Values of circulating tumor DNA for non-small cell lung cancer patients receiving neoadjuvant therapy, progress and challenges: a narrative review.

Background and Objective: The value of circulating tumor DNA (ctDNA) in neoadjuvant therapy (NAT) for lung cancer remains controversial. Therefore, we conducted a review to further investigate the role of ctDNA in non-small cell lung cancer (NSCLC) patients undergoing NAT for individualized management. Methods: A search of online databases (PubMed, Embase, Web of Science, Science Direct, and Cochrane Library) was conducted to evaluate the value of ctDNA in predicting relapse, risk stratification, and efficacy of NAT in NSCLC. Only articles published in English within the last 25 years, between January 1st, 1998 and November 30th, 2023, were included. Additionally, the application of ctDNA in NSCLC is briefly reviewed. Key Content and Findings: ctDNA is a non-invasive and dynamic method that plays an important role in future treatment guidance. Additionally, ctDNA successfully predicted the effect of neoadjuvant immunotherapy before surgery, and positive testing was strongly correlated with a lower major pathological response or complete pathological response rate. Sequential testing of ctDNA may serve as a secondary indicator to guide the adjustment of treatment programs. However, the application of this method has been limited by false negative results, a lack of objective indicators, and high costs. These issues must be addressed by researchers. Conclusions: ctDNA has strong potential in NAT, based on positive preliminary studies. However, its widespread use is limited by the high cost of testing. Further research is needed to explore its value in risk stratification and treatment guidance in the future.

Reappraisal of the current resectability criteria and optimal treatment strategies for pancreatic cancer.

Background: Recent advances in anticancer treatment and prolonged survival are the background of this study. The study aimed to reappraise the Japan Pancreas Society (JPS) resectability criteria in pancreatic cancer and to propose optimal treatment strategies. Methods: Three hundred ninety-six consecutive patients with curative-intent surgery for pancreatic cancer from April 2011 to December 2022 were included. Overall survival based on the resectability criteria was analyzed, and Cox regression analyses were performed to identify factors associated with overall survival. Results: The median survival times (MSTs) based on the current resectability status were 37.4, 20.1, and 26.6 months in resectable (R), in borderline resectable (BR), and unresectable (UR) disease, respectively (P<0.001), revealing an inversion phenomenon between BR and UR. Using the International Association of Pancreatology (IAP) criteria, the MST of biological BR disease was demonstrably worse than that of R disease (27.1 vs. 40.7 months, P=0.04), but no difference was observed between classical BR and UR locally advanced disease (18.8 vs. 18.7 months, P=0.97). Rather, ≤180° superior mesenteric artery (SMA) invasion was a more powerful prognostic factor than >180° SMA/celiac artery invasion in multivariate analysis (hazard ratio: 2.101, 95% confidence interval: 1.296-3.404, P=0.003). When biological BR was combined with BR, and BR with artery invasion was considered locally advanced disease as a new resectability criterion, the MSTs were 38.8, 23.5, and 18.5 months in the new R, new BR, and locally advanced groups, respectively (P<0.001). Conclusions: The decision-making and treatment strategies based on our new classification in pancreatic cancer are considered reasonable for clinical practice.

De-escalation of Axillary Surgery After Neoadjuvant Therapy.

Surgical de-escalation of the axilla has evolved over the past 28 years since the emergence of sentinel lymph node surgery. Well-documented complications of the once standard of care axillary lymph node dissection (ALND), including lymphedema, led physician scientists towards a progressive push to study and incorporate less invasive techniques in the axilla. Many trials have justified oncologic safety of axillary de-escalation in patients who are spared neoadjuvant treatment. The applicability in the neoadjuvant setting, however, is less clear and axillary surgical approaches in this patient population have evolved at a slower pace. This review aims to analyze current data in axillary management for patients undergoing neoadjuvant treatment and to discuss current surgical approaches based on nodal pathologic response.

Enhanced Complement Expression in the Tumor Microenvironment Following Neoadjuvant Therapy: Implications for Immunomodulation and Survival in Pancreatic Ductal Adenocarcinoma.

