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During breast cancer recurrence, drug therapy is planned based on the biological characteristics of the primary tumor. However, the mechanisms underlying these changes have not yet been clarified. A 59-year-old woman underwent breast cancer surgery 23 years previously and received postoperative hormone therapy for 2 years. She had abdominal distention and ascites effusion and was diagnosed with carcinomatous peritonitis due to luminal-type breast cancer after ascites puncture. She received up to the fourth line of treatment. Subsequently, pleural effusion was observed and human epidermal growth factor receptor 2 type breast cancer was diagnosed because of pleurodesis. This case suggests that the cell block diagnostic method based on thoracic and ascites fluid cytology is useful not only for confirming the primary tumor but also for diagnosing the biological characteristics of breast cancer. In the treatment of breast cancer recurrence, it is important to plan the treatment, including aggressive re-biopsy of metastases. [ABSTRACT FROM AUTHOR]

Abstract Background It is essential to collect a sufficient amount of tumor tissue for successful next-generation sequencing (NGS) analysis. In this study, we investigated the clinical risk factors for avoiding re-biopsy for NGS analysis (re-genome biopsy) in cases where a sufficient amount of tumor tissue could not be collected by bronchoscopy. Methods We investigated the association between clinical factors and the risk of re-genome biopsy in patients who underwent transbronchial biopsy (TBB) or endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and required re-genome biopsy in cases enrolled in LC-SCRUM Asia, a prospective nationwide genome screening project in Japan. We also examined whether the frequency of re-genome biopsy decreased between the first and second halves of the enrolment period. Results Of the 572 eligible patients, 236 underwent TBB, and 134 underwent EBUS-TBNA. Twenty-four TBBs required re-genome biopsy, and multivariate analysis showed that the risk of re-genome biopsy was significantly increased in lesions where the tumor lesion was centrally located. In these cases, EBUS-TBNA should be utilized even if the lesion is a pulmonary lesion. However, it should be noted that even with EBUS-TBNA, lung field lesions are at a higher risk of re-canalization than mediastinal lymph node lesions. It was also found that even when tumor cells were detected in rapid on-site evaluation, a sufficient amount of tumor tissue was not always collected. Conclusions For centrally located pulmonary mass lesions, EBUS-TBNA, rather than TBB, can be used to obtain tumor tissues that can be analyzed by NGS.

Background: Chemoradiation therapy (CRT) is the treatment of choice for locally advanced non-small cell lung cancer (LA-NSCLC). Several clinical trials that combine programmed cell death 1 (PD1) axis inhibitors with radiotherapy are in development for patients with LA-NSCLC. However, the effect of CRT on tumor cells programmed cell death ligand-1 (PD-L1) expression is unknown. Methods: In this multicentric retrospective study, we analyzed paired NSCLC specimens that had been obtained pre- and post-CRT. PD-L1 expression on tumor cells was studied by immunohistochemistry. The purpose of this study was to evaluate the feasibility, risk of complications, and clinical relevance of performing re-biopsy after CRT in patients with PD-L1 negative LA-NSCLC. Results: Overall, 31 patients from 6 centers with PD-L1 negative LA-NSCLC were analyzed. The percentage of tumor cells with PD-L1 expression significantly increased between pre- and post-CRT specimens in 14 patients (45%). Nine patients had unchanged PD-L1 expression after CRT, in five patients the rebiopsy material was insufficient for PD-L1 analysis and in two patients no tumor cells at rebiopsy were found. The post-rebiopsy complication rate was very low (6%). All patients with positive PD-L1 re-biopsy received Durvalumab maintenance after CRT, except one patient who had a long hospitalization for tuberculosis reactivation. Median PFS of patients with unchanged or increased PD-L1 expression was 10 and 16.9 months, respectively. Conclusion: CRT administration can induce PD-L1 expression in a considerable fraction of PD-L1 negative patients at baseline, allowing them receiving the maintenance Durvalumab in Europe. Hence, after a definitive CRT, PD-L1 redetermination should be considered in patients with LANSCLC PD-L1 negative, to have a better selection of maintenance Durvalumab candidates. [ABSTRACT FROM AUTHOR]

Background: It is essential to collect a sufficient amount of tumor tissue for successful next-generation sequencing (NGS) analysis. In this study, we investigated the clinical risk factors for avoiding re-biopsy for NGS analysis (re-genome biopsy) in cases where a sufficient amount of tumor tissue could not be collected by bronchoscopy. Methods: We investigated the association between clinical factors and the risk of re-genome biopsy in patients who underwent transbronchial biopsy (TBB) or endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and required re-genome biopsy in cases enrolled in LC-SCRUM Asia, a prospective nationwide genome screening project in Japan. We also examined whether the frequency of re-genome biopsy decreased between the first and second halves of the enrolment period. Results: Of the 572 eligible patients, 236 underwent TBB, and 134 underwent EBUS-TBNA. Twenty-four TBBs required re-genome biopsy, and multivariate analysis showed that the risk of re-genome biopsy was significantly increased in lesions where the tumor lesion was centrally located. In these cases, EBUS-TBNA should be utilized even if the lesion is a pulmonary lesion. However, it should be noted that even with EBUS-TBNA, lung field lesions are at a higher risk of re-canalization than mediastinal lymph node lesions. It was also found that even when tumor cells were detected in rapid on-site evaluation, a sufficient amount of tumor tissue was not always collected. Conclusions: For centrally located pulmonary mass lesions, EBUS-TBNA, rather than TBB, can be used to obtain tumor tissues that can be analyzed by NGS. [ABSTRACT FROM AUTHOR]

BackgroundChemoradiation therapy (CRT) is the treatment of choice for locally advanced non-small cell lung cancer (LA-NSCLC). Several clinical trials that combine programmed cell death 1 (PD1) axis inhibitors with radiotherapy are in development for patients with LA-NSCLC. However, the effect of CRT on tumor cells programmed cell death ligand-1 (PD-L1) expression is unknown.MethodsIn this multicentric retrospective study, we analyzed paired NSCLC specimens that had been obtained pre- and post-CRT. PD-L1 expression on tumor cells was studied by immunohistochemistry. The purpose of this study was to evaluate the feasibility, risk of complications, and clinical relevance of performing re-biopsy after CRT in patients with PD-L1 negative LA-NSCLC.ResultsOverall, 31 patients from 6 centers with PD-L1 negative LA-NSCLC were analyzed. The percentage of tumor cells with PD-L1 expression significantly increased between pre- and post-CRT specimens in 14 patients (45%). Nine patients had unchanged PD-L1 expression after CRT, in five patients the rebiopsy material was insufficient for PD-L1 analysis and in two patients no tumor cells at rebiopsy were found. The post-rebiopsy complication rate was very low (6%). All patients with positive PD-L1 re-biopsy received Durvalumab maintenance after CRT, except one patient who had a long hospitalization for tuberculosis reactivation. Median PFS of patients with unchanged or increased PD-L1 expression was 10 and 16.9 months, respectively.ConclusionCRT administration can induce PD-L1 expression in a considerable fraction of PD-L1 negative patients at baseline, allowing them receiving the maintenance Durvalumab in Europe. Hence, after a definitive CRT, PD-L1 redetermination should be considered in patients with LA-NSCLC PD-L1 negative, to have a better selection of maintenance Durvalumab candidates.

