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The SWOG S1801 trial investigated the role of pembrolizumab, an anti-PD1 immune checkpoint inhibitor, in the perioperative setting of stage III or IV melanoma. This phase 2 trial compared two groups: one receiving pembrolizumab both before and after surgery (neoadjuvant-adjuvant), and another receiving it only post-surgery (adjuvant-only), with event-free survival (EFS) as the primary endpoint. Neoadjuvant strategies, involving pre-surgical drug administration, potentially offer rapid tumor control and a unique opportunity to assess tumor response. However, they may expose to toxicity and delay or preclude surgery. The study met its primary endpoint, with a 72 % EFS rate in the neoadjuvant-adjuvant group, and 49 % in the adjuvant group. Here, we question the results applicability with three potential limitations. Key concerns include an arbitrary rule in event assignment, possibly affecting the event distribution over time. Second, different rates of early censoring between groups introduce the possibility of informative censoring, which could have led to an artefactual benefit in EFS. Lastly, phase 2 trial results, by definition, carry risk of fluke results, and should be confirmed in phase 3 trial before wide adoption. Collectively, these factors must be integrated into a careful interpretation of the SWOG S1801 trial outcomes. More robust data are needed to fully appraise strengths and limitations of neoadjuvant pembrolizumab in melanoma treatment.

PURPOSE: Germline pathogenic variants in checkpoint kinase 2 (CHEK2) are associated with a moderately increased risk of breast cancer (BC). The spectrum of clinicopathologic features and genetics of these tumors has not been fully established. METHODS: We characterized the histopathologic and clinicopathologic features of 44 CHEK2-associated BCs from 35 women, and assessed responses to neoadjuvant chemotherapy. A subset of cases (n = 23) was additionally analyzed using targeted next-generation DNA sequencing (NGS). RESULTS: Most (94%, 33/35) patients were heterozygous carriers for germline CHEK2 variants, and 40% had the c.1100delC allele. Two patients were homozygous, and five had additional germline pathogenic variants in ATM (2), PALB2 (1), RAD50 (1), or MUTYH (1). CHEK2-associated BCs occurred in younger women (median age 45 years, range 25-75) and were often multifocal (20%) or bilateral (11%). Most (86%, 38/44) were invasive ductal carcinomas of no special type (IDC-NST). Almost all (95%, 41/43) BCs were ER + (79% ER + HER2-, 16% ER + HER2 + , 5% ER-HER2 +), and most (69%) were luminal B. Nottingham grade, proliferation index, and results of multiparametric molecular testing were heterogeneous. Biallelic CHEK2 alteration with loss of heterozygosity was identified in most BCs (57%, 13/23) by NGS. Additional recurrent alterations included GATA3 (26%), PIK3CA (226%), CCND1 (22%), FGFR1 (22%), ERBB2 (17%), ZNF703 (17%), TP53 (9%), and PPM1D (9%), among others. Responses to neoadjuvant chemotherapy were variable, but few patients (21%, 3/14) achieved pathologic complete response. Most patients (85%) were without evidence of disease at time of study (n = 34). Five patients (15%) developed distant metastasis, and one (3%) died (mean follow-up 50 months). CONCLUSION: Almost all CHEK2-associated BCs were ER + IDC-NST, with most classified as luminal B with or without HER2 overexpression. NGS supported the luminal-like phenotype and confirmed CHEK2 as an oncogenic driver in the majority of cases. Responses to neoadjuvant chemotherapy were variable but mostly incomplete.

Chemotherapy is used as neoadjuvant therapy for all subgroups of breast cancer, including ER-positive, and HER2-negative cases. However, studies have suggested that using aromatase inhibitors combined with CDK4/6-inhibitors might be an appropriate alternative in selected patients. Thus, the NEOLETRIB trial evaluates the response of ER-positive, HER2-negative luminal A/B breast cancer to the combination of letrozole and ribociclib in the neoadjuvant setting. Comprehensive molecular biology procedures, including sequential single-cell RNA-sequencing of tumor biopsies, are performed during 6 months of treatment with extensive biobanking of blood samples, tumor biopsies and gut microbiome specimens. Our findings will hopefully contribute to an improved selection of patients who may benefit from this drug combination and give new insights into the intra-tumoral changes during this treatment. Trial registration number:NCT05163106 (ClinicalTrials.gov) Article highlights Background & rationale Hormone receptor-positive breast cancer is the most common subtype and accounts for about 70–80% of all breast cancer patients. The rationale for using neoadjuvant therapy in the treatment of early breast cancer is to down-size large, otherwise inoperable tumors, with or without axillary lymph node metastasis, before definite surgery. Chemotherapy is still widely used as neoadjuvant therapy for all subgroups of breast cancer, including ER-positive, and HER2-negative cases. Neoadjuvant endocrine treatment with aromatase inhibitors and a CDK4/6 inhibitor in combination is currently tested in the neoadjuvant setting with promising results. Trial design The NEOLETRIB trial is a Phase-II, multicenter, single-arm, open-label, neoadjuvant trial. Objectives The trial aims to comprehensively study the tumor response to the highly potent drug combination of letrozole and ribociclib in women with locally advanced, ER-positive, luminal A/B breast cancer. In premenopausal women, goserelin will be added to letrozole and ribociclib. Comprehensive molecular biology procedures, including sequential single-cell RNA-sequencing of tumor biopsies, are performed during 6 months of treatment with extensive biobanking of blood samples, tumor biopsies and gut microbiome specimens. Conclusion The findings will hopefully contribute to an improved selection of patients who may benefit from this drug combination, and give new insights into the intra-tumoral changes during this treatment. [ABSTRACT FROM AUTHOR]

Intratumoral TLR9 agonists and anti-PD-1 produce clinical responses and broad immune activation. We conducted a single-arm study of neoadjuvant TLR9 agonist vidutolimod combined with anti-PD-1 nivolumab in high-risk resectable melanoma. In 31 evaluable patients, 55% major pathologic response (MPR) was observed, meeting primary endpoint. MPR was associated with necrosis, and melanophagocytosis with increased CD8+ tumor-infiltrating lymphocytes and plasmacytoid dendritic cells (pDCs) in the tumor microenvironment, and increased frequencies of Ki67+CD8+ T cells peripherally. MPRs had an enriched pre-treatment gene signature of myeloid cells, and response to therapy was associated with gene signatures of immune cells, pDCs, phagocytosis, and macrophage activation. MPRs gut microbiota were enriched for Gram-negative bacteria belonging to the Bacteroidaceae and Enterobacteriaceae families and the small subgroup of Gram-negative Firmicutes. Our findings support that combined vidutolimod and nivolumab stimulates a broad anti-tumor immune response and is associated with distinct baseline myeloid gene signature and gut microbiota. ClinicalTrials.gov identifier: NCT03618641. [Display omitted] • Neoadjuvant intratumoral vidu/nivo produces pathologic responses in stage III melanoma • Response is linked to myeloid cells, pDCs, and CD8+ T cells within tumor • Responder gut microbiota signatures vidu/nivo are distinct from those in anti-PD-1 Neoadjuvant immunotherapy improves relapse-free survival in stage III melanoma. The novel combination of intratumoral vidu/nivo produces 55% major pathologic response (MPR) with an acceptable safety profile. MPR was associated with intratumoral myeloid cells, pDCs, and CD8+ TIL. Gut microbiota signatures in vidu/nivo MPR are distinct from those in anti-PD-1 responders. [ABSTRACT FROM AUTHOR]

Extremity soft tissue sarcoma (ESTS) is a rare malignant nonepithelial disease, calling for combined modality treatments with surgery to further improve local control rates and long-term survival, especially in patients with multiple local recurrences with or without risk of amputation. In this double-arm, open-label, Phase II clinical trial, we will enroll 30 patients with pathologically confirmed ESTS without nodal involvement or distant metastases. Patients are randomly assigned to the combination treatment group or the radiation monotherapy group. Additionally, tumor and biological samples will be obtained directly before and after neoadjuvant therapy, allowing for studies of immune response and primary drug resistance mechanisms. Clinical Trial Registration:ChiCTR2200060659 (http://www.chictr.org.cn) (ClinicalTrials.gov). Article highlights A combined modality treatments with preoperative radiation therapy and intratumoral immunotherapy for patients with extremity soft tissue sarcomas is proposed. The clinical benefit will rely on the enhancement of immune effects and reduction of related toxicities. Neoadjuvant radiation has a comparable effect on local control and long-term survival with adjuvant radiotherapy after prolonged follow-up. Still, it has significant advantages of less late toxicity and potential benefits from de-escalated surgery, especially for patients with borderline resectable extremity soft tissue sarcomas. Neoadjuvant radiotherapy with hypofractionated regimens has a shorter course of treatment since the total dose is split into larger doses given per fraction compared with standard fractionation. Notably, hypofractionated radiotherapy can facilitate antigen presentation and regulate immune function. Intratumoural injection of antitumor immunomodulator can increase therapeutic effectiveness by mediating agent accumulation in the tumor microenvironment and tumor-draining lymph nodes and may also enhance anti-tumor immunity in combination with radiotherapy. Furthermore, intratumoral immunotherapy is expected to decrease systemic immune exposure while keeping the therapeutic benefits of local control. The nRS group (neoadjuvant radiotherapy alone before surgery) will serve as a control, contrasting the nRIS group (neoadjuvant radiotherapy plus immunotherapy before surgery) in further studies. This study will access radiologic and pathological responses for efficacy evaluation and collect biological samples such as blood draws, stool samples and tumor tissues before and after neoadjuvant therapy for comprehensive mechanistic study. Research team was multidisciplinary and consisted of radiation and medical oncologists, musculoskeletal oncologic surgeons, interventional radiologists, nuclear medicine physicians and specialized pathologists. [ABSTRACT FROM AUTHOR]

Background Aim Methods Results Conclusion The optimal care pathway (OCP) for people with breast cancer provides a framework for investigation and management of patients with breast cancer, with delays previously identified regionally.With emphasis on the neoadjuvant pathway, the primary aim of this study was to assess the practicality of implementing the breast cancer OCP timeframes regionally in comparison to nationally referenced standards.A retrospective institutional audit was performed for patients undergoing neoadjuvant therapy for breast cancer. The time from referral to specialist review, completion of investigations, discussion at multidisciplinary team (MDT) meetings, initiation of neoadjuvant chemotherapy (NACT) and surgery were calculated and compared to OCP.Fifty‐three patients were included, with 19 patients living rurally (36%). Twenty‐four patients (45%) were seen by a specialist surgeon within 2 weeks of referral. Following surgical review, 44 patients (83%) completed investigations within 2 weeks, and 43 patient cases (81%) were discussed at MDT meetings within 2 weeks. Forty‐eight patients (91%) were commenced on neoadjuvant treatment within 4 weeks of decision to treat, and 43 patients (81%) underwent surgery within 6 weeks of neoadjuvant treatment completion. Delays from initial referral to NACT were more frequent in rural patients compared to urban (79% vs 94%, P < 0.05).Adherence to OCP timeframes for patients undergoing neoadjuvant therapy in a regional centre was feasible and strategies are needed to bridge gaps identified for rural patients. [ABSTRACT FROM AUTHOR]