Background: Neoadjuvant therapy (NAT) is increasingly being used for pancreatic ductal adenocarcinoma (PDAC) treatment. However, its specific effects on carcinoma cells and the tumor microenvironment (TME) are not fully understood. This study aims to investigate how NAT differentially impacts PDAC's carcinoma cells and TME. Methods: Spatial transcriptomics was used to compare gene expression profiles in carcinoma cells and the TME between 23 NAT-treated and 13 NAT-naïve PDAC patients, correlating with their clinicopathologic features. Analysis of an online single-nucleus RNA sequencing (snRNA-seq) dataset was performed for validation of the specific cell types responsible for NAT-induced gene expression alterations. Results: NAT not only induces apoptosis and inhibits proliferation in carcinoma cells but also significantly remodels the TME. Notably, NAT induces a coordinated upregulation of multiple key complement genes (C3, C1S, C1R, C4B and C7) in the TME, making the complement pathway one of the most significantly affected pathways by NAT. Patients with higher TME complement expression following NAT exhibit improved overall survival. These patients also exhibit increased immunomodulatory and neurotrophic cancer-associated fibroblasts (CAFs); more CD4+ T cells, monocytes, and mast cells; and reduced immune exhaustion gene expression. snRNA-seq analysis demonstrates C3 complement was specifically upregulated in CAFs but not in other stroma cell types. Conclusions: NAT can enhance complement production and signaling within the TME, which is associated with reduced immunosuppression in PDAC. These findings suggest that local complement dynamics could serve as a novel biomarker for prognosis, evaluating treatment response and resistance, and guiding therapeutic strategies in NAT-treated PDAC patients.

Somatic mutations in a multigene panel and impact on prognosis based on TP53 status in Chinese HER2-positive patients undergoing neoadjuvant therapy: A single-institution retrospective cohort.

BACKGROUND: Gene mutations play a crucial role in the occurrence and development of tumors, particularly in breast cancer (BC). Neoadjuvant therapy (NAT) has shown greater clinical benefit in HER2-positive breast cancer. However, further clinical investigation is needed to fully understand the correlation between genetic mutations and NAT efficacy and the long-term prognosis in HER2-positive BC. METHODS: This was a retrospective cohort study of 222 patients receiving NAT between 2017 and 2021 in the Department of Breast Surgery of Fudan University Shanghai Cancer Center. Tumor samples from these patients were subjected to Next Generation Sequencing (NGS) to analyze mutations in 513 cancer-related genes. This study aimed to investigate the association between these genetic mutations and postoperative pathological complete response (pCR), as well as their impact on disease-free survival (DFS). RESULTS: In total, 48.65% patients reached pCR, ER-negative status (p < 0.001), PR-negative status (p < 0.001), Ki67 ≥ 20 (p = 0.011), and dual-targeted therapy (p < 0.001) were all associated with enhanced pCR rates. The frequency of somatic alterations in TP53 (60%), PIK3CA (15%), and ERBB2 (11%) was highest. In the HER2+/HR- cohort, patients who achieved pCR had a significant benefit in prognosis (HR = 3.049, p = 0.0498). KMT2C (p = 0.036) and TP53 (p = 0.037) mutations were significantly increased in patients with DFS events. Moreover, TP53 mutations had prognostic significance in HER2-positive BC patients with HR-negative (HR = 3.712, p = 0.027) and pCR (HR = 6.253, p = 0.027) status and who received herceptin-only targeted therapy (HR = 4.145, p = 0.011). CONCLUSIONS: The genetic mutation profiles of Chinese HER2+ patients who received NAT were discrepant with respect to HR status or DFS events. TP53 mutations have significant prognostic value in patients with NAT for HER2-positive BC and patients benefit differently depending on HR status, the neoadjuvant regimen and response, which highlights the significance of genetic factors in treatment customization based on individual genetic and clinical characteristics.

The efficacy and safety of using pyrotinib combined with capecitabine as neoadjuvant therapy in elderly patients with HER2-positive breast cancer: a single-arm prospective clinical trial.