Abstract Background Few studies assessed the use of endobronchial ultrasound (EBUS)‐guided re‐biopsy for detecting the T790M mutation after epidermal growth factor receptor‐tyrosine kinase inhibitor (EGFR‐TKI) failure. Methods A total of 2996 EBUS procedures were performed during the study period (January 2019–June 2022). In total, 44 consecutive patients who underwent EBUS‐guided re‐biopsy (56 procedures) for detecting the T790M mutation were analyzed. The success rates and T790M mutation frequencies were analyzed according to the re‐biopsy site and EBUS method. Multivariate logistic regression analyses were used to identify factors affecting the likelihood of the T790M mutation. Results The success rates for the mutation analyses using EBUS with a guide‐sheath (EBUS‐GS), EBUS guided transbronchial needle aspiration (EBUS‐TBNA), and EBUS‐GS with EBUS‐TBNA for re‐biopsy were 80.6% (29/36), 93.3% (14/15), and 100% (5/5), respectively. Patients who underwent lymph node biopsy using EBUS‐TBNA had an increased rates of the T790M mutation compared with those undergoing lung biopsy using EBUS‐GS (EBUS‐TBNA, 60.0%; EBUS‐GS with EBUS‐TBNA, 40.0%; EBUS‐GS, 11.1%; p

Purpose: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFRTKIs) are standard first-line treatments for advanced EGFR-mutant non-smallcell lung cancer (NSCLC) patients. However, factors associated with outcomes after progression on first-line therapy are seldom investigated. Materials and methods: From January 2016 to December 2020, we enrolled 242 EGFR-mutant stage IIIB-IV NSCLC patients who progressed on first- or secondgeneration EGFR-TKI treatments, and 206 of them receive second-line treatments after disease progression. The factors that predict the survival outcomes of different second-line treatments after disease progression were evaluated. Clinical and demographic characteristics, including metastatic sites, neutrophil-to-lymphocyte ratio (NLR) at first-line progression, and second-line treatment regimens, and whether re-biopsied after disease progression or not, were reviewed for outcome analysis. Results: The univariate analysis showed that the PFS was shorted in male patients (p =0.049), patients with ECOG performance state = 2 (p =0.014), former smokers (p =0.003), patients with brain metastasis (p =0.04), second-line chemotherapy or EGFR-TKIs other than osimertinib (p =0.002), and NLR =5.0 (p=0.024). In addition, second-line osimertinib was associated with longer OS compared to chemotherapy and other EGFR-TKI treatment (p =0.001). In the multivariate analysis, only second-line osimertinib was an independent predictor of PFS (p =0.023). Re-biopsy after first-line treatment was associated with a trend of better OS. Patients with NLR =5.0 at disease progression had shorter OS than patients with NLR <5.0 (p = 0.008). Conclusion: The benefits of osimertinib necessitate that aggressive re-biopsy after progression on first- or second-generation EGFR-TKI treatment is merited for appropriate second-line treatments to provide better outcomes for these patients. [ABSTRACT FROM AUTHOR]

Background: Renal biopsy is the golden tool for the diagnosis of proliferative lupus nephritis (LN), the level of histological activity, and the risk of end-stage renal disease (ESRD). Objective: This study aimed to investigate the value of repeated renal biopsy in the follow-up of proliferative LN patients and to determine the predictors for re-biopsy and re-induction. Methods: A retrospective study made on 184 LN Egyptian females, data from 2002 to 2020 included history, examination, laboratory investigations, and results of repeated biopsies. Results: Remission was achieved in 46.7% of patients versus 53.3% with non-remission. The non-remission was significantly higher with higher chronicity index (CI), CYC 1ry induction, and AZA 1ry maintenance than with lower CI, MMF 1ry induction, or maintenance (S). About 41.8% of patients had a 2nd biopsy, and 30.9% received reinduction therapy. Significant predictors for non-responding included type of 1ry induction and activity index (AI). In the CYC 1ry induction group, the AI mean±SD in 2nd biopsy (6.83 ±4.02) was significantly lower than in 1st biopsy (10.6 ±4.08) (S), while the CI mean±SD in 2nd biopsy (3.4 ±1.4) was significantly higher than in 1st biopsy (2.5 ±1.2) (S), with no significant difference in the MMF group. Out of the 184 LN patients who had their 1st biopsy, 77 patients (41.8%) had a 2nd biopsy, with no difference as regards the class of LN, but the AI mean±SD was significantly lower in the 2nd biopsy (7.4±4.2) compared to 1st biopsy (10.0±4.4) (S), while the CI mean±SD was higher in the 2nd biopsy (3.0±2.3) compared to the 1st biopsy (2.4±1.6) (S). Conclusions: Repeated renal biopsies are important in the follow-up of Egyptian female patients with proliferative LN, after 1ry induction therapy or an event-based biopsy. The use of MMF reduces the risk for non-remission, and the need for re-biopsy, or re-induction. [ABSTRACT FROM AUTHOR]

Abstract Introduction Success of next generation sequencing (NGS) analysis is becoming indispensable in the treatment of advanced lung cancer. However, the advantages and disadvantages of each sampling method in the NGS analysis have not yet been clarified. Methods We compared the success rates of NGS analysis, and DNA and RNA yields for transbronchial biopsy (TBB), endobronchial ultrasound‐guided transbronchial needle aspiration (EBUS‐TBNA), computed tomography (CT)‐guided biopsy, fluid sample, and surgical biopsy for NGS analysis in patients through the lung cancer genomic screening project for individualized medicine (LC‐SCRUM)‐Asia, a nationwide NGS screening project. In case, sufficient samples could not be collected by TBB and EBUS‐TBNA, re‐biopsy (genome re‐biopsy) was performed. Results A total of 223 patients were enrolled and success rates of NGS analysis were not different between samples obtained through TBB, EBUS‐TBNA, and CT‐guided biopsy; however, success rates for fluid samples and surgical biopsy samples were significantly higher than those of other methods. The risk of genome re‐biopsy was higher with TBB for centrally located lesions. CT‐guided biopsy yielded more samples but had a lower success rate for analysis of RNA‐based NGS than TBB. Conclusions TBB is the mainstay of sampling methods, but for centrally located lesions, EBUS‐TBNA may be a better strategy. For CT‐guided biopsy, the success rate of RNA‐based NGS analysis is low. Fluid samples are expected to yield successful results as surgical biopsy samples, but the latter are better for sample preservation. Determining the optimal method for genome biopsy for each case is important.

Background: Few studies assessed the use of endobronchial ultrasound (EBUS)‐guided re‐biopsy for detecting the T790M mutation after epidermal growth factor receptor‐tyrosine kinase inhibitor (EGFR‐TKI) failure. Methods: A total of 2996 EBUS procedures were performed during the study period (January 2019–June 2022). In total, 44 consecutive patients who underwent EBUS‐guided re‐biopsy (56 procedures) for detecting the T790M mutation were analyzed. The success rates and T790M mutation frequencies were analyzed according to the re‐biopsy site and EBUS method. Multivariate logistic regression analyses were used to identify factors affecting the likelihood of the T790M mutation. Results: The success rates for the mutation analyses using EBUS with a guide‐sheath (EBUS‐GS), EBUS guided transbronchial needle aspiration (EBUS‐TBNA), and EBUS‐GS with EBUS‐TBNA for re‐biopsy were 80.6% (29/36), 93.3% (14/15), and 100% (5/5), respectively. Patients who underwent lymph node biopsy using EBUS‐TBNA had an increased rates of the T790M mutation compared with those undergoing lung biopsy using EBUS‐GS (EBUS‐TBNA, 60.0%; EBUS‐GS with EBUS‐TBNA, 40.0%; EBUS‐GS, 11.1%; p < 0.001). In multivariate analysis, the use of a first‐generation EGFR‐TKI (odds ratio [OR], 4.29; 95% confidence interval [CI], 1.05–17.58; p = 0.043) was associated with occurrence of the T790M mutation. Re‐biopsy of the metastatic site tended to be associated with a higher T790M mutation rate. Mild hemoptysis occurred in 3.6% (2/56) of the patients. Conclusions: EBUS‐guided re‐biopsy can be used for detecting the T790M mutation in patients who failed EGFR‐TKI therapy. The T790M mutation frequency differed according to the re‐biopsy site. The use of a first‐generation EGFR‐TKI was an independent predictor of the T790M mutation. [ABSTRACT FROM AUTHOR]

A 59-year-old woman presented with multiple mediastinal masses 6 months after post-thymectomy for type B2 thymoma. A diagnosis of small-cell carcinoma (SmCC) via a computed tomography-guided biopsy and fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography revealed no primary lesions outside the anterior mediastinum. The pathologically reevaluated post-thymectomy specimen showed no neuroendocrine differentiation. SmCC is presumed to arise either from malignant transformation of the thymoma or de novo formation. She was treated with carboplatin and paclitaxel to achieve complete response. This case highlights the importance of a re-biopsy to guide appropriate treatment in cases of rapid progression during the course of thymoma.