Introduction: Neoadjuvant therapy has become standard of care for locally advanced rectal cancer patients. It is correlated with improved clinical and pathological outcomes, including significant tumor downstaging and organ preservation in certain patients. Magnetic resonance imaging (MRI), which has become the standard for pre-operative staging, is also used for clinical and pre-operative restaging following pre-operative treatment. In this meta-analysis, we aimed to evaluate the concordance between restaging MRI (following the completion of neoadjuvant therapy) and postoperative pathology result. Methods: We conducted a meta-analysis following the PRISMA 2020 guidelines. Two independent reviewers searched PubMed and Google Scholar for studies reporting restaging MRI results compared to pathological outcomes. Outcomes included tumor and nodal staging, circumferential resection margin (CRM) and pathological complete response (pCR). Results: Out of 25,000 studies found on the initial search; 33 studies were included. The studies were published between 2005 and 2023 and included 4100 patients (57.14% males). The median age was 62.45 years. The median interval between the conclusion of neoadjuvant treatment and the subsequent restaging MRI was 6 weeks (range 4.14–8.8 weeks). The pooled concordance rates between the restaging MRI and the pathological outcomes for ypT stage and ypN stage were 63.9% (54.5%–73.3%, I2 = 96.02%) and 60.9% (42.9%–78.9%, I2 = 98.96%), respectively. The pooled concordance for predicting pathological complete response was 70.4% (53.6%–87.1%, I2 = 98.21%). As for the circumferential resection margin (CRM), the pooled concordance was 78.2.% (71.6%–84.8%, I2 = 83.76%). Conclusions: Our findings suggest that the concordance rates between restaging MRI and pathological outcomes in rectal cancer patients following neoadjuvant therapy are limited. Caregivers should take these results into consideration when making clinical decisions about these patients. More data should be gathered about the predictive value of MRI after total neoadjuvant therapy as well as immunotherapy in rectal cancer patients. [ABSTRACT FROM AUTHOR]

Large cell neuroendocrine carcinoma (LCNEC) is a rare and enigmatic tumor, characterized by neuroendocrine features and a poor prognosis similar to small cell lung cancer (SCLC). The present report details the case of a 45-year-old male with oligometastatic stage IV LCNEC who achieved clinical cure after undergoing perioperative immunochemotherapy. Despite the typical non-recommendation of surgery for stage IV cases, based on the insistence of the patient, the present study initiated three cycles of neoadjuvant therapy combining serplulimab (a programmed cell death protein 1 inhibitor) with chemotherapy, resulting in the radiological disappearance of the tumor. Pathological complete response was confirmed following resection of the primary tumor. The treatment continued with three cycles of adjuvant therapy using serplulimab and chemotherapy, followed by maintenance therapy with serplulimab alone. After 17 cycles of maintenance therapy, a positron emission tomography-computed tomography scan revealed a complete metabolic response of the metastasis, and radiological scans revealed no visible tumor or distant metastasis, indicating a clinical cure. Event-free survival has exceeded 11 months, and overall survival has exceeded 14 months. The present case highlights the efficacy of immunochemotherapy in treating advanced LCNEC. [ABSTRACT FROM AUTHOR]

Objective: To analyze the impact of centralization on key metrics, outcomes, and patterns of care at the Irish National Center. Background: Overall survival rates for esophageal cancer in the West have doubled in the last 25 years. An international trend towards centralization may be relevant; however, this model remains controversial, with Ireland centralizing esophageal cancer surgery in 2011. Methods: All patients (n=1245) with adenocarcinoma of the esophagus or junction treated with curative intent involving surgery, including endoscopic surgery, were included (n=461 from 2000 2011, and 784 from 2012 to 2022). All data entry was prospectively recorded. Overall survival was measured (1) for the entire cohort, (2) for patients with locally advanced disease (cT2-3N0-3), and (3) for patients undergoing neoadjuvant therapy. All complications were recorded as per Esophageal Complication Consensus Group definitions, and the Clavien-Dindo severity classification. Data were analyzed using GraphPad Prism (v.6.0) for Windows and SPSS (v.23.0) software (SPSS) R Studio (R version 4.2.2). Survival times were calculated using a log-rank test and Cox regression analysis, and Kaplan-Meier curves were generated. Results: Endotherapy for cT1a/intramucosal cancer adenocarcinoma increased from 40 (9% total) to 245 (31% total) procedures between the pre-centralization and post-centralization (post-C) periods. significantly (P < 0.001) higher proportion of patients with cT2-3N0- disease in the post-C period underwent neoadjuvant therapy (66% 53%). Operative mortality was lower (P=0.02) post-C, at 2% versus 4.5%, and ZIIIa Clavien-Dindo major complications decreased from 33% to 25% (P < 0.01). Recurrence rates were lower post- (38% vs 53%, P < 0.01). Median overall survival was 73.83 versus 47.23 months in the 2012 to 2022 and 2000 to 2011 cohorts, respectively (P < 0.001). For those who received neoadjuvant therapy, the median survival was 28.5 months pre-centralization and 42.5 months post-C (P < 0.001). Conclusions: These data highlight improvements in both operative outcomes and survival from the time of centralization, and a major expansion of endoscopic surgery. Although not providing proof, the study suggests a positive impact of formal centralization with governance on key quality metrics and an evolution in patterns of care. [ABSTRACT FROM AUTHOR]

Background: Neoadjuvant targeted therapy has shown that improve pathologic complete response and facilitate breast-conserving surgery, but the difference between single-agent treatment or dual-HER2 blockade to the conversion of breast-conserving surgery has not been well described. Methods: Via the systematic literature search of PubMed, Web of Science and Cochrane Library databases, 5 eligible studies used to perform this meta-analysis, which was carried out using RevMan version 5.4. Results: A total of 1306 patients from five randomized controlled trials were included in the analysis, revealing a significant increase in the conversion rate to breast-conserving surgery with neoadjuvant targeted therapy (OR 0.30, 95% CI 0.15–0.57; p = 0.0003). The odds ratio (OR) for single-agent treatment compared to dual-HER2 blockade was 1.04 (95% CI 0.73–1.48; p = 0.82). For pathological complete response (pCR), the OR for single-HER2 blockade versus dual-HER2 blockade was 0.43 (95% CI 0.34–0.55; p = 0.01), and for clinical response, it was 0.81 (95% CI 0.59–1.10; p = 0.17). The OR for serious adverse events between single-HER2 and dual-HER2 blockade was 0.72 (95% CI 0.55–0.95; p = 0.02). The risk ratio (RR) for pCR and the shift from mastectomy to BCS was 1.16 (95% CI 0.78–1.72; p = 0.47), while for clinical response and the shift from mastectomy to BCS, it was 2.40 (95% CI 1.44–4.01; p = 0.0008). Conclusion: Neoadjuvant targeted treatment obviously promote the actual implementation rate of breast-conserving surgery, nevertheless, there was no statistically significant increase in single-agent treatment versus dual-HER2 blockade. [ABSTRACT FROM AUTHOR]

Background: Neoadjuvant–adjuvant therapy for locally advanced or potentially resectable metastatic melanoma was expected to improve operability and clinical outcomes over upfront surgery and adjuvant treatment only. Methods: Forty‐seven consecutive patients were treated with neoadjuvant–adjuvant BRAF inhibitors (BRAFi)/MEK inhibitors (MEKi) and surgery. Results: Twelve (26%) patients achieved a pathological complete response and 10 (21%) patients achieved a near‐complete response. In the whole group, median recurrence‐free survival was 19.4 months and median distant metastasis‐free survival (mDMFS) was 21.9 months. In patients with a pathological complete response (pCR)/near‐pCR median recurrence‐free survival (RFS) and distant metastasis‐free survival (DMFS) were significantly longer than in patients with minor pathological response with hazard ratio (HR) = 0.37 (p =.005) for RFS and HR = 0.33 (p =.002) for DMFS. After median follow‐up of 52.5 months, median progression‐free survival since BRAFi/MEKi therapy initiation was 25.1 months. The median time‐to‐treatment‐failure since initiation of neoadjuvant therapy was 22.2 months and was significantly longer in patients with pCR/near‐pCR (HR = 0.45; p =.022). Neoadjuvant therapy did not result in any new specific complications of surgery. After 48 months, RFS and overall survival were 36.3% and 64.8% or 20% and 37.4% in patients with pCR/near‐pCR and pathological partial response/pathological nonresponse, respectively. Conclusions: The authors confirmed that BRAFi/MEKi combination is an effective and safe regimen in the perioperative treatment of stage III/IV melanoma. Major pathological response to neoadjuvant treatment is a surrogate marker of recurrence including DMFS in these patients. Plain Language Summary: Our study presents a large comprehensive analysis of neoadjuvant‐adjuvant systemic therapy in patients diagnosed with marginally resectable stage III or IV melanoma.Neoadjuvant therapy effectively reduced the volume of the disease, which facilitated subsequent surgical resection.After median follow‐up of 52.5 months, median progression‐free survival since therapy initiation was 25.1 months. Twelve patients had complete pathological response and 10 patients had a near‐complete pathological response—and together they had median recurrence‐free survival and distant metastasis‐free survival significantly longer than in patients with pathological partial response or nonresponse.Complete/near‐complete pathological response to neoadjuvant treatment is a surrogate marker of recurrence‐free, including distant metastasis‐free, survival in these patients. The results of this real‐world study indicated that BRAF/MEK‐targeted therapy is effective in neoadjuvant treatment of patients with marginally resectable stage III or IV melanoma, facilitating surgical resection. The level of pathological response to the neoadjuvant treatment is a prognostic factor for disease recurrence (as well for overall survival), and relapses were most often seen in the central nervous system. [ABSTRACT FROM AUTHOR]