Background: Pyrotinib combined with capecitabine has been approved for the treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer in China. To date, the management of early-stage or locally advanced HER2-positive breast cancer in the clinic remains challenging. We conducted this trial to investigate the efficacy and safety of pyrotinib combined with capecitabine as neoadjuvant therapy (NAT) in elderly patients with HER2-positive breast cancer. Due to the stimulation of blood vessels by chemotherapy drugs, the elasticity of blood vessels in the elderly decreases, and then chemotherapy infusion is more likely to lead to phlebitis. Both pyrotinib and capecitabine can be taken to facilitate home treatment for elderly patients with HER2-positive breast cancer (BC). Methods: From January 2020 to March 2021, patients aged between 70 and 81 years old with stage IIA-IIIB HER2-positive breast cancer were screened, enrolled, and assigned to receive six cycles of pyrotinib (320-400 mg, orally, once daily) plus capecitabine (1,250 mg/m2, orally, twice daily) on days 1-14 in every 21-day cycle. The primary endpoint was the objective response rate (ORR). Adverse events (AEs) were assessed in every neoadjuvant cycle. Surgery was performed after the last cycle, and the total pathological complete response (tpCR) was evaluated postoperatively. Results: Of the 23 patients enrolled, the ORR was 100% (23/23; 95% confidence intervals: 85 to 100). All patients underwent surgery with a tpCR rate of 43.5% (10/23; 95% confidence intervals: 23 to 66). The most common AE was diarrhea, occurring in 19 of 23 patients (82.6%); most of these patients sustained mild diarrhea (Grade 1 or Grade 2) and only three had moderate diarrhea (Grade 3). The incidences of other AEs, including weakness, loss of appetite, leukopenia, nausea, vomiting, hand-foot syndrome, etc., were low and the symptoms were mild. No severe AEs (Grade 4 or 5) were observed throughout the treatment. Conclusion: In our study, pyrotinib combined with capecitabine as neoadjuvant therapy in elderly women with HER2-positive breast cancer is safe and showed efficacy in this population, which may be widely used as a protocol for clinical neoadjuvant therapy.

Advances in neoadjuvant therapy for HER2-positive breast cancers: a narrative review.

Background and Objective: Breast cancer (BC) is currently the most frequently diagnosed cancer and the primary cause of cancer-related death among women worldwide. Human epidermal growth factor receptor type 2 (HER2)-positive BC accounts for 14.5-15% of all BCs, with a relatively poor prognosis. Neoadjuvant therapy (NAT) has become a preferred treatment option for HER2+ BCs. With the continuous emergence of various clinical trials and new treatment concepts in BC, the NAT model has changed from chemotherapy alone to the neoadjuvant combination of anti-HER2-targeted therapy with chemotherapy, neoadjuvant endocrine therapy, and so on. Therefore, an up-to-date review is needed to inform the selection of NAT strategies for HER2+ BCs. Methods: This review was administrated with literature from the PubMed database. Manuscripts were searched using the following keywords: "neoadjuvant" or "preoperative", "breast cancer" or "breast neoplasm", "HER2+" or "HER2-positive", titles and abstracts were screened and evaluated independently by two authors. Information relating to the efficacy and safety profile of NAT for patients with HER2+ BCs were included and analyzed qualitatively. Only English-language articles were included. Key Content and Findings: This review discusses the neoadjuvant situation for the surgical management of HER2-positive BCs around the world. In this paper, we describe the efficacy assessment of NAT, analyze clinical effect and toxicity of chemotherapy, and targeted therapy, including monoclonal antibody, tyrosine kinase inhibitors (TKIs) and antibody-drug conjugates (ADCs), and other neoadjuvant treatments in HER2+ BC. The data shows while overall survival is the standard endpoint for efficacy, pathological complete response have been implemented more and more frequently in clinical trials for its convenience. Dual-targeted therapy plus chemotherapy exhibited favorable efficacy in most cases, meanwhile other treatment strategies such as combinations without chemotherapy or including CDK4/6 agents may be applicable in specific situation. Conclusions: As an important part of BC treatment, NAT is lingering in the stage of continuous development, especially for patients with HER2-positive BC. The challenges we are facing today in this field are dose de-escalation without reducing efficacy and choose suitable combination of agents in clinical practice. Moreover, new biomarkers are warrant for individualize treatment.