Chengliang Yuan, Huiqin Jiang, Wei Jiang, Huilin Wang, Cuiyun Su, Shaozhang Zhou Department of Respiratory Oncology, Guangxi Medical University Affiliated Tumor Hospital, Nanning City, Guangxi Zhuang Autonomous Region, 530021, People’s Republic of ChinaCorrespondence: Shaozhang Zhou; Cuiyun SuDepartment of Respiratory Oncology, Guangxi Medical University Affiliated Tumor Hospital, No. 71 Heti Road, Nanning City, Guangxi Zhuang Autonomous Region, 530021, People’s Republic of ChinaTel +86-0771-5320761; +86-0771-5334955Fax +86-0771-5300613Email zhoushaozhang@gxmu.edu.cn; 503893236@qq.comPurpose: The purpose of this study is to compare the different EGFR mutation status in patients with metastatic non-small cell lung cancer (NSCLC) after first-line EGFR-TKIs therapy and analyze its relationship with efficacy and prognosis.Patients and Methods: This study retrospectively analyzed the data of patients with metastatic NSCLC harboring EGFR mutation in the Affiliated Tumor Hospital of Guangxi Medical University from June 2016 to December 2020. Samples were collected before treatment and at the time of disease progression after first-line EGFR-TKIs therapy. Amplification refractory mutation system (ARMS) PCR and next-generation sequencing (NGS) were used to detect EGFR mutation. ORR, DCR, and PFS of different EGFR mutation groups were compared.Results: The EGFR mutation rate of re-biopsy was 60.23%. The inconsistency rate of EGFR mutations in the same and different simple types was 72.22% (26/36) and 92.31% (48/52), respectively. Alterations in terms of EGFR mutations were divided into four groups: Group A: EGFR-sensitive mutation negative and T790M negative (39.77%); Group B: EGFR-sensitive mutation positive and T790M negative (18.19%); Group C: EGFR-sensitive mutation negative and T790M positive (36.36%); Group D: EGFR-sensitive mutation positive and T790M positive (5.68%). The differences between the four groups in ORR and DCR were not statistically significant (P> 0.05). The median PFS of all patients was 10.65 months. PFS of Group A, B, C, and D was 12.26, 7.96, 10.55, and 13.81 months, respectively, with statistical significance (Log rank P = 0.014).Conclusion: EGFR mutation status in metastatic NSCLC patients receiving the first- and second-generation TKIs after disease progression show diversity. Monitoring the EGFR mutation changes is of great importance for subsequent clinical decision-making and exploring the underlying mechanisms of acquired resistance.Keywords: non-small cell lung cancer, EGFR-TKIs, re-biopsy, EGFR gene mutation status

Personalized medicine using molecular-targeted drugs to achieve better therapeutic response and long-term prognosis is common practice for lung cancer treatment. However, in cases before gene batch tests were available, medical treatment continued without the detection of rare mutations. We report a sixty-seven-old year man diagnosed with adenocarcinoma T1cN3M1a, stage IVA. Initial screening performed 7 years earlier using EGFR mutation and ALK immunohistochemical tests were negative. Although first-line cytotoxic combination chemotherapy was remarkably effective, a gradual regression of the primary lesion was noted. After a recent bronchoscopic re-biopsy, RET fusion was detected by gene panel test. In addition, we were able to confirm RET from FFPE specimens obtained from 7-year-old pleural effusion cell blocks. Subsequent administration of the molecular-targeted drug selpercatinib, was highly effective for the primary lesion and all metastatic lesions including brain metastases. We describe a case of RET fusion-positive lung cancer where molecular targeted therapy and cytotoxic drug showed a drastic response and long-term therapy was well maintained. Next generation sequencing was able to correctly diagnose RET fusion mutation using re-biopsy specimen after going undiagnosed for 7 years.

Abstract Background Epidermal growth factor receptor‐tyrosine kinase inhibitor (EGFR‐TKI) has been considered as an effective treatment in epidermal growth factor receptor‐mutant (EGFR‐mutant) advanced non‐small cell lung cancer (NSCLC). However, most patients develop acquired resistance eventually. Here, we compared and analyzed the genetic alterations between tissue assay and circulating tumor DNA (ctDNA) and further explored the resistance mechanisms after EGFR‐TKI treatment. Methods and Materials Amplification refractory mutation system‐polymerase chain reaction (ARMS‐PCR), Cobas® ARMS‐PCR and next‐generation sequencing (NGS) were performed on tissue samples after pathological diagnosis. Digital droplet PCR (ddPCR) and NGS were performed on plasma samples. The association between genetic alterations and clinical outcomes was analyzed retrospectively. Results Thirty‐seven patients were included. The success rate of re‐biopsy was 91.89% (34/37). The total detection rate of EGFR T790M was 62.16% (23/37) and the consistency between tissue and ctDNA was 78.26% (18/23). Thirty‐four patients were analyzed retrospectively. For tissue re‐biopsy, 24 patients harbored concomitant mutations. Moreover, tissue re‐biopsy at resistance showed 21 patients (21/34, 61.76%) had the concomitant somatic mutation. The three most frequent concomitant mutations were TP53 (18/34, 52.94%), MET (4/34, 11.76%), and PIK3CA (4/34, 11.76%). Meanwhile, 21 patients (21/34, 61.76%) with EGFR T790M mutation. Progression‐free survival (PFS) and overall survival (OS) were better in patients with T790M mutation (p = 0.010 and p = 0.017) or third‐generation EGFR‐TKI treatment (p

Objective. We present a case of aggressive triple-negative breast cancer (TNBC) in a young woman. Despite benefiting from promising therapies such as antibodydrug conjugates and immune checkpoint inhibitors, the management still represents a challenge. Case presentation. We discuss the case of a 35-year-old woman who was diagnosed with invasive left TNBC and PD-L1 negative status in December 2022, following a coreneedle biopsy. Germline panel genetic testing including BRCA was negative. The multidisciplinary team decided to start neoadjuvant chemotherapy with epirubicin and docetaxel. However, the treatment was interrupted after five sessions because of the local progression of the disease. Docetaxel and carboplatin were then administered for an additional two sessions, but the local course of the disease continued. Subsequently, the patient underwent radiotherapy for the left breast and locoregional lymph node areas from July to August 2023. A PET-CT investigation shortly after revealed disease progression, with the appearance of bone metastases. At this time, the multidisciplinary team decided to initiate treatment with sacituzumab govitecan in September 2023. The disease remained stable until February 2024, when pulmonary and lymphatic metastases appeared. The treatment with sacituzumab govitecan continued until June 2024, when the disease progressed with the appearance of brain metastases. The patient then underwent whole-brain radiotherapy, and a decision was made to re-biopsy the left axillary lymph nodes. The result confirmed the diagnosis of triple-negative breast cancer metastasis, but with positive PD-L1 expression in immune cells (IC=5%). The treatment with atezolizumab and paclitaxel was initiated in July 2024. The patient has remained clinically stable since then, but local progression continues to pose a challenge for the multidisciplinary team. Conclusions. Although several promising therapeutic algorithms have emerged in recent years, the identification of effective therapies for TNBC remains a significant ongoing challenge. Additionally, our case underscores the importance of re-biopsy to determine the status of key biomarkers such as BRCA1/2, HER2 and PD-L1, which could guide treatment in subsequent lines. [ABSTRACT FROM AUTHOR]

Introduction: Success of next generation sequencing (NGS) analysis is becoming indispensable in the treatment of advanced lung cancer. However, the advantages and disadvantages of each sampling method in the NGS analysis have not yet been clarified. Methods: We compared the success rates of NGS analysis, and DNA and RNA yields for transbronchial biopsy (TBB), endobronchial ultrasound‐guided transbronchial needle aspiration (EBUS‐TBNA), computed tomography (CT)‐guided biopsy, fluid sample, and surgical biopsy for NGS analysis in patients through the lung cancer genomic screening project for individualized medicine (LC‐SCRUM)‐Asia, a nationwide NGS screening project. In case, sufficient samples could not be collected by TBB and EBUS‐TBNA, re‐biopsy (genome re‐biopsy) was performed. Results: A total of 223 patients were enrolled and success rates of NGS analysis were not different between samples obtained through TBB, EBUS‐TBNA, and CT‐guided biopsy; however, success rates for fluid samples and surgical biopsy samples were significantly higher than those of other methods. The risk of genome re‐biopsy was higher with TBB for centrally located lesions. CT‐guided biopsy yielded more samples but had a lower success rate for analysis of RNA‐based NGS than TBB. Conclusions: TBB is the mainstay of sampling methods, but for centrally located lesions, EBUS‐TBNA may be a better strategy. For CT‐guided biopsy, the success rate of RNA‐based NGS analysis is low. Fluid samples are expected to yield successful results as surgical biopsy samples, but the latter are better for sample preservation. Determining the optimal method for genome biopsy for each case is important. [ABSTRACT FROM AUTHOR]

Background Most non‐small cell lung cancer (NSCLC) patients relapse on anaplastic lymphoma kinase‐tyrosine kinase inhibitor (ALK‐TKI) therapy because of acquired resistance. Rebiopsy is recommended to provide optimal therapy after relapse for some ALK‐TKI therapies; however, little clinical data exists on the clinical efficacy of ALK‐TKI tailored to secondary mutation. Methods A retrospective study was conducted to analyze the patterns of ALK‐TKI treatment and clinical outcomes, including progression free survival (PFS), of ALK‐positive NSCLC patients who received rebiopsy. Based on the rebiopsy results, secondary mutations in the ALK gene that were shown to be associated with the efficacy of ALK‐TKI therapy in the preclinical or clinical setting were defined as “sensitive mutations (SM)”. Results Among 71 patients who received ALK‐TKI for NSCLC at our institution, 20 patients received rebiopsy, and secondary SM were found in eight patients. The objective response rate (ORR) of the cases with SM who received ALK‐TKI therapy was 88.9%, while the ORR of the patients without SM who received ALK TKI or chemotherapy was 20.0%; however, the PFS of the patients with SM was relatively short (with SM vs. without SM: 5.6 months vs. 5.1 months). Conclusions The selection of ALK‐TKI based on the rebiopsy result was associated with a high ORR and relatively short PFS. The mechanism responsible for the short PFS of sensitive ALK‐TKI to secondary mutation should be clarified.