Background: The utility of sentinel lymph node biopsy (SLNB) in older patients remains controversial. Advancements in human epidermal growth factor receptor 2 (HER2)-directed therapy have revolutionized disease response rates and prognosis, supporting efforts to re-evaluate the utility of SLNB. We aimed to assess the differences in treatment and overall survival (OS) in older patients with HER2-positive breast cancer based on SLNB. Methods: Using the National Cancer Database (2010–2020), patients ≥ 70 years of age diagnosed with cT1-2/cN0/M0, HER2-positive breast cancer were identified. Logistic regression assessed associations with SLNB, systemic therapy, and radiation. Cox proportional hazard models were used to identify factors associated with OS. Analyses were stratified by treatment sequence, i.e. upfront surgery or neoadjuvant therapy (NAT) followed by surgery. Results: Of the 17,609 patients included, 94% underwent upfront surgery (n = 16,492) and the remaining underwent NAT (n = 1117). Those who underwent SLNB were more likely to receive adjuvant therapy, irrespective of nodal status {upfront surgery/systemic therapy (odds ratio [OR] 2.82, 95% confidence interval [CI] 2.17–3.67); upfront surgery/radiation (OR 3.97, 95% CI 3.03–5.21); NAT/radiation (OR 5.69, 95% CI 1.83–17.69)}. The breast pathologic complete response (pCR) rate was highest among the hormone receptor (HR)-negative/HER2-positive subtype (50.0%), of which none were found to be ypN+. Comorbidity burden was associated with significantly lower rates of adjuvant systemic therapy and worse OS. Conclusions: Patients who underwent SLNB, regardless of pN status, were more likely to receive adjuvant therapy. Nodal positivity is exceedingly rare for patients with a breast pCR following NAT, especially among the HR-negative/HER2-positive subtype. It is reasonable to consider omission of SLNB in select subgroups of older patients with HER2-positive breast cancer. [ABSTRACT FROM AUTHOR]

Background: In response to the COVID-19 pandemic, the Pandemic Breast Cancer Consortium (PBCC) published recommendations for triage of breast cancer patients. The recommendations included neoadjuvant treatment of early-stage breast cancer patients experiencing delays in surgery. This study evaluated national patterns of neoadjuvant treatment according to triage guidelines. Methods: Patients treated with surgery (upfront or post-neoadjuvant) in 2018–2020 were collected from the National Cancer Database. The proportions of patients treated according to the PBCC triage guidelines were calculated in 2020 and compared with similar cohorts in 2018–2019. Patient and hospital factors were evaluated for association with treatment. Results: Among cT1N0 ER+/PR+/HER2– patients, those treated in 2020 were more likely to receive neoadjuvant endocrine therapy (NET) compared with those before that time (odds ratio [OR], 3.08; range, 2.93–3.24). Among the patients with cT2N0 or cT1N1 disease, NET was more common in 2020 (OR, 1.76; range, 1.65–1.88). Academic facility, black or Asian race, more comorbidities, and the New England/Middle Atlantic region were associated with NET use. Conclusions: During the COVID-19 pandemic, expanded utilization of neoadjuvant therapy for surgical breast cancer patients was observed. Health care system limitations during the pandemic contributed to expanded adoption of neoadjuvant therapy for early breast cancer, contrary to usual practice. Long-term outcomes for patients treated according to PBCC recommendations should be closely monitored. [ABSTRACT FROM AUTHOR]

OBJECTIVES The goal was to explore clinical factors and build a predictive model for the disease-free and overall survival of patients with non-small cell lung cancer (NSCLC) receiving neoadjuvant chemotherapy combined with immune checkpoint inhibitors. METHODS Inclusion criteria for patients in this multicentre study were as follows: (i) Patients who were diagnosed with stages I–III NSCLC after a bronchoscopy biopsy or puncture; (ii) patients who were examined with computed tomography/positron emission tomography-computed tomography before treatment and surgery; (iii) patients who received neoadjuvant chemotherapy combined with immune checkpoint inhibitors for 2 to 6 cycles preoperatively; (iv) patients whose peripheral blood indicators and tumour markers were assessed before treatment and preoperatively; (v) patients who underwent radical lung cancer surgery after neoadjuvant therapy. Cases were divided into high- and low-risk groups according to 78 clinical indicators based on a 10-fold Least Absolute Shrinkage and Selection Operator selection. We used Cox proportional hazards models to predict disease-free and overall survival. Then, we used time-dependent area under the curve and decision curve analyses to examine the accuracy of the results. RESULTS Data were collected continuously, and 212 and 85 cases were randomly assigned to training and testing sets, respectively. The area under the curve for the prediction of disease-free survival (training: 1 year, 0.83; 2 years, 0.81; 3 years, 0.83 versus testing: 1 year, 0.65; 2 years, 0.66; 3 years, 0.70), overall survival (training: 1 year, 0.86; 2 years, 0.85; 3 years, 0.86 versus testing: 1 year, 0.66; 2 years, 0.57; 3 years, 0.70) were determined. The coefficient factors including pathological response; preoperative tumour maximum diameter; preoperative lymph shorter diameter; preoperative tumour and lymph maximum standardized uptake value; change in tumour standardized uptake value preoperatively; and blood-related risk factors were favourably associated with prognosis (P  < 0.001). CONCLUSIONS Our prediction model, which integrated data from preoperative positron emission tomography-CT, preoperative blood parameters and pathological response, was able to make highly accurate predictions for disease-free and overall survival in patients with NSCLC receiving neoadjuvant immunity with chemical therapy. [ABSTRACT FROM AUTHOR]

OBJECTIVES Elderly-specific data for multimodal treatment of oesophageal cancer (EC) is lacking. This study aimed to evaluate the safety and efficacy of multimodal treatment in older EC patients and to compare the impact of neoadjuvant chemotherapy (NCT) and neoadjuvant chemoradiotherapy (NCRT). METHODS Patients diagnosed with oesophageal squamous cell carcinoma or adenocarcinoma who received NCT/NCRT were identified in the National Cancer Database (NCDB, 2004–2015). First, we compared baseline and post-treatment characteristics between younger (<70 years) and older patients (≥70 years). Logistic regression was used to investigate risk factors of postoperative mortality. Second, we evaluated the effect of neoadjuvant chemotherapy on postoperative mortality and overall survival in the older cohort. Inverse probability of treatment weights and multivariable analyses were used to compensate for differences in baseline covariates. RESULTS We 1st compared outcomes of neoadjuvant therapy plus oesophagectomy in 14 778 eligible EC patients. The older group experienced higher rates of postoperative mortality at 30 days (5.8%) and 90 days (13.5%) compared to younger patients. Postoperative mortality was significantly related to the Charlson–Deyo score and treatment-related factors including neoadjuvant therapy type and minimally invasive technique. Second, among the 3141 older patients (with a median follow-up of 57.8 months and 2029 deaths), those receiving NCT obtained significantly lower postoperative mortality and improved overall survival compared with NCRT (inverse probability of treatment weights-adjusted P  = 0.05; hazard ratio 0.85; 95% Cl 0.72–0.99). CONCLUSIONS Neoadjuvant therapy plus oesophagectomy carries increased short-term mortality risk in older EC patients. NCT in older EC patients showed lower postoperative mortality but no statistically significant differences in overall survival, with a point estimate favouring NCT compared to the NCRT group, making NCT a potential option for consideration in specific cases. [ABSTRACT FROM AUTHOR]

The utility of neoadjuvant chemotherapy is expanding in the treatment of breast cancer. Although individual trials have shown comparable survival between patients receiving neoadjuvant and adjuvant chemotherapy, large-scale data analyses for outcomes in patients with locally advanced breast cancer (LABC) are lacking. We conducted an individual-level statistical analysis using patients from six randomized controlled trials (RCTs) investigating survival outcomes with neoadjuvant versus adjuvant chemotherapy in breast cancer by abstracting and analyzing only the patients with LABC. Individual patient data for 779 patients with LABC were collected from six RCTs. Overall and disease-free survival rates were compared between patients receiving neoadjuvant vs. adjuvant chemotherapy with the Cox hazard model and log-rank statistics. Since chemotoxicity causing delays to surgical care is a potential drawback of neoadjuvant chemotherapy, local cohort data were then employed to assess the actual incidence of this, along with the causes behind any delays to surgery in patients receiving neoadjuvant chemotherapy. A time interval from neoadjuvant chemotherapy to surgery of >8 weeks was investigated in a local cohort of 563 patients, representing all locally treated patients receiving neoadjuvant chemotherapy between 2006 and 2019. The statistical analysis demonstrated no overall or disease-free survival differences in LABC patients receiving neoadjuvant vs. adjuvant chemotherapy (p = 0.96 and 0.74, respectively). Within our cohort, 31 (5.5%) patients treated with neoadjuvant chemotherapy experienced a delay of >8 weeks to surgery, with only 13 (2.3%) attributed to chemotherapy-related complications. Our study provides further support for the paradigm shift towards delivering chemotherapy for breast cancer patients in the neoadjuvant setting. [ABSTRACT FROM AUTHOR]

Simple Summary: A review of the latest research at PubMed and major cancer conferences was conducted to find out the current treatments for advanced stomach and esophagogastric junction cancers. In the West, neoadjuvant and perioperative chemotherapy is preferred for localized tumors. In East Asia, adjuvant chemotherapy is preferred. Studies are looking at how well immunotherapy and other drugs work in the perioperative setting. To choose the best treatment for advanced gastric cancer, including adenocarcinoma of the esophago-gastric junction, it is important to know biomarkers like HER2 expression, PD-L1 combined positive score (CPS), Claudin 18.2, and microsatellite instability (MSI). The standard first-line therapy is a combination of fluoropyrimidine and a platinum derivative. The choice of chemotherapy with antibodies depends on the biomarker. This article reviews recent clinical trial results and looks at the future of systemic therapy. Background: The prognosis of patients diagnosed with locally advanced and metastatic gastric and esophago-gastric junction cancer is critical. The optimal choice of systemic therapy is essential to optimize survival outcomes. Methods: A comprehensive literature review via PubMed and analysis of major oncology congresses (European Society for Medical Oncology and American Society of Clinical Oncology websites) were conducted to ascertain the current status and latest developments in the systemic treatment of patients with localized or advanced gastric and esophago-gastric junction adenocarcinoma. Results: While neoadjuvant and perioperative chemotherapy for localized tumor stages is the preferred approach in the Western Hemisphere, adjuvant chemotherapy remains the preferred course of action in East Asia. The administration of chemotherapy, typically in the form of combinations comprising platinum and fluoropyrimidine compounds in combination with docetaxel, represents a standard of care. Investigations are underway into the potential of immunotherapy and other biologically targeted agents in the perioperative setting. To select the most appropriate therapy for advanced gastric cancer, including adenocarcinoma of the esophago-gastric junction, it is essential to determine biomarkers such as HER2 expression, PD-L1 combined positive score (CPS) (combined positive score), Claudin 18.2, and microsatellite instability (MSI). In the present clinical context, the standard first-line therapy is a combination of fluoropyrimidine and a platinum derivative. The selection of chemotherapy in combination with antibodies is contingent upon the specific biomarker under consideration. Conclusions: This article reviews the current state of the art based on recent clinical trial results and provides an outlook on the future of systemic therapy. [ABSTRACT FROM AUTHOR]