Skeletal Muscle Change During Neoadjuvant Therapy and Its Impact on Prognosis in Patients With Gastrointestinal Cancers: A Systematic Review and Meta-Analysis.

Background: Gastrointestinal cancers are the most common malignant tumors worldwide. As the improvement of survival by surgical resection alone for cancers is close to the bottleneck, recent neoadjuvant therapy has been emphasized and applied in the treatment. Despite the advantage on improving the prognosis, some studies have reported neoadjuvant therapy could reduce skeletal muscle and therefore affect postoperative outcomes. However, the conclusions are still controversial. Methods: PubMed, CINAHL, Embase, and Cochrane Library were searched from inception to September 2, 2021. The inclusion criteria were observational studies, published in English, of individuals aged ≥18 years who underwent neoadjuvant therapy with gastrointestinal cancers and were assessed skeletal muscle mass before and after neoadjuvant therapy, with sufficient data on skeletal muscle change or the association with clinical outcomes. Meta-analysis was conducted by using the STATA 12.0 package when more than two studies reported the same outcome. Results: A total of 268 articles were identified, and 19 studies (1,954 patients) were included in the review. The fixed effects model showed that the risk of sarcopenia increased 22% after receiving neoadjuvant therapy (HR=1.22, 95% CI 1.14, 1.31, Z=4.286, P<0.001). In the random effects model, neoadjuvant therapy was associated with skeletal muscle loss, with a standardized mean difference of -0.20 (95% CI -0.31, -0.09, Z=3.49, P<0.001) and a significant heterogeneity (I2 = 62.2%, P<0.001). Multiple meta regression indicated that population, neoadjuvant therapy type, and measuring tool were the potential sources of heterogeneity. The funnel plot revealed that there was no high publication bias in these studies (Begg's test, P=0.544) and the sensitivity analysis showed stable results when separately excluding studies. For the postoperative outcomes, the results revealed that muscle loss during neoadjuvant therapy was significantly related to overall survival (HR=2,08, 95% CI =1.47, 2.95, Z=4.12, P<0.001, I2 = 0.0%), but not related to disease-free survival and other short-term outcomes. Conclusions: This systematic review and meta-analysis revealed that skeletal muscle decreased significantly during neoadjuvant therapy in patients with gastrointestinal cancers and skeletal muscle loss was strongly associated with worse overall survival. More high-quality studies are needed to update and valid these conclusions in a more specific or stratified way. Systematic Review Registration: [https://www.crd.york.ac.uk/PROSPERO/], identifier PROSPERO (CRD42021292118).

Critical issues in pathologic evaluation of pancreatic ductal adenocarcinoma resected after neoadjuvant treatment: a narrative review.

BACKGROUND AND OBJECTIVE: Preoperative neoadjuvant therapy (NAT) is increasingly used in the treatment of patients with potentially resectable pancreatic ductal adenocarcinoma (PDAC). Because NAT often induces heterogeneous tumor response and extensive fibrosis both in tumor and adjacent pancreatic tissue, pathologic assessment of posttherapy pancreatectomy specimens is challenging. A limited number of studies examined the optimal grossing and sampling methods, tumor response grading (TRG), and the prognostic value of posttherapy tumor (ypT) and lymph node (ypN) stages of treated PDAC patients. In this review, we will provide an overview of the current status and critical issues in pathologic evaluation of PDAC resected after NAT. METHODS: In PubMed, Google Scholar and Web of Science, we reviewed existing English literature (published up to December 2021) highlighting the most recent ones using electronic databases and authors' experience to outline the challenging aspects and new perspectives on pathologic assessment of the treated PDAC. KEY CONTENT AND FINDINGS: The recent recommendations from the Pancreatobiliary Pathology Society (PBPS) provide the much-needed guidelines for systematic and standardized pathologic evaluation and reporting of treated PDAC for optimal patient care. For treated PDAC, tumor size measured by gross and radiology is not reliable. Histologic validation of tumor size on consecutive mapping sections is recommended for accurate ypT stage. A tumor size of 1.0 cm seems to be a better cutoff for ypT2 for treated PDACs. The published data suggested that the MD Anderson Cancer Center (MDA) TRG system is easy to use, has a better interobserver agreement and better correlation with patient prognosis compared to the College of American Pathologists (CAP) and Evans grading systems and may be used as an alternative TRG system for the CAP cancer protocol. CONCLUSIONS: Systemic and standardized grossing and sampling are essential for accurate pathologic evaluation and reporting for optimal care of PDAC patients who received NAT. Future studies on optimal sampling and integration of histopathology with artificial intelligence (AI), molecular and immunohistochemical markers are needed for better and personalized care of treated PDAC patients.