Background Re‐biopsy is important for exploring resistance mechanisms, especially for non‐small cell lung cancer (NSCLC) patients who develop resistance to EGFR‐tyrosine kinase inhibitors (TKIs). Liquid biopsy using circulating tumor DNA has come into use for this purpose. This retrospective study investigated the status of re‐biopsy and liquid biopsy in NSCLC patients with EGFR mutations and evaluated their effect on clinical strategies and prognosis. Methods Five hundred fifty‐five NSCLC patients with resistance to EGFR‐TKIs were included and divided into three groups: re‐biopsy, liquid biopsy, and no re‐biopsy. Amplification refractory mutation system (ARMS) PCR or super ARMS PCR was used to detect EGFR mutations. Results Three hundred eight (55.5%) patients underwent re‐biopsy; 45.5% (140/308) were positive for T790M. The most common re‐biopsy procedure was computed tomography‐guided percutaneous core needle biopsy (60.1%), followed by effusion drainage (29.5%) and superficial lymph node biopsy (6.5%). One hundred eighteen (21.3%) patients underwent liquid biopsy; the T790M detection rate was 41.5% (49/118.) Of the 308 patients who underwent re‐biopsy, 69 were examined for EGFR mutations with plasma. The concordance rate of T790M detection between tissue and plasma was 66.7%. A statistical difference in further treatment after EGFR‐TKI failure was observed among all groups (P = 0.014). Patients in the biopsy groups were more likely to receive third‐generation EGFR‐TKIs. Multivariate analysis showed that re‐biopsy had a significant impact on overall survival (P

Without global standard diagnostic criteria, distinguishing multiple primary lung cancers (MPLCs) from intrapulmonary metastasis or histologic transformation has been a big challenge in clinical practice. Here, we described a rare case of metachronous adenocarcinoma and small cell lung cancer (SCLC) in a patient who developed drug resistance to pembrolizumab. Both DNA-sequencing and RNA-sequencing were performed on primary adenocarcinoma and resistant lesions. Through the comparison of primary adenocarcinoma and novel lesion mutation profiles, along with bioinformatic estimation of immune proportion by using RNA sequence data, we revealed the origin and tumor microenvironment of the two lesions. No shared mutations were detected between lung adenocarcinoma (LUAD) and SCLC from the same patient, suggesting these two lesions might be from separate primary lung cancers. Compared to LUAD, SCLC showed a relatively cold microenvironment, including negative PD-L1. The patient obtained durable clinical benefits upon treatment with atezolizumab, without experiencing immune-related adverse events. Disease progression should be monitored with prompt re-biopsy and molecular profiling to spot a potential histologic change and to shed light on therapeutic alternatives. The use of atezolizumab, either alone or in combination with other agents, may be a potential therapeutic strategy for patients with both LUAD and SCLC.

What is the incidence of complex mosaic in preimplantation genetic testing (PGT) blastocysts and can it be managed in clinical practice? A retrospective study of PGT cycles conducted between January 2018 and October 2019 at a single centre. Biopsies of blastocysts were collected and analysed by next-generation sequencing (NGS). Complex mosaic blastocysts were defined as those with three or more mosaic chromosomes. The cryopreserved complex mosaic blastocysts underwent a second round of biopsy, NGS analysis and vitrification. The euploid blastocysts identified by the re-biopsy were warmed again for embryo transfer. The main outcomes included the prevalence of the complex mosaic and the ongoing pregnancy rate. The prevalence of the complex mosaic was 2.4% (437/17,979). The prevalence of the complex mosaic was not associated with maternal age and morphological quality. A total of 89 complex mosaic blastocysts underwent re-biopsy and 96.6% (86/89) survived the first warming. For the re-biopsy samples, 61.6% (53/86) were euploid. The poor-quality blastocysts had higher rates of aneuploidy compared with good-quality blastocysts. The survival rate for blastocysts undergoing the second warming was 100% (18/18) and resulted in an ongoing pregnancy rate of 38.9% (7/18) as well as the birth of six healthy infants. Re-biopsy may rescue blastocysts with development potential for transfer and improve the cumulative pregnancy rate per stimulation cycle in patients containing complex mosaic blastocysts. [ABSTRACT FROM AUTHOR]

Background: Epidermal growth factor receptor‐tyrosine kinase inhibitor (EGFR‐TKI) has been considered as an effective treatment in epidermal growth factor receptor‐mutant (EGFR‐mutant) advanced non‐small cell lung cancer (NSCLC). However, most patients develop acquired resistance eventually. Here, we compared and analyzed the genetic alterations between tissue assay and circulating tumor DNA (ctDNA) and further explored the resistance mechanisms after EGFR‐TKI treatment. Methods and Materials: Amplification refractory mutation system‐polymerase chain reaction (ARMS‐PCR), Cobas® ARMS‐PCR and next‐generation sequencing (NGS) were performed on tissue samples after pathological diagnosis. Digital droplet PCR (ddPCR) and NGS were performed on plasma samples. The association between genetic alterations and clinical outcomes was analyzed retrospectively. Results: Thirty‐seven patients were included. The success rate of re‐biopsy was 91.89% (34/37). The total detection rate of EGFR T790M was 62.16% (23/37) and the consistency between tissue and ctDNA was 78.26% (18/23). Thirty‐four patients were analyzed retrospectively. For tissue re‐biopsy, 24 patients harbored concomitant mutations. Moreover, tissue re‐biopsy at resistance showed 21 patients (21/34, 61.76%) had the concomitant somatic mutation. The three most frequent concomitant mutations were TP53 (18/34, 52.94%), MET (4/34, 11.76%), and PIK3CA (4/34, 11.76%). Meanwhile, 21 patients (21/34, 61.76%) with EGFR T790M mutation. Progression‐free survival (PFS) and overall survival (OS) were better in patients with T790M mutation (p = 0.010 and p = 0.017) or third‐generation EGFR‐TKI treatment (p < 0.0001 and p = 0.073). Interestingly, concomitant genetic alterations were significantly associated with a worse prognosis for patients with EGFR T790M mutation receiving third‐generation EGFR‐TKIs (p = 0.037). Conclusions: Multi‐platforms are feasible and highly consistent for re‐biopsy after EGFR‐TKI resistance. Concomitant genetic alterations may be associated with a poor prognosis for patients with EGFR T790M mutation after third‐generation EGFR‐TKIs. [ABSTRACT FROM AUTHOR]

Without global standard diagnostic criteria, distinguishing multiple primary lung cancers (MPLCs) from intrapulmonary metastasis or histologic transformation has been a big challenge in clinical practice. Here, we described a rare case of metachronous adenocarcinoma and small cell lung cancer (SCLC) in a patient who developed drug resistance to pembrolizumab. Both DNA-sequencing and RNA-sequencing were performed on primary adenocarcinoma and resistant lesions. Through the comparison of primary adenocarcinoma and novel lesion mutation profiles, along with bioinformatic estimation of immune proportion by using RNA sequence data, we revealed the origin and tumor microenvironment of the two lesions. No shared mutations were detected between lung adenocarcinoma (LUAD) and SCLC from the same patient, suggesting these two lesions might be from separate primary lung cancers. Compared to LUAD, SCLC showed a relatively cold microenvironment, including negative PD-L1. The patient obtained durable clinical benefits upon treatment with atezolizumab, without experiencing immune-related adverse events. Disease progression should be monitored with prompt re-biopsy and molecular profiling to spot a potential histologic change and to shed light on therapeutic alternatives. The use of atezolizumab, either alone or in combination with other agents, may be a potential therapeutic strategy for patients with both LUAD and SCLC. [ABSTRACT FROM AUTHOR]