The standard of care for the treatment of locally advanced rectal cancer (LARC) results in an excellent local disease control but the metastasis rates remain high. PRODIGE 23 demonstrated improved disease-free survival (DFS) and metastasis-free survival (MFS) with total neoadjuvant therapy versus standard of care in this population. Long-term analysis of overall survival (OS) is reported here. The study design, participants, and primary endpoint DFS have been reported for this multicenter, randomized, open-label, phase III trial investigating the neoadjuvant chemotherapy with mFOLFIRINOX (6 cycles) followed by chemoradiotherapy, surgery, and adjuvant chemotherapy (6 cycles), versus chemoradiotherapy, surgery, and adjuvant chemotherapy (12 cycles) in patients with locally advanced rectal adenocarcinoma under peritoneal reflection on magnetic resonance imaging, and staged cT3/T4. Key secondary endpoints included OS, MFS, and local and metastatic recurrence rate. With a median follow-up of 82.2 months, the 7-year DFS was 67.6% [95% confidence interval (CI) 60.7% to 73.9%] and 62.5% (95% CI 55.6% to 68.6%) [restricted mean survival time (RMST) difference 5.73 months, 95% CI 0.05-11.41 months, P = 0.048] in the neoadjuvant chemotherapy and the standard-of-care groups, respectively. The 7-year MFS was 79.2% (95% CI 73.0% to 84.4%) in the neoadjuvant chemotherapy group and 72.3% (95% CI 65.8% to 77.8%) in the standard-of-care group (RMST difference 6.1 months, 95% CI 0.93-11.37 months, P = 0.021). The 7-year OS was 81.9% (95% CI 75.8% to 86.6%) in the neoadjuvant chemotherapy group and 76.1% (95% CI 69.7% to 81.2%) in the standard-of-care group (RMST difference 4.37 months, 95% CI 0.35-8.38 months, P = 0.033). The safety profile remained unchanged since the previous analysis. Neoadjuvant chemotherapy with mFOLFIRINOX followed by chemoradiotherapy improved OS, confirmed long-term DFS and MFS benefits in LARC patients, and should be considered as one of the best options of care for these patients. • With standard-of-care trimodality therapy for LARC, the 5-year metastasis rate is 25%-35%. • PRODIGE 23 investigated mFOLFIRINOX induction chemotherapy before standard of care, versus standard of care for LARC. • With 7 years of follow-up, induction chemotherapy significantly improved MFS. • DFS and OS were also significantly improved using mFOLFIRINOX induction chemotherapy. [ABSTRACT FROM AUTHOR]

Immunotherapy has revolutionised the treatment of advanced hepatocellular carcinoma (HCC). In addition, several phase III trials of immunotherapy in combination with surgical or locoregional therapies for early-to intermediate-stage HCC have recently reported positive results, and other phase III trials in the same patient population are currently in progress. As the application of immunotherapy is shifting to include patients with earlier stages of HCC, one looming question now emerges: What is the role of immunotherapy in the pre-liver transplant population? Liver transplantation is a potentially curative therapy for HCC and confers the additional advantage of restoring a normal, healthy liver. In pre-transplant patients, immunotherapy may improve downstaging success and tumour control at the cost of some immunologic risks. These include immune-related toxicities, which are particularly relevant in a uniquely vulnerable population with chronic liver disease, and the possibility of acute rejection after transplantation. Ultimately, the goal of immunotherapy in this population will be to effectively expand access to liver transplantation while preserving pre- and post-transplant outcomes. In this review, we discuss the mechanisms supporting combination immunotherapy, summarise key recent clinical data from major immunotherapy trials, and explore how immunotherapy can be applied in the neoadjuvant setting prior to liver transplantation in selected high-risk patients. [ABSTRACT FROM AUTHOR]

Background and aim: Docetaxel, oxaliplatin, leucovorin and 5-fluorouracil (FLOT) may improve overall survival (OS) in patients with locally advanced gastric and gastroesophageal cancer. Our study aims to determine the pathological response in these patients with the FLOT chemotherapy in the Neoadjuvant setting. This is the first study conducted in our country. Methods: We conducted a retrospective cross-sectional study from March 2018 to December 2020. After ethical review committee approval, all patients who fulfilled the inclusion criteria and received treatment at our tertiary care center were included in the study. SPSS version 22 was used for data analysis. Frequencies and percentages were calculated for categorical. Values were presented as mean ± standard deviation (SD) for continuous variables. The chi-square test was used to determine the difference between categorical variables. A p-value of ≤0.05 was considered the level of significance. Kaplan- Meier curves were used to calculate survival analysis. Results: Out of 41, 35 patients with locally advanced resectable gastric or gastroesophageal adenocarcinoma were included in our study analysis. The entire cohort had a male predominance, with a mean age of 59. All patients received neoadjuvant FLOT. Pathological treatment response achieved was 77%, of which 66% had partial and 11% had complete response. There is a significant association of pathological response with age, gender, stage, grade, co-morbid and number of chemotherapy cycles received (p-value =<0.05). The OS was 80% with the mean OS was 2.6 years (31 months). Conclusion: Our study shows comparable response rates to other studies conducted internationally. Our findings confirm that FLOT is an effective and well-tolerated perioperative regimen with reasonable response rates in the Pakistani population. A more extensive longitudinal study would ensure these preliminary results in the local patient population. [ABSTRACT FROM AUTHOR]

Checkpoint inhibitors (ICIs) have demonstrated substantial efficacy in the treatment of numerous solid tumors, including head and neck cancer. Their inclusion in the therapeutic paradigm in metastatic lines of treatment has certainly improved the outcomes of these patients. Starting from this assumption, numerous studies have been conducted on ICIs in other earlier disease settings, including studies conducted in patients in neoadjuvant settings. However, how many and which studies are truly significant? Can they lay concrete foundations for further future studies and therefore allow us to continue to have this interesting future perspective? Through a review of the existing literature, coupled with insights gleaned from clinical practice and from the main recently published studies, we aim to examine the therapeutic potential of ICIs in patients affected by head and neck cancer in a neoadjuvant treatment setting and encourage researchers to set up successful future clinical trials. [ABSTRACT FROM AUTHOR]

Background: Neoadjuvant treatment (NAT) is standard for borderline resectable pancreatic cancer (BRPC). However, consensus is lacking on the optimal surgical timing for patients with BRPC undergoing NAT. The aim of this study was to investigate the long‐term outcomes of patients undergoing NAT for BRPC and suggest optimal resection timing. Methods: Prospectively collected data for 282 patients with BRPC between January 2007 and December 2019 were retrospectively reviewed. There were 164 patients who underwent NAT followed by surgery, 45 for chemotherapy only, and 73 for upfront surgery. Among them, 150 patients who underwent R0 or R1 resection following NAT were investigated to identify prognostic factors. Results: Patients receiving NAT followed by surgery showed the best survival (median overall survival [OS]; NAT followed by surgery vs. upfront surgery vs. chemotherapy only; 35 vs. 23 vs. 16 months). In the NAT group, 54 (36.0%) patients received less than 3 months of NAT, 68 (45.3%) received ≥3, <6 months, and 28 (18.7%) received longer than 6 months. Patients receiving ≥3 months of NAT showed an improved OS compared to <3 months (median; not reached vs. 27 months). In the FOLFIRINOX group, patients who received more than eight FOLFIRINOX cycles showed a good prognosis (<6 vs. 6–7 vs. ≥8 cycles; median survival, 26 vs. 41 months vs. not‐reached). However, >12 cycles did not carry a survival benefit compared to 8–11 cycles. Conclusion: The optimal resection timing following NAT is once a patient undergoes at least 3 months of neoadjuvant chemotherapy or at least eight FOLFIRINOX cycles. [ABSTRACT FROM AUTHOR]

Background: Preoperative chemotherapy with 5-fluorouracil and cisplatin (FP) followed by surgery has been considered a standard treatment for patients with stage II/III esophageal squamous cell carcinoma (ESCC) based on the results of a phase III trial (JCOG9907) in Japan. Subsequently, the phase III NExT trial (JCOG1109) revealed the survival benefit of the neoadjuvant DCF regimen, which adds docetaxel to FP, and it became a standard treatment. However, the long-term results and prognostic factors of neoadjuvant DCF therapy in the real world are unknown. Methods: We retrospectively investigated 50 patients with ESCC treated with neoadjuvant DCF therapy from July 2012 to December 2017 at The University of Tokyo Hospital. Results: Median overall survival (OS) and progression-free survival (PFS) were 32.3 [95% confidence interval (CI) 21.0–NA] and 10.0 months (95% CI 6.3–15.6), respectively. Median OS [not reached (95% CI 31.5–NA) vs. 21.4 months (95% CI 13.5–33.0); p = 0.028] and PFS [83.3 months (95% CI 6.4–NA) vs. 7.4 months (95% CI 6.0–12.8] were significantly longer in patients with an objective response than in non-responders. Of 44 surgical cases, median PFS tended to be longer in pathological lymph node metastasis-negative patients. Conversely, survival did not differ according to cStage (II/III vs. IV) or the average relative dose intensity (ARDI, ≥ 85% vs. < 85%). Discussion: The response to neoadjuvant DCF therapy could predict patient prognosis. Additionally, pN+ tended to increase the recurrence risk, whereas cStage and ARDI did not influence survival. [ABSTRACT FROM AUTHOR]

Mesenchymal–epithelial transition (MET) exon 14 (METex14) skipping mutation is a rare (3%–4%) driver mutation in non‐small cell lung cancer (NSCLC). Tepotinib, a selective MET inhibitor, has shown promise in treating METex14 skipping‐mutated NSCLC. However, its feasibility for perioperative application remains unclear. This report describes a 60‐year‐old man with stage IIIA (cT2N2M0) lung adenocarcinoma harboring a METex14 skipping mutation. After initial treatment with savolitinib was discontinued due to grade 4 transaminitis, the patient was switched to tepotinib, resulting in significant tumor regression. Six months later, further shrinkage was observed, and surgery revealed remarkable pathological response with no residual tumor in lymph nodes (ypT2N0M0, IB). Postoperative tepotinib continued, with no relapse at 6‐month follow‐up. This case highlights the potential of tepotinib as neoadjuvant therapy for resectable METex14 skipping‐mutated NSCLC, warranting further clinical trials. [ABSTRACT FROM AUTHOR]