Circulating tumor DNA predicts neoadjuvant immunotherapy efficacy and recurrence-free survival in surgical non-small cell lung cancer patients.

Background: There is currently a lack of effective biomarkers to evaluate efficacy of neoadjuvant therapy (NAT) for resectable non-small cell lung cancer (NSCLC) patients. Circulating tumor DNA (ctDNA) has been investigated as a non-invasive tool for the assessment of tumor burden and minimal residual disease (MRD). The utility of ctDNA profiling in reflecting NAT efficacy, however, has not been confirmed. This study explored the association of ctDNA change with treatment response to NAT and recurrence-free survival (RFS) after surgery. Methods: Eligible patients with stage IB-IIIA NSCLC were retrospectively included if they had received neoadjuvant immunotherapy combined with chemotherapy (IO+Chemo), dual immunotherapy (IO+IO), or chemotherapy alone (Chemo). We conducted ctDNA profiling before and after NAT, after surgery, and during follow-ups using an ultra-deep lung cancer-specific MRD (LC-MRD) sequencing panel. Results: A total of 22 patients who received NAT followed by surgery between August 2018 and July 2019 were included in this study. The major pathological response (MPR) rates were 58.33% (7/12) in the IO+Chemo group, 25.00% (1/4) in the IO+IO group, and 16.67% (1/6) in the Chemo group. The ctDNA dynamics during NAT were highly concordant with pathologic response, demonstrating 100% sensitivity and 83.33% specificity, for an overall accuracy of 91.67%. Pre-surgery detectable ctDNA (after NAT) trended to correlate with inferior RFS [hazard ratio (HR), 7.41; 95% confidence interval (CI): 0.91-60.22, log-rank P=0.03]. At 3-8 days after surgery, ctDNA was detectable in 31.8% of patients and was an independent risk factor for recurrence (HR, 5.37; 95% CI: 1.27-22.67; log-rank P=0.01). The presence of ctDNA at 3 months after surgery showed 83% sensitivity and 90% specificity for predicting relapse (C-index, 0.79; 95% CI: 0.62-0.95). During disease monitoring after surgery, molecular recurrence by means of ctDNA preceded radiographic relapse, with a median time of 6.83 months. Conclusions: This study investigated the potential of ctDNA in evaluating NAT efficacy in NSCLC, implying the high concordance between ctDNA and pathological response. We also set out the prognostic value of perioperative ctDNA in predicting recurrence.

Application of ultrasound-guided placement of markers for locating axillary lymph nodes of breast cancer.