Core needle biopsy is an effective method of obtaining tissue diagnosis. However, a diagnostic dilemma arises when lesional tissue is non-diagnostic which obviates considering radiological guided re-biopsy (RB) or an open surgical biopsy but the question raised is which serves as a better diagnostic tool. We retrospectively reviewed data from a prospectively collected database of 4516 core needle biopsies performed in our specialist musculoskeletal tumour centre over a 6-year period. Our aim was to evaluate the management of non-diagnostic biopsies (NDB) and establish a safe and accurate diagnostic strategy in the presence of a NDB. Two hundred fifteen (4.8%) NDB cases with complete follow-up were identified. Of these 157 (73%) were treated definitively on the basis of imaging and 58 (27%) had a RB, 48 (83%) of which led to a positive histological diagnosis. The remaining 10 were again non-diagnostic giving a total of 167 patients being treated definitively without a tissue diagnosis. The sensitivity and specificity for multidisciplinary team (MDT) assessment as a diagnostic tool was 0.75 and 0.88 respectively while that for RB was 0.91 and 0.9. Re-biopsy after first non-diagnostic core needle biopsy offers high sensitivity and specificity, especially in the presence of malignancy. In the absence of tissue diagnosis, however, MDT assessment is also highly accurate and a safe strategy in managing this complex group of patients. Diagnostic Level III. [ABSTRACT FROM AUTHOR]

Purpose: The sampling and accurate diagnosis of lymph nodes during the clinical history of lung cancer are essential for selecting the appropriate treatment strategies. This study aims to evaluate the feasibility of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in patients with previously treated lung cancer. Methods: Patients who underwent EBUS-TBNA after treatment for lung cancer were retrospectively reviewed. We classified the patients into two groups; Group 1 (G1): Indicated to have a recurrence of new lesions after radical surgery or chemo/radiotherapy with a curative intent; and Group 2 (G2): Indicated to have residual tumor cells after undergoing primary treatment for chemo/radiotherapy or re-staging after induction therapy prior to surgery. Results: Seventy previously treated lung cancer cases (G1, n = 52; G2, n = 18) were enrolled. Thirty-two cases (61.5%) had recurrent disease in G1, and 9 cases (50.0%) had nodal metastasis in G2. The diagnostic accuracy was 95.2% in G1 and 88.9% in G2. Twenty-four cases were examined for epidermal growth factor receptor (EGFR) mutations, and 9 (37.5%) cases had mutations, including two cases with a T790M mutation. Furthermore, in one case, a re-biopsy revealed that the initial adenocarcinoma had transformed into small cell lung cancer. Conclusion: Performing EBUS-TBNA during lung cancer treatment showed a high diagnostic yield. Samples obtained by EBUS-TBNA were helpful in determining when to perform repeat biomarker testing as well as for making pathological re-evaluations. [ABSTRACT FROM AUTHOR]

Aim: The initial mutation status of non-small cell lung cancer (NSCLC) is important for guiding treatment. However, re-biopsy is needed to determine the new mutation status in patients receiving targeted therapy or who develop resistance during first-line therapy. Endobronchial ultrasound (EBUS) is an important tool to obtain adequate tissue for molecular analyses. Materials and Methods: We used a clinical database of 349 patients who were previously included in a multi-center study. Adequacy of tissue collected, new molecular profile, and treatment regimens were evaluated. Results: A total of 50 patients (median age of 60 ± 9 years) received biopsy by EBUS. The success rate was 36% (n = 18), and repeat re-biopsy was performed for patients with anthracosis (n = 32). In 18 patients, only one lymph node station was sampled. Initial histopathology was adenocarcinoma in 28 patients, squamous cell carcinoma (SCC) in 18 patients, and not otherwise specified (NOS) in four patients. No correlation was found between initial treatment type and success rate of the procedure (p = 0.101). After re-biopsy in six patients (five of whom had newly detected mutations), targetable mutations were detected for T790M (n = 2), EGF-Rexon 19 (n = 1), c-Met (n = 1), and EGFR-21 (n = 2). Conclusion: : In cases of resistance to treatment, re-biopsy should be performed to detect different gene amplifications. Re-biopsy with EBUS is an effective method for an appropriate progressive lesion. [ABSTRACT FROM AUTHOR]

Abstract Background The EGFR-T790M mutation is clinically detected using re-biopsy in approximately 50% of patients with acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in advanced non-small cell lung cancer (NSCLC) who harbor EGFR mutations. However, little is known about the population of NSCLC patients who develop acquired resistance due to the T790M mutation. In this study, we focused on the emergence of the T790M mutation and analyzed patients refractory to initial EGFR-TKIs with successful re-biopsy samples. Methods Seventy-eight advanced NSCLC patients with EGFR mutations who had successful re-biopsy samples after resistance to initial EGFR-TKI treatment were enrolled at 5 institutions in Japan. We validated the association between the emergence of the T790M mutation and their clinical profiles. Results Thirty-nine patients tested positive for T790M and 39 tested negative in the re-biopsy samples. The objective response rate to initial EGFR-TKIs was higher in patients with the T790M mutation than in those without the mutation (89.7% versus 51.2%, p

• Re-biopsy in advanced NSCLC is feasible with a low rate of complications. • Changes in PD-L1 TPS can be observed in 33% of patients with advanced NSCLC at progression. • Change of PD-L1 TPS was significantly more likely in chemotherapy-treated patients compared to immunotherapy-treated patients. Re-biopsy in progressive advanced Non-Small-Cell Lung Cancer (NSCLC) after first line treatment may reveal information about evolving tumor biology during treatment. Our study aims to investigate the feasibility, risk of complications, and clinical relevance of performing re-biopsy systematically. NSCLC patients with advanced, non-targetable disease, receiving first line systemic treatment, were included in a prospective single-centre study (NCT03512847). A diagnostic biopsy was performed at baseline and repeated at time of progression, preferentially from the progressive lesions as determined by CT or PET/CT. The primary endpoint was feasibility, including complication rate to re-biopsy. Secondary endpoints were clinical relevance, defined as a potential of changing treatment or follow-up, due to new histological evidence, specifically a change in PD-L1 Tumor Proportion Score (TPS). Fifty-one patients with progressive advanced NSCLC had re-biopsy performed. Median time from patients' acceptance to biopsy was seven days (range: 0–31). Complication rate was 6% (n = 3) represented by pneumothorax, hydro-pneumothorax and pneumonia, respectively. No severe or chronic complications occurred. Sufficient material for PD-L1 analyses was obtained in 46 of 51 patients: the remaining five cases had insufficient tissue for analyses, no malignant cells/only suspected malignant cells, questioning whether progression was real. PD-L1 TPS change was observed in 33% of patients (n = 15) and 17% (n = 8) had potentially clinically relevant changes. A significantly higher chance of PD-L1 TPS change was observed in chemotherapy-treated patients. Our study showed that re-biopsy is feasible, with low risk of complications, and can be clinically relevant in patients with suspected progression in advanced NSCLC. [ABSTRACT FROM AUTHOR]

Abstract Background Although EGFR-TKI is the preferred treatment for NSCLC patients with sensitive mutations, subsequent drug resistance is almost inevitable. The specific mechanisms of EGFR-TKI drug resistance can be identified through repeat biopsy. Methods To better understand the clinical characteristics of TKI resistance in NSCLC patients, we retrospectively reviewed studies of acquired TKI drug resistance using repeat biopsy from the last decade. The relevant literature was retrieved from January 2005 to August 2015 in the databases Medline and Embase. The search terms were NSCLC or non-small cell lung cancer and T790 M. Results A total of 478 patients with NSCLC tested by repeated biopsy were confirmed to have acquired TKI resistance. Analysis indicated that 240 patients (50.21%) of the 478 patients with acquired TKI drug resistance had the T790 M mutation. The detection rate of T790 M in different repeat biopsy sites was also different, with the highest positive rate in the lymph nodes (60%) and the lowest detection rate in cerebrospinal fluid (less than 5%). In addition, patients with T790 M had longer overall survival compared to those without the mutation (P