Background: We aimed to evaluate outcomes of organ preservation by local excision (LE) compared to proctectomy following neoadjuvant therapy for rectal cancer. Methods: This retrospective observational study using the National Cancer Database (NCDB) included patients with locally advanced non-metastatic rectal cancer (ypT0–1 tumors) treated with neoadjuvant therapy between 2004 and 2019. Outcomes of patients who underwent LE or proctectomy were compared. 1:1 propensity score matching including patient demographics, clinical and therapeutic factors was used to minimize selection bias. Main outcome was overall survival (OS). Results: 11,256 of 318,548 patients were included, 526 (4.6%) of whom underwent LE. After matching, mean 5-year OS was similar between the groups (54.1 vs. 54.2 months; p = 0.881). Positive resection margins (1.2% vs. 0.6%; p = 0.45), pathologic T stage (p = 0.07), 30-day mortality (0.6% vs. 0.6%; p = 1), and 90-day mortality (1.5% vs. 1.2%; p = 0.75) were comparable between the groups. Length of stay (1 vs. 6 days; p < 0.001) and 30-day readmission rate (5.3% vs. 10.3%; p = 0.02) were lower in LE patients. Multivariate analysis of predictors of OS demonstrated male sex (HR 1.38, 95% CI 1.08–1.77; p = 0.009), higher Charlson score (HR 1.52, 95% CI 1.29–1.79; p < 0.001), poorly differentiated carcinoma (HR 1.61, 95% CI 1.08–2.39; p = 0.02), mucinous carcinoma (HR 3.53, 95% CI 1.72–7.24; p < 0.001), and pathological T1 (HR 1.45, 95% CI 1.14–1.84; p = 0.002) were independent predictors of increased mortality. LE did not correlate with worse OS (HR 0.91, 95% CI 0.42–1.97; p = 0.82). Conclusion: Our findings show no overall significant survival difference between LE and total mesorectal excision, including ypT1 tumors. Moreover, patients with poorly differentiated or mucinous adenocarcinomas generally had poorer outcomes, regardless of surgical method. [ABSTRACT FROM AUTHOR]

Simple Summary: Neoadjuvant therapy, used before surgery, is an important part of breast cancer treatment. Not only can it shrink tumors, but it can also provide valuable information on how the cancer responds to treatment, which can help physicians tailor further therapy. For aggressive types of breast cancer, such as HER2-positive and triple-negative breast cancers, targeted therapies and immunotherapy are often added to standard chemotherapy. Achieving a complete response to treatment (i.e., total absence of viable tumor from tissue removed during surgery) is usually a good sign, but it does not always mean better long-term outcomes for every patient. This review examines the evolution of neoadjuvant therapy in high-risk breast cancer and discusses recent clinical trials focused on optimizing treatment. It also highlights the need for new approaches to improve outcomes, especially for patients whose cancer does not fully respond to initial treatments. The use of neoadjuvant systemic therapy (NST) has become increasingly important in the treatment of breast cancer because of its various advantages. These include the ability to downstage tumors without compromising locoregional control and the potential to obtain valuable information about clinical and biological response to therapy with implications for individual prognoses. Surgical response assessment paves the way for response-adapted therapy, and pathological complete response (pCR; defined as ypT0/is ypN0) serves as an additional endpoint for drug development trials. Recommended NST regimens commonly consist of anthracyclines and taxane, with dose-dense anthracyclines and weekly paclitaxel often preferred, whenever feasible. For patients with human epidermal growth factor receptor-2 (HER2)-positive tumors, dual anti-HER2 therapy (trastuzumab and pertuzumab) is indicated together with NST in case of elevated risk of recurrence. For patients with triple-negative breast cancer (TNBC), adding carboplatin to NST correlates with improved pCR and survival rates, as does the addition of immune checkpoint inhibitors. For hormone receptor (HR)-positive/HER2-negative cancers, emerging data on NST including immune checkpoint inhibitors may elevate the significance of NST in high-risk luminal breast cancer. Here, we present a synthesis of the results from neoadjuvant clinical trials that aim at optimizing treatment options for patients with high-risk breast cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: The primary treatment for operable pancreatic cancer involves surgery followed by adjuvant therapy, with an increasing use of perioperative or neoadjuvant chemotherapy. We performed a network meta-analysis to assess the comparative efficacy of various treatment approaches for resectable pancreatic cancer. A total of 24 studies were incorporated, comparing 21 treatments with surgery in isolation. Eleven treatments showed superior efficacy compared to surgery alone. Excluding Asian studies, the perioperative regimen of gemcitabine combined with nab-paclitaxel was the most effective regimen. The findings endorse the utilization of perioperative and multi-agent chemotherapy as the favored intervention for operable PC in Western nations. The primary treatment for operable pancreatic cancer (PC) involves surgery followed by adjuvant therapy. Nevertheless, perioperative or neoadjuvant chemotherapy (CT) may be used to mitigate the likelihood of recurrence and mortality. This network meta-analysis (NMA) assesses the comparative efficacy of various treatment approaches for resectable PC. A thorough search was carried out on January 31, 2023, encompassing PubMed/MEDLINE, Cochrane Library, and Embase databases. We incorporated randomized clinical trials (RCTs) that compared surgical interventions with or without (neo)adjuvant or perioperative therapies for operable PC. We conducted a fixed-effects Bayesian NMA. We presented the effect sizes in terms of hazard ratios (HRs) for overall survival (OS) along with 95% credible intervals (95% CrIs). The treatment was deemed statistically superior when the 95% credible interval (CrI) did not encompass a null value (hazard ratio < 1). Treatment rankings were established based on the surface under the cumulative ranking curve (SUCRA). A total of 24 studies were incorporated, comparing 21 treatments with surgery in isolation. Eleven treatments showed superior efficacy compared to surgery alone, with HRs ranging from 0.38 for perioperative treatments to 0.73 for adjuvant 5-fluorouracil. After the exclusion of studies conducted in Asia, it was found that the perioperative regimen of gemcitabine combined with nab-paclitaxel was the most effective regimen (SUCRA, p = 0.99). The findings endorse the utilization of perioperative CT, especially multi-agent CT, as the favored intervention for operable PC in Western nations. [ABSTRACT FROM AUTHOR]

Simple Summary: Approximately 40% of all diagnoses of rectal cancer in Spain are locally advanced. A multimodal treatment is needed, and one of its pillars is radiotherapy, with a classic dose scheme of up to 50–50.4 Gy concomitantly with oral capecitabine or 5-fluorouracil. Dose escalation is being explored to achieve higher rates of a pathological complete response, but the optimal dose and its impact on the outcomes are unclear. Our study aimed to evaluate the percentage of complete pathological responses obtained with an intensified neoadjuvant radiotherapy treatment scheme. We confirmed in a homogeneous population (49 patients treated with standard radiotherapy vs. 50 patients treated with dose-escalated radiotherapy) higher rates of a pathological complete response with a dose of up to 54 Gy concomitantly with oral capecitabine. Neoadjuvant radiotherapy intensification is useful for specimen sterilization and should be offered to selected patients. Locally advanced rectal cancer requires a multimodal treatment. Radiotherapy is being explored for intensification to improve the rates of pathological complete responses (ypCR rates) which are correlated with better outcomes. This study reports a comparison between standard versus escalated doses in a preoperative scenario. The ypCR rates, toxicity, postoperative complications, and disease-free and overall survival at 5 years are described. From 2012 to 2019, 99 patients were analyzed retrospectively: standard arm (mean of 47.5 Gy) vs. dose-escalated arm (mean of 54.3 Gy). All patients were treated with 3DRT in 25 fractions, with concomitant capecitabine and surgery performed according to the total mesorectal excision principles in both arms. The ypCR was reported using the "College of American Pathologist grades"; the gastrointestinal (GI) and genitourinary (GU) toxicity was reported using the "Common Terminology Criteria for Adverse Events" (CTCAE 4.0). The ypCR rates were higher in the dose-escalated group (25% vs. 10.64%; p = 0.07), with a lower rate of non-treatment response (61.36% vs. 38.64%; p = 0.11). No statistical differences between the arms were found in terms of the oncological outcomes, postoperative complications (p = 0.15), second surgeries (p = 0.62), or deaths (p = 0.62). The CTCAE acute GI and GU toxicity were grade I or II in both arms. Our study presents a long-term follow-up in comparative cohorts. [ABSTRACT FROM AUTHOR]

Purpose: PreOperative radiotherapy (RT) is commonly used in the treatment of brain metastasis and different cancer types but has never been used in primary glioblastoma (GBM). Here, we aim to establish, describe, and validate the use of PreOperative RT for the treatment of GBM in a preclinical model. Methods: Rat brains were locally irradiated with 30-Gy, hypofractionated in five doses 2 weeks before or after the resection of intracranial GBM. Kaplan-Meier analysis determined survival. Hematoxylin-eosin staining was performed, and nuclei size and p21 senescence marker were measured in both resected and recurrent rodent tumors. Immunohistochemistry assessed microglia/macrophage markers, and RNAseq analyzed gene expression changes in recurrent tumors. Akoya Multiplex Staining on two human patients from our ongoing Phase I/IIa trial served as proof of principle. Results: PreOperative RT group median survival was significantly higher than PostOperative RT (p < 0.05). Radiation enlarged cytoplasm and nuclei in PreOperative RT resected tumors (p < 0.001) and induced senescence in PostOperative RT recurrent tumors (p < 0.05). Gene Set Enrichment Analysis (GSEA) suggested a more proliferative profile in PreOperative RT group. PreOperative RT showed lower macrophage/microglia recruitment in recurrent tumors (p < 0.01) compared to PostOperative RT. Akoya Multiplex results indicated TGF-ß accumulation in the cytoplasm of TAMs and CD4 + lymphocyte predominance in PostOperative group. Conclusions: This is the first preclinical study showing feasibility and longer overall survival using neoadjuvant radiotherapy before GBM resection in a mammalian model. This suggests strong superiority for new clinical radiation strategies. Further studies and trials are required to confirm our results. [ABSTRACT FROM AUTHOR]

