poor prognosis.

Clinical characteristics of rectal cancer patients with neoadjuvant chemoradiotherapy: a nationwide population-based cohort study in South Korea

Jun Woo Bong,Yeonuk Ju,Jihyun Seo,Jung Ae Lee,Sang Hee Kang,Sun Il Lee,Byung Wook Min 대한외과학회 2021 Annals of Surgical Treatment and Research(ASRT) Vol.100 No.5

Purpose: Neoadjuvant chemoradiotherapy has been accepted as a standard treatment for stage II–III rectal cancer. This study aimed to evaluate the clinical characteristics of patients who underwent neoadjuvant chemoradiotherapy for rectal cancer and effects on overall survival (OS) of neoadjuvant chemoradiotherapy in South Korea. Methods: Patients who underwent curative resection for rectal cancer from 2014 to 2016 were retrospectively reviewed from the database of the National Quality Assessment program in South Korea. Patients were categorized into the upfront surgery group and neoadjuvant chemoradiotherapy group. We evaluated factors associated with the administration of neoadjuvant chemoradiotherapy and its effects on OS. Inverse probability of treatment weighting was performed to account for baseline differences between subgroups. Results: A total of 6,141 patients were categorized into the upfront surgery group (n = 4,237) and neoadjuvant chemoradiotherapy group (n = 1,904). The neoadjuvant chemoradiotherapy was more frequently administered to male, midrectal cancer, and younger patients. In the neoadjuvant chemoradiotherapy group, old age, underweight, and pathologic stage were significant risk factors of OS, and male sex, the level of tumor and clinical stages were not associated with OS. After adjustment, the OS of the neoadjuvant chemoradiotherapy group followed the OS of the upfront surgery group of the same pathologic stage. Conclusion: Male sex and the level of tumor were not related to the OS of rectal cancer patients with neoadjuvant chemoradiotherapy. The OS of patients who underwent neoadjuvant chemoradiotherapy was decided by their pathologic stages regardless of clinical stages.

Genomic Correlates of Unfavorable Outcome in Locally Advanced Cervical Cancer Treated with Neoadjuvant Chemoradiation

Yuchun Wei,Chuqing Wei,Liang Chen,Ning Liu,Qiuxiang Ou,Jiani C. Yin,Jiaohui Pang,Zhenhao Fang,Xue Wu,Xiaonan Wang,Dianbin Mu,Yang Shao,Jinming Yu,Shuanghu Yuan 대한암학회 2022 Cancer Research and Treatment Vol.54 No.4

Purpose Neoadjuvant therapy modality can increase the operability rate and mitigate pathological risks in locally advanced cervical cancer, but treatment response varies widely. It remains unclear whether genetic alterations correlate with the response to neoadjuvant therapy and disease-free survival (DFS) in locally advanced cervical cancer. Materials and Methods A total of 62 locally advanced cervical cancer (stage IB-IIA) patients who received neoadjuvant chemoradiation plus radical hysterectomy were retrospectively analyzed. Patients’ tumor biopsy samples were comprehensively profiled using targeted next generation sequencing. Pathologic response to neoadjuvant treatment and DFS were evaluated against the association with genomic traits. Results Genetic alterations of PIK3CA were most frequent (37%), comparable to that of Caucasian populations from The Cancer Genome Atlas. The mutation frequency of genes including TERT, POLD1, NOS2, and FGFR3 was significantly higher in Chinese patients whereas RPTOR, EGFR, and TP53 were underrepresented in comparison to Caucasians. Germline mutations were identified in 21% (13/62) of the cohort and more than half (57%) had mutations in DNA damage repair genes, including BRCA1/2, TP53 and PALB2. Importantly, high tumor mutation burden, TP53 polymorphism (rs1042522), and KEAP1 mutations were found to be associated with poor pathologic response to neoadjuvant chemoradiation treatment. KEAP1 mutations, PIK3CA-SOX2 co-amplification, TERC copy number gain, and TYMS polymorphism correlated with an increased risk of disease relapse. Conclusion We report the genomic profile of locally advanced cervical cancer patients and the distinction between Asian and Caucasian cohorts. Our findings highlight genomic traits associated with unfavorable neoadjuvant chemoradiation response and a higher risk of early disease recurrence. PurposeNeoadjuvant therapy modality can increase the operability rate and mitigate pathological risks in locally advanced cervical cancer, but treatment response varies widely. It remains unclear whether genetic alterations correlate with the response to neoadjuvant therapy and disease-free survival (DFS) in locally advanced cervical cancer.Materials and MethodsA total of 62 locally advanced cervical cancer (stage IB-IIA) patients who received neoadjuvant chemoradiation plus radical hysterectomy were retrospectively analyzed. Patients’ tumor biopsy samples were comprehensively profiled using targeted next generation sequencing. Pathologic response to neoadjuvant treatment and DFS were evaluated against the association with genomic traits.ResultsGenetic alterations of <i>PIK3CA</i> were most frequent (37%), comparable to that of Caucasian populations from The Cancer Genome Atlas. The mutation frequency of genes including <i>TERT, POLD1, NOS2</i>, and <i>FGFR3</i> was significantly higher in Chinese patients whereas <i>RPTOR, EGFR</i>, and <i>TP53</i> were underrepresented in comparison to Caucasians. Germline mutations were identified in 21% (13/62) of the cohort and more than half (57%) had mutations in DNA damage repair genes, including <i>BRCA1/2, TP53</i> and <i>PALB2</i>. Importantly, high tumor mutation burden, <i>TP53</i> polymorphism (rs1042522), and <i>KEAP1</i> mutations were found to be associated with poor pathologic response to neoadjuvant chemoradiation treatment. <i>KEAP1</i> mutations, <i>PIK3CA-SOX2</i> co-amplification, <i>TERC</i> copy number gain, and <i>TYMS</i> polymorphism correlated with an increased risk of disease relapse.ConclusionWe report the genomic profile of locally advanced cervical cancer patients and the distinction between Asian and Caucasian cohorts. Our findings highlight genomic traits associated with unfavorable neoadjuvant chemoradiation response and a higher risk of early disease recurrence.