Abstract Background When epidermal growth factor receptor (EGFR) gene mutation-positive non-small cell lung cancer (NSCLC) acquires resistance to the initial tyrosine kinase inhibitor (TKI) treatment, reassessing the tumor DNA by re-biopsy is essential for further treatment selection. However, the process of TKI-sensitive tumor re-progression and whether re-biopsy is possible in all cases of acquired resistance to EGFR-TKI remain unclear. Methods We retrospectively analyzed data from 69 consecutive patients with EGFR gene mutation-positive advanced NSCLC who had been treated with EGFR-TKI and exhibited disease relapse after initial disease remission. The relapsing lesions were identified at the time of RECIST-progressive disease (PD) and clinical-PD (when the attending physician judged the patient as clinically relapsing and stopped EGFR-TKI therapy). We determined the potential re-biopsy methods for each relapsing lesion and evaluated their feasibility according to difficulty and invasiveness criteria as follows: category A, accessible by conventional biopsy techniques; category B, difficult (but possible) to biopsy and accessible with invasive methods; and category C, extremely difficult to biopsy or inaccessible without using highly invasive methods, including surgical biopsy. Results The total feasibility rate of re-biopsy (category A or B) was 68% at RECIST-PD and 84% at clinical-PD, and the most common accessible relapsing lesions were primary tumors at RECIST-PD and pleural effusion at clinical-PD. All relapsing lesions at primary sites (categories A and B) were assessed as having the potential for re-biopsy. However, re-biopsy for metastasis was assessed as difficult in a substantial proportion of the study population (42 and 20% category C at RECIST-PD and clinical-PD, respectively). Conclusions Re-biopsy of relapsing disease is feasible in many cases, although it may present difficulties in cases with, e.g., metastatic relapsing lesions. To facilitate treatment strategies in NSCLC patients with relapse after EGFR-TKI therapy, re-biopsy should be standardized with the use of simpler and more reliable methods.

• The EGFR T790M is the most common resistant mechanism of 1st or 2nd generation EGFR-TKIs. • Damaging nonsynonymous mutations in pre-EGFR-TKI was lower in T790M-mediated resistance. • Coexisting mutations in tumor before EGFR-TKI treatment may contribute to T790M resistance. The T790M secondary mutation of epidermal growth factor receptor gene (EGFR) is the most common mechanism of acquired resistance to first- or second-generation EGFR tyrosine kinase inhibitors (TKIs). We investigated the association between gene mutation profile in EGFR mutation–positive non–small cell lung cancer (NSCLC) before EGFR-TKI treatment and T790M status after EGFR-TKI treatment. A total of 57 EGFR mutation–positive NSCLC patients who had undergone a repeat biopsy (tissue or liquid) after failure of treatment with a first- or second-generation EGFR-TKI and who had sufficient tumor tissue available from before treatment for genetic analysis was enrolled. The gene mutation profile of tumor tissue obtained before EGFR-TKI treatment was evaluated by next-generation sequencing with a comprehensive cancer gene panel (409 genes). The number of potentially damaging nonsynonymous mutations was predicted with PolyPhen-2 software. Progression-free survival during EGFR-TKI treatment did not differ significantly between patients who developed T790M-mediated resistance and those who developed T790M-independent resistance. The predicted number of damaging nonsynonymous mutations in pretreatment tumor tissue was significantly lower in patients who developed T790M-mediated resistance than in those with T790M-independent resistance (P = 0.049). Coexisting mutations in tumor tissue before EGFR-TKI treatment may contribute to the emergence of cell clones responsible for development of T790M-dependent or T790M-independent TKI resistance in patients with EGFR -mutated NSCLC. Multiplex genomic testing of pretreatment tumor tissue may thus provide a means of identifying patients likely to develop T790M-mediated TKI resistance and therefore inform treatment selection. [ABSTRACT FROM AUTHOR]

Purpose: To describe diagnostic results following re-biopsy of blastocysts with inconclusive results on preimplantation genetic screening for aneuploidy (PGT-A) and to evaluate the reproductive potential of re-biopsied blastocysts. Methods: This retrospective cohort study included all trophectoderm biopsies submitted for PGT-A by a large in vitro fertilization center to a single genetics laboratory from June 2016 to October 2018. PGT-A was performed using next-generation sequencing (NGS). No-result blastocysts that underwent re-biopsy were subsequently classified as euploid, aneuploid, mosaic/segmental, or no-result. Ongoing pregnancy and clinical loss rates were assessed following transfer of re-biopsied blastocysts. Logistic regressions were conducted to account for age and blastocyst morphology. Results: Of the trophectoderm biopsies submitted for PGT-A, 635/25,199 (2.5%) were categorized as no-result. Those that underwent re-biopsy (n = 250) had a 95.2% diagnostic rate with 140 (56.0%) receiving euploid diagnoses. Thirty-six re-biopsied blastocysts deemed euploid were subsequently transferred, resulting in 18 (50.0%) ongoing pregnancies and 5 (13.9%) clinical losses. After adjusting for age and blastocyst morphology, there remained a lower ongoing pregnancy rate and a trend towards higher clinical loss rate following transfer of a re-biopsied blastocyst. When compared to blastocysts that underwent the same number of vitrification-warming cycles but only one biopsy, there were no differences in outcomes. Conclusions: Failure to obtain an analytical result does not change the probability that a given blastocyst is euploid. Pregnancy outcomes following transfer of re-biopsied blastocysts are favorable, but further data must be accrued for an adequately powered comparison with outcomes after transfer of blastocysts biopsied once. [ABSTRACT FROM AUTHOR]

Background: Most non‐small cell lung cancer (NSCLC) patients relapse on anaplastic lymphoma kinase‐tyrosine kinase inhibitor (ALK‐TKI) therapy because of acquired resistance. Rebiopsy is recommended to provide optimal therapy after relapse for some ALK‐TKI therapies; however, little clinical data exists on the clinical efficacy of ALK‐TKI tailored to secondary mutation. Methods: A retrospective study was conducted to analyze the patterns of ALK‐TKI treatment and clinical outcomes, including progression free survival (PFS), of ALK‐positive NSCLC patients who received rebiopsy. Based on the rebiopsy results, secondary mutations in the ALK gene that were shown to be associated with the efficacy of ALK‐TKI therapy in the preclinical or clinical setting were defined as "sensitive mutations (SM)". Results: Among 71 patients who received ALK‐TKI for NSCLC at our institution, 20 patients received rebiopsy, and secondary SM were found in eight patients. The objective response rate (ORR) of the cases with SM who received ALK‐TKI therapy was 88.9%, while the ORR of the patients without SM who received ALK TKI or chemotherapy was 20.0%; however, the PFS of the patients with SM was relatively short (with SM vs. without SM: 5.6 months vs. 5.1 months). Conclusions: The selection of ALK‐TKI based on the rebiopsy result was associated with a high ORR and relatively short PFS. The mechanism responsible for the short PFS of sensitive ALK‐TKI to secondary mutation should be clarified. [ABSTRACT FROM AUTHOR]

Introduction: Numerous studies conducted until date have reported that the chemotherapy regimen could affect the programmed cell death ligand 1 (PD-L1) expression status in patients with non-small cell lung cancer (NSCLC). Materials and methods: A total of 36 NSCLC patients for whom both the surgically resected specimens of the primary tumors and re-biopsy specimens of the recurrent tumors were available were enrolled in this study. The PD-L1 expression status and tumor-infiltrating CD8-positive T lymphocytes (CD8+TILs) count were measured in paired samples by immunohistochemistry. The concordance rate in the tumor immune microenvironment (TIME) classification based on the PD-L1 expression status and CD8+TILs count was analyzed. Results: While the PD-L1 expression levels were similar between the surgical and re-biopsy specimens in 77.8% of cases, in 16.7% of cases, the expression levels were higher in the re-biopsy specimens. When the analysis was confined to patients who had received platinum-based chemotherapy, the percentage increased to 42.9%. The TIME classification changed in the re-biopsy specimens as compared to the surgical specimens in one-third of the patients, especially in those who had received chemotherapy previously. The TIME classification in the re-biopsy specimens more closely resembled that in the metastatic lymph nodes as compared to that in the primary tumor. Conclusion: In patients with recurrent NSCLC, especially those who have received chemotherapy previously, a recent re-biopsy sample is required to determine whether PD-1/PD-L1 inhibitors should be used for treatment or not. [ABSTRACT FROM AUTHOR]