The ever-growing knowledge regarding NSCLC molecular biology has brought innovative therapies into clinical practice; however, the treatment situation in the non-metastatic setting is rapidly evolving. Indeed, immunotherapy-based perioperative treatments are currently considered the standard of care for patients with resectable NSCLC in the absence of EGFR mutations or ALK gene rearrangements. Recently, data have been presented on the use of tyrosine kinase inhibitors (TKIs) in the adjuvant and locally advanced setting for patients with NSCLC harboring such driver gene alterations. The aim of the current work is to review the available evidence on the use of targeted treatments in the non-metastatic setting, together with a summary of the ongoing trials designed for actionable gene alterations other than EGFR and ALK. To date, 3-year adjuvant osimertinib treatment has been demonstrated to improve DFS and OS and to reduce CNS recurrence in resected EGFR-mutated NSCLC in stage IB–IIIA (TNM 7th edition). The use of osimertinib after chemo-radiation in stage III unresectable EGFR-mutated NSCLC showed the relevant PFS improvement. In the ALK-positive setting, 2-year alectinib treatment was shown to clearly improve DFS compared to adjuvant standard chemotherapy in resected NSCLC with stage IB (≥4 cm)–IIIA (TNM 7th edition). Several trials are ongoing to establish the optimal adjuvant TKI treatment duration, as well as neoadjuvant TKI strategies in EGFR- and ALK-positive disease, and (neo)adjuvant targeted treatments in patients with actionable gene alterations other than EGFR or ALK. In conclusion, our review depicts how the current treatment scenario is expected to rapidly change in the context of non-metastatic NSCLC with actionable gene alterations, hence appropriate molecular testing from the early stages has become crucial to establish the most adequate approaches both in the perioperative and the locally advanced disease. [ABSTRACT FROM AUTHOR]

Objectives: To assess the efficacy and safety of preoperative neoadjuvant everolimus in renal angiomyolipomas (AML) patients with or without Tuberous Sclerosis Complex (TSC). Materials and Methods: This multi‐institutional retrospective study enrolled renal AML patients who underwent partial nephrectomy (PN) or total nephrectomy after receiving at least 1 month of pre‐operative everolimus. Imaging evaluations were collected before and after treatment, along with demographic, surgical, and follow‐up information. The primary outcome was tumor volume reduction of ≥25%, with additional outcomes including recurrence, perioperative outcomes, renal function, and safety. Results: From January 2015 to July 2022, 68 renal AML patients were studied—41 with TSC and 27 without. During everolimus treatment, 61.0% (25/41) of TSC patients and 44.4% (12/27) of non‐TSC patients achieved tumor reduction of ≥25%. Additionally, 41.5% (17/41) of TSC patients and 18.5% (5/27) of non‐TSC patients achieved a ≥ 50% reduction. Three TSC patients and 1 non‐TSC patient discontinued treatment due to side‐effects. Most patients (92.7% TSC, 85.2% non‐TSC) underwent PN. After everolimus treatment, the necessary total nephrectomy decreased to 41.2% (7/17) from baseline. Postoperatively, 1 grade 3 and 3 grade 2 complications occurred, with no grade 4 or 5 complications. After a median follow‐up of 24 months, only 1 TSC patient recurred with a diameter >3 cm. Retrospective nature is the major limitation of this study. Conclusion: Everolimus was effective and well‐tolerated in neoadjuvant treatment for renal AML, especially in TSC patients. This neoadjuvant combination strategy of everolimus and PN could effectively controls recurrence and preserves renal function. [ABSTRACT FROM AUTHOR]

Background: The National Comprehensive Cancer Network (NCCN)-recommended treatment for patients with borderline-resectable pancreatic cancer (BRPC) and locally advanced pancreatic cancer (LAPC) involves a combination of neoadjuvant FOLFIRINOX chemotherapy and the curative surgical resection of the tumor. This study seeks to identify the clinical, radiological, laboratory, and pathologic predictors that can anticipate the oncological outcomes of patients. Methods: In this study, we conducted a retrospective analysis of patients who had undergone curative surgical resection for BRPC, LAPC, or resectable disease with high-risk features after receiving neoadjuvant FOLFIRINOX at two institutions. We evaluated by means of multivariate analysis whether clinical and laboratory response, tumor markers, radiological response, and pathologic tumor response grade correlated with overall survival (OS) and disease-free survival (DFS). Results: The study enrolled a total of 70 patients with BRPC, LAPC, and resectable disease with high-risk features who underwent resection after neoadjuvant FOLFIRINOX. Age above 65 years and fewer than nine cycles of chemotherapy (OR 4.2; 95% CI 1.4–12.0; p-value 0.007); locally advanced tumors after neoadjuvant treatment (NAT) (OR 7.0; 95% CI 1.9–25.7; p-value 0.003); and lymph node disease and histological tumor regression grade 2 and 3 (OR 4.3; 95% CI 0.9–19.2; p-value 0.05) were risk factors linked to adverse OS and DFS. The median OS and DFS were 33 (22–43.9) months and 16.5 (11.3–21.6) months, respectively. Conclusions: Classification as a LA tumor after NAT was the only preoperative radiological factor that predicted adverse survival in patients undergoing curative surgery after NAT. Other clinical, biochemical, and radiological measures of response were not found to predict OS. Patient age, the cumulative administration of more than eight cycles of chemotherapy, and a significant pathological response were associated with better OS. The results of this study are important for treatment decision-making and prognostication in patients with BRPC and LAPC. [ABSTRACT FROM AUTHOR]

Objectives: To determine whether 6 months of preoperative apalutamide for intermediate‐risk prostate cancer (IRPCa) reduces the aggregate postoperative radiotherapy risk and to evaluate associations of molecular perturbations with clinical outcomes in this study cohort. Patients and Methods: Between May 2018 and February 2020, eligible patients with IRPCa (Gleason 3 + 4 or 4 + 3 and clinical T2b‐c or prostate‐specific antigen level of 10–20 ng/mL) were treated with apalutamide 240 mg/day for 6 months followed by radical prostatectomy (RP) in this single‐arm, phase II trial. The primary endpoint was presence of any adverse pathological feature at risk of pelvic radiation (pathological T stage after neoadjuvant therapy [yp]T3 or ypN1 or positive surgical margins). Translational studies, including germline and somatic DNA alterations and RNA and protein expression, were performed on post‐apalutamide RP specimens, and assessed for associations with clinical outcomes. Results: A total of 40 patients underwent a RP, and only one patient discontinued apalutamide prior to 6 months. In all, 40% had adverse pathological features at time of RP, and the 3‐year biochemical recurrence (BCR) rate was 15%, with 27.5% being not evaluable. Genomic alterations frequently seen in metastatic PCas, such as androgen receptor (AR), tumour protein p53 (TP53), phosphatase and tensin homologue (PTEN), or BReast CAncer associated gene (BRCA1/2) were underrepresented in this localised cohort. Adverse pathological features and BCR at 3‐years were associated with increased expression of select cell cycle (e.g., E2F targets: adjusted P value [Padj] < 0.001, normalised enrichment score [NES] 2.47) and oxidative phosphorylation (Padj < 0.001, NES 1.62) pathways. Conclusions: Preoperative apalutamide did not reduce the aggregate postoperative radiation risk to the pre‐specified threshold in unselected men with IRPCa. However, transcriptomic analysis identified key dysregulated pathways in tumours associated with adverse pathological outcomes and BCR, which warrant future study. Further investigation of preoperative therapy is underway for men with high‐risk PCa. [ABSTRACT FROM AUTHOR]

Emerging data supporting the rise of perioperative immune checkpoint inhibitors (ICIs) as a standard of care in the treatment of early stage, surgically resectable non‐small cell lung cancer (NSCLC) dominated the NSCLC news in 2023. Adjuvant pembrolizumab became the second adjuvant ICI to receive US Food and Drug Administration approval in early 2023 after the 2021 approval of adjuvant atezolizumab and the 2022 approval of neoadjuvant nivolumab with chemotherapy. Subsequently in 2023, multiple phase 3 trials examining perioperative ICIs were positive and demonstrated clinically meaningful outcomes by prolonging event‐free survival, improving pathologic complete response rates, and trending toward improved overall survival in most. Perioperative pembrolizumab became the first ICI to attain US Food and Drug Administration approval in this setting through the KEYNOTE‐671 trial (ClinicalTrials.gov identifier NCT03425643), which also demonstrated a definitive overall survival benefit in the entire study population. However, questions remain regarding patient selection for either approach and how we can optimize biomarkers to determine who needs adjuvant therapy after surgery. Adjuvant, neoadjuvant, and perioperative (both neoadjuvant and adjuvant) immune checkpoint inhibitors are now a standard of care in the treatment of early stage, surgically resectable non–small cell lung cancer. Questions remain regarding patient selection and personalization of postsurgical treatment approaches. [ABSTRACT FROM AUTHOR]

Purpose of Review: This review provides an update on approved and emerging systemic therapies in the treatment of locally advanced or metastatic non-melanoma skin cancers (squamous cell carcinoma, basal cell carcinoma, Merkel cell carcinoma). Recent Findings: Many studies demonstrate the effectiveness of immunotherapy for all types of non-melanoma skin cancer. For basal cell carcinoma (BCC), hedgehog inhibitors (HHI) remain first-line but with poor tolerability. Numerous clinical trials studying both neoadjuvant and adjuvant use of anti-PD-1 and anti-PD-L1 therapies in advanced NMSC are under investigation. Summary: There is a growing number of systemic therapies available to treat non-melanoma skin cancers. The advent of immunotherapy has revolutionized the field and greatly improved survival compared to historical survival rates with cytotoxic chemotherapy. [ABSTRACT FROM AUTHOR]

Background: Talazoparib monotherapy in patients with germline BRCA-mutated, early-stage triple-negative breast cancer (TNBC) showed activity in the neoadjuvant setting in the phase II NEOTALA study (NCT03499353). These biomarker analyses further assessed the mutational landscape of the patients enrolled in the NEOTALA study. Methods: Baseline tumor tissue from the NEOTALA study was tested retrospectively using FoundationOne®CDx. To further hypothesis-driven correlative analyses, agnostic heat-map visualizations of the FoundationOne®CDx tumor dataset were used to assess overall mutational landscape and identify additional candidate predictive biomarkers of response. Results: All patients enrolled (N = 61) had TNBC. In the biomarker analysis population, 75.0% (39/52) and 25.0% (13/52) of patients exhibited BRCA1 and BRCA2 mutations, respectively. Strong concordance (97.8%) was observed between tumor BRCA and germline BRCA mutations, and 90.5% (38/42) of patients with tumor BRCA mutations evaluable for somatic-germline-zygosity were predicted to exhibit BRCA loss of heterozygosity (LOH). No patients had non-BRCA germline DNA damage response (DDR) gene variants with known/likely pathogenicity, based on a panel of 14 non-BRCA DDR genes. Ninety-eight percent of patients had TP53 mutations. Genomic LOH, assessed continuously or categorically, was not associated with response. Conclusion: The results from this exploratory biomarker analysis support the central role of BRCA and TP53 mutations in tumor pathobiology. Furthermore, these data support assessing germline BRCA mutational status for molecular eligibility for talazoparib in patients with TNBC. [ABSTRACT FROM AUTHOR]