BACKGROUND: With the continuous improvement of pathological complete response (pCR) rate after neoadjuvant therapy (NAT), it is necessary to locate the tumor bed and axillary lymph nodes (ALNs) for subsequent surgery. Therefore, breast tissue markers emerge. This study aims to evaluate the feasibility and accuracy of ultrasound (US)-guided placement of markers for locating ALNs of breast cancer. METHODS: A total of 285 patients who received US-guided placement of markers for locating ALNs in our hospital were selected. Among these patients, 87 patients were in the early breast cancer (EBC) group with negative ALNs and 198 ones were in the NAT group with positive ALNs. Data including the basic information of patients, position and size of ALN, process of US-guided marker placement, placement success rate, complications, detection rate of marker by imaging, and shift rate were recorded. RESULTS: All patients were successfully undergone US-guided marker placement. And the average operation time was 2 minutes with no adverse reactions. All the patients underwent surgery successfully. US, computer tomography (CT) and magnetic resonance imaging (MRI) were used to detect the marker. The detection rate of markers by US and CT/MRI were 100% (87/87) in EBC group, and 98.5% (195/198) and 100% (198/198) by US and CT/MRI, respectively, in NAT group. The postoperative marker shift rate was 2.1% (6/285), including 3.4% (3/87) marker shift rate in EBC group and 1.5% (3/198) in NAT group, with no statistically significant difference between them. CONCLUSIONS: US-guided marker placement in ALNs of breast cancer is simple and safe, with firm positioning and low shift rate, which is convenient for clinical promotion.

Assisted computer and imaging system improve accuracy of breast tumor size assessment after neoadjuvant chemotherapy.

BACKGROUND: The use of neoadjuvant therapy (NAT) in patients with early breast cancer is becoming increasingly common. The purpose of this study was to explore the combined use of breast pathology cabinet X-ray system (CXS) to accurately assess the response to neoadjuvant treatment of breast cancer and establish a standard evaluation system. METHODS: A total of 100 patients with breast cancer after neoadjuvant treatment were randomly selected. Preoperative imaging evaluation of tumor masses were significantly degenerated, and they were randomly divided into experimental and control groups of 50 cases each. Compared with the traditional two methods of material extraction, the effective material extraction rate is comparative. Take the two largest diameters of the largest two-dimensional surface of the tumor bed as the measurement object, the macro-description value is D1/D2, the radiographic system description measurement value is the experimental group d1/d2, and the correction under the microscope is worth the true size of the tumor bed H1/H2 as the final test standard, calculate the difference between D1/D2 and d1/d2 with H1 and H2, and compare the difference between d1- H1, d2 - H2 and D1- H1, D2 - H2. RESULTS: The average group of tissue samples in the experimental group was 16.4, and the average group of tissue samples in the control group was 16.7, and there was no difference between the two groups; The effective tissue blocks of tumor bed samples in the experimental group were11.8, and the control group was 7.5. There is difference between the two groups. The average effective percentage of tumor bed in the experimental group was 72%, and the average effective percentage of tumor bed in the control group was 44.8%. The difference was also statistically significant; d1- H1, d2 - H2 and D1- H1, D2 - H2 are all different. CONCLUSIONS: CXS assists the collection of breast tumor bed, which can significantly improve the efficiency of tumor bed collection and save the cost of collection. Compared with the maximum diameter of the tumor bed by eyes, the CXS mapping value is closer to the value measured under the microscope.

Neoadjuvant therapy: theoretical, biological and medical consideration.

Neoadjuvant therapy (NAT) is widely utilized in the routine management of cancer patients and various clinical trials for the treatment of breast, ovarian, rectal, esophageal, head and neck, lung, prostate and many other cancer types. There is a number of potential benefits of applying systemic treatment before the operation. NAT may significantly reduce the tumor burden thus allowing less traumatic surgery. NAT is often considered as personalized in vivo drug sensitivity test, as it allows rapid evaluation of tumor response to a given therapy and consequent adjustment of further treatment planning. NAT is an invaluable tool for in-human testing of novel therapeutic compounds, as it deals with yet chemonaive patients and permits pathological and molecular analysis of treatment-exposed tumor tissues. There are also some arguments against the use of NAT. The delay of surgery may increase the chances for metastatic tumor spread. NAT often results in the selection of treatment-resistant tumor clones, which cannot be eliminated by subsequent adjuvant therapy. NAT is likely to compromise visual inspection of surgical wound, as it reduces the size of tumor lumps and makes them invisible for the operating physician. Animal models cannot fully recapitulate the complexity of human cancer biology, the sophistication of modern surgical interventions, and the spectrum of tumor drug sensitivity in neoadjuvant and adjuvant settings. Therefore, studies on the rationale for NAT are largely limited to human studies.