Background: Re‐biopsy is important for exploring resistance mechanisms, especially for non‐small cell lung cancer (NSCLC) patients who develop resistance to EGFR‐tyrosine kinase inhibitors (TKIs). Liquid biopsy using circulating tumor DNA has come into use for this purpose. This retrospective study investigated the status of re‐biopsy and liquid biopsy in NSCLC patients with EGFR mutations and evaluated their effect on clinical strategies and prognosis. Methods: Five hundred fifty‐five NSCLC patients with resistance to EGFR‐TKIs were included and divided into three groups: re‐biopsy, liquid biopsy, and no re‐biopsy. Amplification refractory mutation system (ARMS) PCR or super ARMS PCR was used to detect EGFR mutations. Results: Three hundred eight (55.5%) patients underwent re‐biopsy; 45.5% (140/308) were positive for T790M. The most common re‐biopsy procedure was computed tomography‐guided percutaneous core needle biopsy (60.1%), followed by effusion drainage (29.5%) and superficial lymph node biopsy (6.5%). One hundred eighteen (21.3%) patients underwent liquid biopsy; the T790M detection rate was 41.5% (49/118.) Of the 308 patients who underwent re‐biopsy, 69 were examined for EGFR mutations with plasma. The concordance rate of T790M detection between tissue and plasma was 66.7%. A statistical difference in further treatment after EGFR‐TKI failure was observed among all groups (P = 0.014). Patients in the biopsy groups were more likely to receive third‐generation EGFR‐TKIs. Multivariate analysis showed that re‐biopsy had a significant impact on overall survival (P < 0.001). Conclusion: Re‐biopsy plays a pivotal role in the management of patients with NSCLC and resistance to EGFR‐TKIs. Liquid biopsy may be an alternative if difficulties performing re‐biopsy exist. [ABSTRACT FROM AUTHOR]

The significance of evaluating oncogenes, including EGFR mutations, ALK abnormalities, and PD-L1 expression has become broadly recognized with recent advances in molecular biology. It is now extremely important to investigate tumor oncogene status in each patient at the initial diagnosis. By contrast, the significance of conducting a re-biopsy in the salvage setting has not been systematically reviewed. This review reports that the significance of a re-biopsy varies depending on the clinical situation. [ABSTRACT FROM AUTHOR]

Introduction: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors TKIs) are highly effective in EGFR-mutant advanced lung cancer. The most common resistance mechanism to EGFR-TKI is the development of T790M mutation in Exon 20. Osimertinib, a highly selective EGFR-TKI, has been approved for use in patients who progress on the first-line TKI and harbor the T790M mutation. Objective: The primary objective is to prospectively study the incidence of T790M mutation in patients who progress on the first-line EGFR-TKI. Secondary objectives include clinical characteristics that predict for T790M mutation and outcomes with osimertinib. Materials and Methods: This single-center, prospective observational study included 90 patients who progressed on first-line EGFR TKI. All patients had DNA extracted from tissue re-biopsy or plasma circulating tumor DNA (re-biopsy was not feasible or inadequate). T790M mutation was detected using amplification refractory mutation system-polymerase chain reaction, and patients harboring T790M mutation were started on osimertinib (80 mg once daily) until progression or unacceptable side effects. Results: At progression, T790M mutation was detected in 47/90 patients (52.2%). On binary logistic regression model analysis, variables that were independently predictive of the development of T790M were younger age (odds ratio [OR] 4.3, 95% confidence interval [CI] 1.14-16.6, P = 0.031); nonerlotinib TKI use (OR 8.3, 95% CI 1.24-55.8, P = 0.029); and pure adenocarcinoma histology (OR 6.2, 95% CI 1.60-24.7, P = 0.008). Forty-six patients were started on osimertinib. The overall response rate and median progression-free survival were 65.21% and 12.45 months (standard deviation [SD] 1.03, 95% CI 10.41-14.48), respectively. Osimertinib was well tolerated with most toxicities being Grade 1 and 2 diarrhea and skin rash. Conclusions: In our prospective cohort, half of all patients had a T790M mutation at progression on the first-line EGFR TKI. Tissue biopsy is feasible in the majority of patients. Clinical outcomes with osimertinib were consistent with those reported. [ABSTRACT FROM AUTHOR]

Background: The EGFR-T790M mutation is clinically detected using re-biopsy in approximately 50% of patients with acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in advanced non-small cell lung cancer (NSCLC) who harbor EGFR mutations. However, little is known about the population of NSCLC patients who develop acquired resistance due to the T790M mutation. In this study, we focused on the emergence of the T790M mutation and analyzed patients refractory to initial EGFR-TKIs with successful re-biopsy samples.Methods: Seventy-eight advanced NSCLC patients with EGFR mutations who had successful re-biopsy samples after resistance to initial EGFR-TKI treatment were enrolled at 5 institutions in Japan. We validated the association between the emergence of the T790M mutation and their clinical profiles.Results: Thirty-nine patients tested positive for T790M and 39 tested negative in the re-biopsy samples. The objective response rate to initial EGFR-TKIs was higher in patients with the T790M mutation than in those without the mutation (89.7% versus 51.2%, p < 0.001). Moreover, there was a significant difference in the maximal tumor shrinkage rate relative to baseline in T790M-positive tumors compared with T790M-negative tumors (42.7% versus 24.0%, p = 0.001). Multivariate analysis demonstrated that the maximum tumor shrinkage rate was a significant predictive factor for the detection of the T790M mutation (p = 0.023, odds ratio 1.03, 95% confidence interval 1.00-1.05).Conclusions: Our retrospective observations suggested that the maximum tumor shrinkage rate with initial EGFR-TKI treatment might be one of the promising predictive biomarkers for emerging refractory tumors with the EGFR-T790M mutation. [ABSTRACT FROM AUTHOR]

Abstract Background Anti-HER2 therapy has not demonstrated a survival advantage in the second-line setting of patients with HER2-positive gastric cancer. We conducted this study to assess changes in HER2 status and to identify possible biomarkers for acquired resistance after the use of trastuzumab as the first-line therapy. Patients and methods Patients with advanced or recurrent HER2-positive gastric adenocarcinoma who were diagnosed with progressive disease after the first-line trastuzumab-based therapy and developed pathologically confirmed adenocarcinoma within 3 months after completion of trastuzumab-based therapy were enrolled in this study. We collected re-biopsied samples from the HER2-positive patients who had developed resistance to trastuzumab and re-evaluated their HER2 status. Amplification of EGFR and c-met , as well as PIK3CA mutation, were comparatively analysed when samples were available. Results Among 33 eligible patients, loss of HER2 was identified in 20 patients (60.6%) with refractory disease. Immunohistochemistry showed that the rate of HER2 overexpression was greatly reduced after therapy (pre-HER2 3+: 24 [72.7%] vs. post-HER2 3+: 13 [39.4%]). We found that the use of fixatives other than 10% neutral buffered formalin significantly reduced the HER2-positive rate. EGFR amplification, c-met amplification and PIK3CA mutation before and after trastuzumab-based therapy were observed in 10.3% and 3.8%, 17.9% and 4.2% and 4.0% and 4.2% of cases, respectively. Conclusion Re-evaluation of HER2 status is needed to determine the appropriate use of anti-HER2–targeted therapy after disease progression. Our results also highlight the importance of formalin fixation conditions for HER2 testing. Highlights • The HER2 status was re-evaluated using re-biopsied samples from the patients with HER2-positive gastric cancer. • Among 33 eligible patients, the loss of HER2 was identified in 20 patients (60.6%) with refractory disease. • The use of fixatives, other than 10% neutral buffered formalin, reduced the HER2-positive rate. [ABSTRACT FROM AUTHOR]