Re-Excision Rate in Breast Conservation Surgery after Neoadjuvant Chemotherapy

송정현,박정영,최정은,강수환,이수정,배연경 한국유방암학회 2017 Journal of Breast Disease Vol.5 No.1

Purpose: The purpose of this study was to compare the success rate of re-excision and breast-conserving surgery (BCS) between patients who received neoadjuvant chemotherapy and those who did not. Methods: In this retrospective cohort study, 256 women who had clinical T2 breast cancer and planned to receive, as initial treatment either BCS (n=197) or neoadjuvant chemotherapy (n=59) between January 2009 and December 2012 were included. The data, including age, initial tumor size, mammographic microcalcification, ultrasound multifocality and axillary nodal status, were collected. The pathologic tumor size, p-multifocality, histologic type, estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, Ki-67, ductal carcinoma in situ (DCIS) and extensive intraductal component (EIC) were also reviewed. The re-excision and BCS success rates were investigated. Univariate analysis and regression model were used. To reduce the effect of selection bias, propensity score matching-based analysis was also performed. Results: Of the 256 patients, 178 patients (90.4%, 178/197) in the non-neoadjuvant group and 56 patients (94.9%, 56/59) in the neoadjuvant group received BCS (p=0.406). In propensity-matched cohorts (n=118), the re-excision rate was similar in the two groups (35.6% in neoadjuvant group vs. 35.6% in non-neoadjuvant group, p=1.000). BCS success rate was slightly higher in neoadjuvant group (94.9%, 56/59) than in non-neoadjuvant group (86.4% [51/59], p=0.205). In logistic regression model, clinicopathologic factors associated with re-excision were pathologic multifocality (odds ratio [OR], 4.56; p=0.0142), high Ki-67 (≥50%) (OR, 0.7; p=0.0243) and DCIS component (OR, 2.67; p=0.0261). Conclusion: This study showed that neoadjuvant chemotherapy could increase the success rate of BCS but could not decrease that of re-excision. The re-excision rate is more associated with pathologic finding rather than the effect of neoadjuvant chemotherapy.

The Role of Neutrophil-to-Lymphocyte Ratio in Predicting Pathological Response for Resectable Non–Small Cell Lung Cancer Treated with Neoadjuvant Chemotherapy Combined with PD-1 Checkpoint Inhibitors

Xiaoyan Sun,Yingnan Feng,Bin Zhang,Wuhao Huang,Xiaoliang Zhao,Hua Zhang,Dongsheng Yue,Changli Wang 대한암학회 2022 Cancer Research and Treatment Vol.54 No.4

Purpose The aim of our study was to investigate the value of baseline and preoperative neutrophil-to-lymphocyte ratio (NLR) in predicting the pathological response and disease-free survival (DFS) of neoadjuvant chemotherapy alone or combined with programmed cell death-1 (PD-1) checkpoint inhibitors in patients with resectable non–small cell lung cancer (NSCLC). Materials and Methods Resectable NSCLC patients who underwent neoadjuvant chemotherapy alone or combined with PD-1 checkpoint inhibitors between January 2018 and January 2020 were included. Peripheral venous blood samples of the patients were collected within 3 days prior to the first neoadjuvant treatment and within 3 days prior to surgery. Results A total of 79 patients in neoadjuvant chemotherapy combined with PD-1 checkpoint inhibitors group and 89 patients in neoadjuvant chemotherapy alone group were included. Thirty-five point four percent of the patients achieved pathological complete response (pCR) in neoadjuvant chemotherapy combined with PD-1 checkpoint inhibitors group, whereas only 9.0% reached pCR in the group of neoadjuvant chemotherapy. High NLR level were correlated with poor pathological response and DFS in neoadjuvant chemotherapy or combined with PD-1 checkpoint inhibitors group. Multivariate analysis revealed that baseline NLR could independently predict pathological response and DFS in the neoadjuvant chemotherapy combined with PD-1 checkpoint inhibitors group. Conclusion High NLR level were correlated with poor pathological response and shorter DFS in patients with NSCLC undergoing neoadjuvant chemotherapy or combined with PD-1 checkpoint inhibitors. Meanwhile, baseline NLR could independently predict response to pathological response and DFS, revealing its potential as a screening tool in NSCLC patients who received neoadjuvant chemotherapy combined with PD-1 checkpoint inhibitors.