Molecular subtyping of breast cancer is based mostly on HR/HER2 and gene expression-based immune, DNA repair deficiency, and luminal signatures. We extend this description via functional protein pathway activation mapping using pre-treatment, quantitative expression data from 139 proteins/phosphoproteins from 736 patients across 8 treatment arms of the I-SPY 2 Trial (ClinicalTrials.gov: NCT01042379). We identify predictive fit-for-purpose, mechanism-of-action-based signatures and individual predictive protein biomarker candidates by evaluating associations with pathologic complete response. Elevated levels of cyclin D1, estrogen receptor alpha, and androgen receptor S650 associate with non-response and are biomarkers for global resistance. We uncover protein/phosphoprotein-based signatures that can be utilized both for molecularly rationalized therapeutic selection and for response prediction. We introduce a dichotomous HER2 activation response predictive signature for stratifying triple-negative breast cancer patients to either HER2 or immune checkpoint therapy response as a model for how protein activation signatures provide a different lens to view the molecular landscape of breast cancer and synergize with transcriptomic-defined signatures.

The utility of neoadjuvant chemotherapy is expanding in the treatment of breast cancer. Although individual trials have shown comparable survival between patients receiving neoadjuvant and adjuvant chemotherapy, large-scale data analyses for outcomes in patients with locally advanced breast cancer (LABC) are lacking. We conducted an individual-level statistical analysis using patients from six randomized controlled trials (RCTs) investigating survival outcomes with neoadjuvant versus adjuvant chemotherapy in breast cancer by abstracting and analyzing only the patients with LABC. Individual patient data for 779 patients with LABC were collected from six RCTs. Overall and disease-free survival rates were compared between patients receiving neoadjuvant vs. adjuvant chemotherapy with the Cox hazard model and log-rank statistics. Since chemotoxicity causing delays to surgical care is a potential drawback of neoadjuvant chemotherapy, local cohort data were then employed to assess the actual incidence of this, along with the causes behind any delays to surgery in patients receiving neoadjuvant chemotherapy. A time interval from neoadjuvant chemotherapy to surgery of >8 weeks was investigated in a local cohort of 563 patients, representing all locally treated patients receiving neoadjuvant chemotherapy between 2006 and 2019. The statistical analysis demonstrated no overall or disease-free survival differences in LABC patients receiving neoadjuvant vs. adjuvant chemotherapy (p = 0.96 and 0.74, respectively). Within our cohort, 31 (5.5%) patients treated with neoadjuvant chemotherapy experienced a delay of >8 weeks to surgery, with only 13 (2.3%) attributed to chemotherapy-related complications. Our study provides further support for the paradigm shift towards delivering chemotherapy for breast cancer patients in the neoadjuvant setting.

Abstract Background Neoadjuvant targeted therapy has shown that improve pathologic complete response and facilitate breast-conserving surgery, but the difference between single-agent treatment or dual-HER2 blockade to the conversion of breast-conserving surgery has not been well described. Methods Via the systematic literature search of PubMed, Web of Science and Cochrane Library databases, 5 eligible studies used to perform this meta-analysis, which was carried out using RevMan version 5.4. Results A total of 1306 patients from five randomized controlled trials were included in the analysis, revealing a significant increase in the conversion rate to breast-conserving surgery with neoadjuvant targeted therapy (OR 0.30, 95% CI 0.15–0.57; p = 0.0003). The odds ratio (OR) for single-agent treatment compared to dual-HER2 blockade was 1.04 (95% CI 0.73–1.48; p = 0.82). For pathological complete response (pCR), the OR for single-HER2 blockade versus dual-HER2 blockade was 0.43 (95% CI 0.34–0.55; p = 0.01), and for clinical response, it was 0.81 (95% CI 0.59–1.10; p = 0.17). The OR for serious adverse events between single-HER2 and dual-HER2 blockade was 0.72 (95% CI 0.55–0.95; p = 0.02). The risk ratio (RR) for pCR and the shift from mastectomy to BCS was 1.16 (95% CI 0.78–1.72; p = 0.47), while for clinical response and the shift from mastectomy to BCS, it was 2.40 (95% CI 1.44–4.01; p = 0.0008). Conclusion Neoadjuvant targeted treatment obviously promote the actual implementation rate of breast-conserving surgery, nevertheless, there was no statistically significant increase in single-agent treatment versus dual-HER2 blockade.

Esophageal cancer has a poor prognosis and survival rate due to its high incidence in Asia, lack of early symptoms and limited treatment options. In recent years, many clinical trials have demonstrated that immunotherapy has greatly improved the survival of patients with esophageal cancer. In addition, the combination of neoadjuvant immunotherapy with other popular therapeutic regimens has shown good efficacy and safety. In this review, we summarize the progress of clinical trials and some breakthroughs in neoadjuvant immunotherapy for esophageal cancer in recent years and suggest the possibility of multimodal neoadjuvant immunotherapy regimens, as well as directions for future development. [ABSTRACT FROM AUTHOR]

Anaplastic thyroid cancer (ATC), a rare and highly aggressive malignancy, is characterized by an exceptionally poor prognosis, where the majority of patients present with extensive local invasion and/or distant metastases. 20–30% of ATCs harbor the BRAF‐V600E mutation. Neoadjuvant BRAF‐targeted therapy may have the potential to downstage and facilitate surgical resection for patients with locally advanced and unresectable primary tumors with BRAF mutation and may convey a survival advantage in those with metastatic disease. There is emerging evidence to support the use of other targeted agents, including multikinase inhibitors, as well as the incorporation of immunotherapy into the treatment regimen. Rapid molecular and pathological diagnosis and expert multidisciplinary discussion at specialized treatment centers are critical to expedite investigations and initiate treatment for this complex and rapidly progressive disease. [ABSTRACT FROM AUTHOR]

Introduction: Several trials of perioperative immunotherapy for resectable non-small cell lung cancer (NSCLC) reported positive results. They were designed to adjuvant, neoadjuvant and sandwich (neoadjuvant plus adjuvant) immunotherapy with immune checkpoint inhibitors and chemotherapy (CT). The differences between neoadjuvant and sandwich modalities were unclear. Method: We performed a systematic review and Bayesian network meta-analysis by retrieving relevant literature from PubMed, EMBASE, Cochrane Library, Web of Science, ClinicalTrials.gov, WHO ICTRP and major international conferences. Results: We analyzed 8 studies involving 3429 patients, including 6 neoadjuvant plus adjuvant (Neo-Adj) and 2 neoadjuvant (Neo) trials. Neo-Adj had better event-free survival (EFS) (hazard ratio [HR] = 0.57, 95% confidence interval [CI]: 0.45–0.71) than CT. There existed no difference between Neo-Adj and Neo in EFS (HR = 0.87, 95% CI: 0.53–1.46) and overall survival (OS) (HR = 1.04, 95% CI: 0.38–2.57). Neo might have lower incidence of treatment-related adverse events (TRAEs) (relative risk [RR] = 0.96, 95% CI: 0.87–1.12) than Neo-Adj. Subgroup analysis of PD-L1 ≥ 50% suggested that EFS of Neo-Adj (HR = 0.46, 95% CI: 0.27–0.76) and Neo (HR = 0.24, 95% CI: 0.06–0.89) was better than CT, and Neo-Adj potentially caused shorter EFS than Neo (HR = 1.92, 95% CI: 0.46–7.84). Conclusions: Our results suggest that Neo-Adj and Neo have similar EFS for patients with PD-L1 < 1% or 1–49%. However, patients with PD-L1 ≥ 50% may obtain more EFS benefit from Neo than Neo-Adj. Neo might present a more favorable assessment than Neo-Adj when evaluating OS. Moreover, adding adjuvant immunotherapy may increase toxicity. [ABSTRACT FROM AUTHOR]

The ever-growing knowledge regarding NSCLC molecular biology has brought innovative therapies into clinical practice; however, the treatment situation in the non-metastatic setting is rapidly evolving. Indeed, immunotherapy-based perioperative treatments are currently considered the standard of care for patients with resectable NSCLC in the absence of EGFR mutations or ALK gene rearrangements. Recently, data have been presented on the use of tyrosine kinase inhibitors (TKIs) in the adjuvant and locally advanced setting for patients with NSCLC harboring such driver gene alterations. The aim of the current work is to review the available evidence on the use of targeted treatments in the non-metastatic setting, together with a summary of the ongoing trials designed for actionable gene alterations other than EGFR and ALK. To date, 3-year adjuvant osimertinib treatment has been demonstrated to improve DFS and OS and to reduce CNS recurrence in resected EGFR-mutated NSCLC in stage IB–IIIA (TNM 7th edition). The use of osimertinib after chemo-radiation in stage III unresectable EGFR-mutated NSCLC showed the relevant PFS improvement. In the ALK-positive setting, 2-year alectinib treatment was shown to clearly improve DFS compared to adjuvant standard chemotherapy in resected NSCLC with stage IB (≥4 cm)–IIIA (TNM 7th edition). Several trials are ongoing to establish the optimal adjuvant TKI treatment duration, as well as neoadjuvant TKI strategies in EGFR- and ALK-positive disease, and (neo)adjuvant targeted treatments in patients with actionable gene alterations other than EGFR or ALK. In conclusion, our review depicts how the current treatment scenario is expected to rapidly change in the context of non-metastatic NSCLC with actionable gene alterations, hence appropriate molecular testing from the early stages has become crucial to establish the most adequate approaches both in the perioperative and the locally advanced disease.