Objective: Acquired T790M mutations account for 50%–60% of tyrosine kinase inhibitor (TKI)-resistant mechanisms in EGFR mutation-positive (m+) non-small-cell lung cancer (NSCLC) patients, and re-biopsy is recommended to detect these mutations. We investigated the re-biopsy status and the T790M incidence rate in patients after treatment with icotinib, which is the first-generation EGFR-TKI widely used in China. Patients and methods: Target patients had EGFRm+NSCLC, who were progressed after icotinib therapy. The primary end point was the re-biopsy rate (number of cases in which re-biopsies were performed successfully/total number of patients progressed after icotinib therapy). Secondary end points included the T790M mutation incidence rate, differences between the first biopsy and re-biopsy, and details of why re-biopsy was not performed in relevant patients. Results: A total of 77 adenocarcinoma patients were evaluated (median age, 58 years). Tissue re-biopsy was successful in 41 patients (53.2%). Compared with the first biopsy, percutaneous tissue biopsies increased from 51.2% to 70.7% (P=0.008), while bronchoscopy biopsies and the surgical rate decreased from 19.5% to 14.6% (P,0.001) and 17.1% to 7.3% (P,0.001), respectively. Primary lung lesions were more common in the first biopsy than in re-biopsy (80.5% vs 65.9%, P=0.008), but metastatic lesions were more often selected for re-biopsy (14/41 [34.1%], including metastases in the bone, lymph nodes, and liver). The incidence rate of T790M was 56.1% (23/41). The reasons for not performing re-biopsies included lesion sizes and/or locations unsuitable for biopsy (n=17), a positive circulating tumor DNA (ctDNA) result (n=3), patient unwillingness (n=7), older age or severe comorbidity (n=4), and poor health (n=5). No severe complications were found. Conclusion: In this real-world study, the re-biopsy rate was 53.2% and the incidence rate of T790M mutations was 56.1%. Further efforts are needed to increase the re-biopsy rate in patients who progress after icotinib therapy. [ABSTRACT FROM AUTHOR]

Background: In cases of EGFR‐tyrosine kinase inhibitor (TKI) failure, re‐biopsy may be useful to understand resistance mechanisms and guide further treatment decisions. However, performing re‐biopsy is challenging because of several hurdles. We assessed the feasibility of re‐biopsy in advanced non‐small cell lung cancer (NSCLC) patients in real‐world clinical practice. Methods: We retrospectively reviewed the clinical and pathologic data of advanced NSCLC patients who experienced disease progression after previous treatment with EGFR‐TKIs at a single tertiary hospital in Korea between January 2014 and December 2016. Re‐biopsy specimens included small biopsy, surgical tissue, or liquid‐based cytology. EGFR mutation was tested using peptide nucleic acid‐mediated clamping PCR. Results: Of the 230 NSCLC patients that experienced progression after EGFR‐TKI therapy, 105 (45.7%) underwent re‐biopsy. Re‐biopsy was successfully performed in 94 (89.5%) patients, and 11 patients were diagnosed with no malignancy. The complication rate was 8.6%, including seven cases of pneumothorax. EGFR mutation testing was performed on 75 patients using re‐biopsy specimens. Of the 57 patients who had sensitizing mutations at diagnosis, T790M mutations were found in 19 (33.3%), while 38 (66.7%) had no T790M mutation. Multivariate analysis showed that the re‐biopsy group was younger (P = 0.002) and exhibited a previous response to EGFR‐TKIs (P < 0.001). Conclusion: Re‐biopsy in advanced NSCLC is feasible in real world clinical practice, particularly in younger patients and those who achieved a previous response to EGFR‐TKIs. [ABSTRACT FROM AUTHOR]

Recurrent breast cancer poses considerable diagnostic and therapeutic challenges for clinic. Clinical suspicion of recurrence must be first confirmed by imaging studies. Then re-biopsy of suspected recurrence and metastasis in patients with breast cancer is recommended in the practice guidelines of the National Comprehensive Cancer Network (NCCN) and European Society for Medical Oncology (ESMO) to confirm whether the molecular subtype changes. It may change the individual treatment plan directly. Our research provided an integrated algorithm for locally recurrent or distant metastatic breast cancer, including early relapse detection and subsequently a new practical PET/CT imaging guide biopsy approach for surveilling molecular subtype shifts of the recurrent breast cancer. In our results, 18F-FDG PET/CT appears to be more sensitive and accurate than conventional imaging technologies in early detecting locally recurrent or metastatic breast cancer. PET/CT-guided percutaneous FDG-avid target biopsies offers a new integrated precise re-biopsy algorithm for pathologic confirm and surveillance of molecular subtype shifts of the recurrent breast cancer. The precise algorithm for breast cancer recurrence and metastasis can be established in one stop, opening a window of opportunity for breast cancer patients to improve precise individual therapy and prolong survival. [ABSTRACT FROM AUTHOR]

The aim of this study was to compare the accuracy of the QuantStudio 3D Digital polymerase chain reaction (dPCR) system and a PCR‐based next generation sequencing (NGS) system for detecting a secondary mutation in the epidermal growth factor receptor (EGFR) gene T790M in non‐small cell lung cancer (NSCLC) patients previously diagnosed with EGFR‐activating mutations. Twenty‐five patients with NSCLC previously treated with EGFR‐TKIs were examined. The patients were treated daily with either erlotinib or gefitinib. New biopsies, followed by DNA sequencing on an Ion Torrent systems using the Ion Torrent AmpliSeq Cancer Hotspot Panel and dPCR were performed. A comparison of NGS, sensitive PCR, and dPCR revealed that the sensitivities of NGS and dPCR were similar in this study. As well, T790M was detected in as low as about 5% of mutant allelic frequencies, which represented 5% of the total reads on site mapped reads in NGS and greater than 5% of the dPCR reads, which represented mutant and wild type copies. The strategy in which NGS sequencing is followed by revealed acquired mutation with dPCR may be a reasonable one. We demonstrated the utility of combining NGS and dPCR as a tool for monitoring T790M. NGS and dPCR with formalin‐fixed paraffin‐embedded (FFPE) specimens might become a standard genomic test for exploring acquired resistance to targeted molecular medicines. [ABSTRACT FROM AUTHOR]

Blood biopsy has many advantages over tissue biopsy for diagnosing acquired T790M mutation in patients with non-small-cell lung cancer, such as being less risky and painful. New techniques with high sensitivity (eg, droplet digital PCR) show promising results during blood biopsy, but the positive rates of identification are still quite unclear. Whether there are other factors, except technology, affecting the results of blood biopsy is unclear. In this study, we used conventional amplification refractory mutation system to detect tumor tissue or blood for T790M mutation in patients clinically resistant to tyrosine kinase inhibitors. A total of 45 patients treated at West China Hospital between 2014 and 2016 were analyzed. The positive rate of T790M mutation was 70.8% based on tissue biopsy and 37.5% based on blood biopsy. Of the 24 patients whose epidermal growth factor receptor gene was genotyped through tissue and blood biopsy, 10 (41.7%) were concordant for T790M mutation status (κ=0.006). Of the 17 patients positive for T790M by tissue biopsy, 7 (41.2%) were positive for T790M by blood biopsy, and 3 of these 7 were only weakly positive. Of the 7 patients negative for T790M by tissue biopsy, 2 (28.6%) were positive by blood biopsy. Our T790M detection rate is higher than that reported by other studies using digital droplet PCR. These results suggest that other factors (eg, clinical features), intrinsically connected with circulating tumor DNA level, also affect the results of blood biopsy, and thus cannot be controlled through technological optimization. [ABSTRACT FROM AUTHOR]

Objective Disease progression because of acquired resistance is common in advanced or metastatic epidermal growth factor receptor (EGFR)-mutation positive non-small cell lung cancer (NSCLC), despite initial response to EGFR-tyrosine kinase inhibitors (TKIs). In Japan, transbronchial tissue biopsy is the most common sampling method used for re-biopsy to identify patients eligible for treatment. We aimed to investigate the success rate of re-biopsy and re-biopsy status of patients with advanced or metastatic NSCLC completing first-line EGFR-TKI therapy. Patients and methods This was a retrospective, multi-center, Japanese study. The target patients in the study were EGFR mutation-positive NSCLC patients. The primary endpoint was the success rate (number of cases in which tumor cells were detected/total number of re-biopsies performed × 100). Secondary endpoints included differences between the status of the first biopsy and that of the re-biopsy in the same patient population, and the details of cases in which re-biopsy could not be carried out. Re-biopsy-associated complications were also assessed. Results Overall, 395 patients were evaluated (median age 63 years), with adenocarcinoma being the most common tumor type. Re-biopsy was successful in 314 patients (79.5%). Compared with the sampling method at first biopsy, at re-biopsy, the surgical resection rate increased from 1.8% to 7.8%, and percutaneous tissue biopsy increased from 7.6% to 29.1%, suggesting the difficulty of performing re-biopsy. Approximately half of the patients had T790M mutations, which involved a Del19 mutation in 55.6% of patients and an L858R mutation in 43.0%. Twenty-three patients (5.8%) had re-biopsy- associated complications, most commonly pneumothorax. Conclusions Success rate for re-biopsy in this study was approximately 80%. Our study sheds light on the re-biopsy status after disease progression in patients with advanced or metastatic NSCLC. This information is important to improve the selection of patients who may benefit from third-generation TKIs. [ABSTRACT FROM AUTHOR]