Role of Neoadjuvant Chemotherapy in the Management of Advanced Ovarian Cancer

Zhao, Dan,Wu, Ling-Ying,Wang, Xiao-Bing,Li, Xiao-Guang Asian Pacific Journal of Cancer Prevention 2015 Asian Pacific journal of cancer prevention Vol.16 No.6

Objective: To analyze efficacy of neoadjuvant chemotherapy for advanced ovarian cancer. Materials and Methods: A total of 107 patients with advanced ovarian cancer undergoing cytoreductive surgery were divided into a neoadjuvant chemotherapy group (n=61) and a primary debulking group (n=46) and retrospectively analyzed. Platinum-based adjuvant chemotherapy was applied to both groups after cytoreductive surgery ande overall and progression-free survival times were calculated. Results: No significant difference was observed in duration of hospitalization ($20.8{\pm}6.1$ vs. $20.2{\pm}5.4$ days, p>0.05). The operation time of neoadjuvant chemotherapy group was shorter than the initial surgery group ($3.1{\pm}0.7$ vs. $3.4{\pm}0.8$ h, p<0.05). There were no significant differences in median overall survival time between neoadjuvant chemotherapy group and surgery group (42 vs. 55 months, p>0.05). Similarly, there was no difference in median progression-free survival between neoadjuvant chemotherapy group and surgery group (16 vs. 17 months, p>0.05). The surgical residual tumor size demonstrated no significant difference between initial surgery and neoadjuvant chemotherapy groups (p>0.05). Multivariate analysis showed that more than 3 cycles of regimen with neoadjuvant chemotherapy was associated with more resistance to chemotherapy compared with patients without receiving neoadjuvant chemotherapy (OR: 5.962, 95%CI: 1.184-30.030, p<0.05). Conclusions:Neoadjuvant chemotherapy can shorten the operation time. However, it does not improve survival rates of advanced ovarian cancer patients.

진행된 국소 자궁경부암에서 Vinblastine-Bleomycin-Cisplatin을 사용한 선행 항암화학요법의 효과

김창남,조윤제,허주엽 경희대학교 1996 慶熙醫學 Vol.12 No.3-4

유방암에서 수술 전 항암화학요법이 생물학적 예후인자들에 미치는 영향

하기원(Gi Won Ha),윤현조(Hyun Jo Youn),정성후(Sung Hoo Jung) 대한외과학회 2008 Annals of Surgical Treatment and Research(ASRT) Vol.74 No.6

Purpose: The selection of systemic therapy for breast cancer is based on the expression pattern of biological prognostic markers. Neoadjuvant chemotherapy has been considered the standard care for locally advanced breast cancer. However, its effect on the expression of biological prognostic markers is controversial. The aim of this study was to determine whether neoadjuvant chemotherapy may alter these expression patterns in patients suffering with breast cancer. Methods: We determined the protein expression levels of estrogen receptor (ER), progesterone receptor (PR), p53 and HER-2/neu in the preoperative core needle biopsies and the final surgical specimens from 15 patients who received neoadjuvant chemotherapy between January 2002 and June 2007. As a control group, we analyzed the samples from patients who did not receive neoadjuvant chemotherapy. Results: The pathologic complete tumor response rate (pCR) of the neoadjuvant chemotherapy group was 6.7% (1/15). Of those patients who did not achieve a pCR (n=14), no significant differences in the biological prognostic markers expression were observed between the two groups. Alteration of the ER or PR status occurred in 42.8% (6/14) of the patients after neoadjuvant chemotherapy and in 14.3% (2/14) of the control patients, showing there was no significant difference between the two groups (P=0.210). The hormonal receptor status was changed in 3 cases (21.4%) after neoadjuvant chemotherapy. Conclusion: There were no significant differences for the changes in the expression of ER, PR, p53 and HER-2/neu from the preoperative core needle biopsy to the final surgical specimens between those patients who had received neoadjuvant chemotherapy and those patients who didn’t. However, changes of the ER or PR status and the hormonal receptor status occurred in 42.8% and 21.4%, respectively, of the patients who underwent neoadjuvant chemotherapy. As these changes may impact treatment, we suggest that immunohistochemical assay is necessary before and after neoadjuvant chemotherapy in patients with breast cancer.