Despite consensus guidelines, most patients with early-stage triple-negative (TN) and HER2-positive (HER2+) breast cancer do not see a medical oncologist prior to surgery and do not receive neoadjuvant chemotherapy (NAC). To understand barriers to care, we aimed to characterize the relationship between geography (region of residence and cancer centre proximity) and receipt of a pre-treatment medical oncology consultation and NAC for patients with TN and HER2+ breast cancer. Using linked administrative datasets in Ontario, Canada, we performed a retrospective population-based analysis of women diagnosed with stage I–III TN or HER2+ breast cancer from 2012 to 2020. The outcomes were a pre-treatment medical oncology consultation and the initiation of NAC. We created choropleth maps to assess the distribution of the outcomes and cancer centres across census divisions. To assess the relationship between distance to the nearest cancer centre and outcomes, we performed multivariable regression analyses adjusted for relevant factors, including tumour extent and nodal status. Of 14,647 patients, 29.9% received a pre-treatment medical oncology consultation and 77.7% received NAC. Mapping demonstrated high interregional variability, ranging across census divisions from 12.5% to 64.3% for medical oncology consultation and from 8.8% to 64.3% for NAC. In the full cohort, compared to a distance of ≤5 km from the nearest cancer centre, only 10–25 km was significantly associated with lower odds of NAC (OR 0.83, 95% CI 0.70–0.99). Greater distances were not associated with pre-treatment medical oncology consultation. The interregional variability in medical oncology consultation and NAC for patients with TN and HER2+ breast cancer suggests that regional and/or provider practice patterns underlie discrepancies in the referral for and receipt of NAC. These findings can inform interventions to improve equitable access to NAC for eligible patients.

Abstract In recent years, significant improvement has been made in the management of non‐small cell lung cancer (NSCLC), primarily driven by advances in targeted therapy and immunotherapy. Research on neoadjuvant targeted therapy has also experienced considerable development, primarily directed towards NSCLC harboring epidermal growth factor receptor or anaplastic lymphoma kinase mutations. Nevertheless, there remains a dearth of studies investigating neoadjuvant targeted therapy in the context of BRAF (V‐Raf murine sarcoma viral oncogene homolog B) V600E mutant NSCLC. Herein, we describe the clinical trajectory of a stage IIIA NSCLC patient who underwent a two‐month course of neoadjuvant targeted therapy comprising BRAF and MEK (mitogen‐activated extracellular signal‐regulated kinase) inhibitors prior to surgical intervention, and subsequent postoperative evaluation unveiled a pathological complete response. The case reported here indicates the efficacy and safety of combining BRAF and MEK inhibitors as neoadjuvant targeted therapy in BRAF V600E‐mutant NSCLC and suggests the potential viability of such a therapeutic modality in improving treatment outcomes in this subset of NSCLC.

Non-small cell lung cancer (NSCLC) that is operable still carries a high risk of recurrence, approaching 50% of all operable cases despite adding adjuvant chemotherapy. However, the utilization of immunotherapy and targeted therapy moving beyond the metastatic NSCLC setting and into early-stage perioperative management has generated tremendous enthusiasm and has been practice-changing. Adjuvant atezolizumab in NSCLC first demonstrated a clinical benefit with an immune checkpoint inhibitor. Then, with studies studying a significant benefit in major pathologic response in surgical patients treated preoperatively with immunotherapy compared to only chemotherapy, neoadjuvant nivolumab and chemotherapy were evaluated and showed significant event-free survival benefit leading to subsequent studies evaluating perioperative immunotherapy and chemotherapy. Meanwhile, with regards to targeted therapies, adjuvant osimertinib in EGFR-mutated NSCLC and adjuvant alectinib in ALK-rearranged NSCLC have both received regulatory approvals following demonstrated clinical benefit in clinical trials. With rapidly evolving changes in the field, new combinations such as multiple immunotherapy agents and antibody-drug conjugates in development, perioperative NSCLC management has quickly become complicated with different pathways to perioperative treatment. Furthermore, circulating tumor DNA and studies looking at better tools to prognosticate immunotherapy response will help with decision-making regarding which patients should receive immunotherapy and if so, either only pre-operatively or both pre- and post-operatively. In this review, we look at the evolution of systemic therapy in the perioperative setting from adjuvant chemotherapy to adjuvant immunotherapy to perioperative immunotherapy and look at perioperative targeted therapy while looking ahead to future considerations.

Abstract Background Inetetamab is the first domestically developed innovative anti-HER2 monoclonal antibody in China, proven effective and safe in HER2-positive advanced breast cancer. However, its efficacy and safety in neoadjuvant treatment of HER2-positive locally advanced breast cancer (LABC) remain to be validated. Methods This prospective cohort study aimed to evaluate the efficacy and safety of inetetamab combined with pertuzumab, taxanes, and carboplatin (TCbIP) in neoadjuvant therapy for HER2-positive LABC, comparing it to data from patients treated with the TCbHP regimen (trastuzumab combined with pertuzumab, taxanes, and carboplatin) using propensity score matching (PSM). The primary endpoint was total pathological complete response (tpCR). Adverse events (AEs), objective response rate (ORR), and near-pCR were key secondary endpoints. Results Forty-four patients with clinical stage IIA-IIIC HER2-positive LABC were prospectively enrolled and treated with the TCbIP regimen. The tpCR rate among 28 patients who completed surgery was 60.7%, comparable to and slightly higher than the TCbHP group in PSM (60.7% vs. 53.6%, P = 0.510). The ORR was 96.4%, and the DCR reached 100.0%. The most common ≥ grade 3 AE was neutropenia (21.4% vs. 11.9%, P = 0.350). No significant reduction in left ventricular ejection fraction was observed, and no patient withdrew from treatment due to AEs. Conclusion Neoadjuvant therapy with TCbIP showed good efficacy and safety in patients with HER2-positive LABC and might be another promising option for neoadjuvant treatment. Trial registration NCT05749016 (registration date: Nov 01, 2021).

Abstract This study aimed to assess the cost-utility and budget impact of dual to single HER2 targeted neoadjuvant therapy for HER2-positive breast cancer in Sri Lanka. A five-health state Markov model with lifetime horizon was used to assess the cost-utility of neoadjuvant trastuzumab (T) plus pertuzumab (P) or lapatinib (L) compared to single therapy of T with chemotherapy (C), in public healthcare system and societal perspectives. Input parameters were estimated using local data, network meta-analysis, published reports and literature. Costs were adjusted to year 2021 (1USD = LKR194.78). Five-year budget impact for public healthcare system was assessed. Incremental cost-effectiveness ratios in societal perspective for neoadjuvantLTC plus adjuvantT (strategy 3), neoadjuvantPTC plus adjuvantT (strategy 2), neoadjuvantLTC plus adjuvantLT (strategy 5), and neoadjuvantPTC plus adjuvantPT (strategy 4) compared to neoadjuvantTC plus adjuvantT (strategy 1) were USD2716, USD5600, USD6878, and USD12127 per QALY gained, respectively. One GDP per-capita (USD3815) was considered as the cost-effectiveness threshold for the analysis. Even though only the ICER for strategy 3 was cost-effective, uncertainty of efficacy parameter was revealed. For strategy 2 neoadjuvant PTC plus adjuvant T, a 25% reduction of neoadjuvant regimen cost was required to be cost effective for use in early HER2 positive breast cancer.

Breast cancer (BC) is the most frequent type of cancer among women. The neoadjuvant therapy was administered before surgery, and the adjuvant therapy was administered post-surgery. The goal of this systematic review is to study the effects of adjuvant and neoadjuvant BC therapy on patient outcomes and mortality. In July 2023, systematic searches were conducted through the Cochrane Library, Web of Sciences, Google Scholar, EMBASE, and PubMed databases. The search method focused on studies that included all patients with BC stages 1, 2, and 3 and excluded studies that included patients with metastatic and recurrent BC. The risk of bias in the included studies was evaluated using the Cochrane risk of bias technique. Throughout our search, 27 relevant studies with 161,552 patients were discovered. Anti-human epidermal growth factor 2 therapy (trastuzumab, pertuzumab), chemotherapy (anthracycline), endocrine therapy (tamoxifen, aromatase inhibitor), and bisphosphonates were recommended treatments for BC patients. Choices for radiotherapy included whole breast, partial breast, tumor bed boost, regional nodes, and chest wall choices after breast-conserving surgery. We discover that while the majority of treatments reduced the mortality or recurrence rates of BC, anthracycline, chemotherapy, and radiation led to an overall rise in non-BC deaths. The systemic assessment discovered several variables that impact a patient’s quality of life. Based on these advantages and disadvantages, various treatment options for patients and recommendations for groups of women are made.

Abstract Purpose HER3, a member of the EGFR receptor family, plays a central role in driving oncogenic cell proliferation in breast cancer. Novel HER3 therapeutics are showing promising results while recently developed HER3 PET imaging modalities aid in predicting and assessing early treatment response. However, baseline HER3 expression, as well as changes in expression while on neoadjuvant therapy, have not been well-characterized. We conducted a prospective clinical study, pre- and post-neoadjuvant/systemic therapy, in patients with newly diagnosed breast cancer to determine HER3 expression, and to identify possible resistance mechanisms maintained through the HER3 receptor. Experimental design The study was conducted between May 25, 2018 and October 12, 2019. Thirty-four patients with newly diagnosed breast cancer of any subtype (ER ± , PR ± , HER2 ±) were enrolled in the study. Two core biopsy specimens were obtained from each patient at the time of diagnosis. Four patients underwent a second research biopsy following initiation of neoadjuvant/systemic therapy or systemic therapy which we define as neoadjuvant therapy. Molecular characterization of HER3 and downstream signaling nodes of the PI3K/AKT and MAPK pathways pre- and post-initiation of therapy was performed. Transcriptional validation of finings was performed in an external dataset (GSE122630). Results Variable baseline HER3 expression was found in newly diagnosed breast cancer and correlated positively with pAKT across subtypes (r = 0.45). In patients receiving neoadjuvant/systemic therapy, changes in HER3 expression were variable. In a hormone receptor-positive (ER +/PR +/HER2-) patient, there was a statistically significant increase in HER3 expression post neoadjuvant therapy, while there was no significant change in HER3 expression in a ER +/PR +/HER2+ patient. However, both of these patients showed increased downstream signaling in the PI3K/AKT pathway. One subject with ER +/PR −/HER2− breast cancer and another subject with ER +/PR +/HER2 + breast cancer showed decreased HER3 expression. Transcriptomic findings, revealed an immune suppressive environment in patients with decreased HER3 expression post therapy. Conclusion This study demonstrates variable HER3 expression across breast cancer subtypes. HER3 expression can be assessed early, post-neoadjuvant therapy, providing valuable insight into cancer biology and potentially serving as a prognostic biomarker. Clinical translation of neoadjuvant therapy assessment can be achieved using HER3 PET imaging, offering real-time information on tumor biology and guiding personalized treatment for breast cancer patients.