Neoadjuvant Setting Research Articles

Attrition with adjuvant, neoadjuvant, and perioperative immunotherapy-based treatment protocols in patients with resectable non-small-cell lung cancer. A meta-analysis of prospective trials.

Histological Grade Has Clinical Validity in Neoadjuvant-Treated Breast Cancer: A Multicenter Study.

Rationale:The success of tyrosine kinase inhibtors in the neoadjuvant and adjuvant setting provides a rationale for exploring selpercatinib in the perioperative setting to improve patient outcomes in early-stage lung cancer. However, selpercatinib is currently only approved as first-line treatment for advanced rearrangement during transfection (RET) fusion-positive non-small cell lung cancer (NSCLC), limiting its use and potential benefit for earlier stage patients. Hence, this case report explores selpercatinib’s potential use in early-stage disease to address this treatment gap and improve patient outcomes.Patient concerns:We report the case of a 75-year-old female with no history of smoking who was referred to our institute with a chest computed tomography scan revealing a mass in the right lower lung lobe.Diagnoses:The patient was diagnosed with RET fusion-positive lung adenocarcinoma based on findings from radiologic findings from computed tomography (CT) and positron emission tomography-CT scans, histopathological examination, and molecular profiling through next-generation sequencing.Interventions:The patient was treated with 4 cycles of carboplatin and pemetrexed. A follow-up CT scan revealed the progression of the mediastinal lymph node, leading to the decision to initiate selpercatinib treatment. Due to a major size reduction of the primary lesion and the absence of tumor cells in the lymph nodes, the patient underwent curative lobectomy and lymphadenectomy.Outcomes:Preoperative selpercatinib induced tumor regression, enabling surgical resection. Histopathological examination of the resected tumor revealed a major pathological response to preoperative selpercatinib treatment.Lessons:This case highlights the potential of selpercatinib in the perioperative setting, suggesting that it induces tumor regression and enabling of curative surgery in early-stage RET fusion-positive NSCLC. Our findings support the further investigation of selpercatinib in early stages and provide a rationale for future treatment strategies of early-stage RET fusion-positive NSCLC patients.

Intratumoral heterogeneity (ITH) of HER2 expression and HER3 upregulation have been associated with resistance to HER2-targeted therapies. However, their predictive role in the neoadjuvant setting remains controversial. We retrospectively analyzed 59 patients with HER2-positive invasive breast carcinoma treated with neoadjuvant chemotherapy and anti-HER2 agents at the Agostino Gemelli University Hospital (2018-2020). HER2 ITH was assessed on pre-treatment biopsies and residual tumors (when applicable) by immunohistochemistry and SISH. HER3 expression was also evaluated using IHC and categorized as negative, low, or high. The association with pathological complete response (pCR) and event-free survival (EFS) was assessed. pCR was achieved in 49.2% of patients. HER2 ITH was present in 23.7% of biopsies and was significantly associated with a lower pCR rate (p = 0.005). In multivariate analysis, HER2 ITH (OR 0.156, p = 0.030), HER2 score (3 + vs 2 + , OR 9.63, p = 0.044), and PgR negativity (OR 0.306, p = 0.029) emerged as independent predictors of pCR. HER3 expression did not significantly correlate with pCR or EFS, although a non-significant trend toward reduced EFS was observed in HER3-high cases. HER2 ITH negatively impacts pathological response to neoadjuvant therapy in HER2-positive breast cancer and may serve as a potential predictive biomarker. HER3 expression, while not significantly associated with outcome in this cohort, warrants further investigation as a possible contributor to therapeutic resistance. Standardized assessment protocols for both markers could improve patient stratification, guide treatment intensification, and support the integration of novel targeted agents in HER2-positive breast cancer.

Lung cancer (LC) remains the leading cause of cancer-related mortality worldwide. In recent years, mortality rates have declined due to antismoking policies, earlier detection, and the advent of targeted therapies and immunotherapy, particularly for non-small cell lung cancer (NSCLC), which accounts for 85% of all cases. With improved survival, however, LC patients are increasingly exposed to competing causes of mortality, among which cardiovascular disease (CVD) is highly prevalent, affecting 30–50% of patients and contributing to nearly 30% of deaths. This burden reflects both shared risk factors and the cardiotoxic potential of radiotherapy, chemotherapy, and immunotherapy. Beyond acute adverse cardiovascular events during treatment, real-world data indicate that immune checkpoint inhibitors (ICIs) may also exert chronic cardiovascular effects, significantly accelerating the atherosclerotic process in multimorbid patients. These findings underscore the importance of accurate baseline assessment and aggressive management of cardiovascular risk factors in LC patients—particularly in the adjuvant and neoadjuvant settings, where longer survival is anticipated. Moreover, long-term monitoring should be implemented through a tailored, multiparametric strategy that integrates novel biomarkers and advanced artificial intelligence–assisted imaging techniques. Achieving this ambitious goal requires the close collaboration of a multidisciplinary team, with cardiologists playing a pivotal role. This review will address the complexity of LC patients, focusing on the interplay of cardio-immuno-metabolic factors, summarizing the cardiovascular impact of immunotherapy across metastatic, locally advanced, and perioperative settings, and outlining practical strategies for the management of these vulnerable patients.

Melanoma is one of the most aggressive and lethal forms of skin cancer, with acral melanoma (AM) associated with the poorer prognosis among melanoma subtypes. Historically, it was considered that more extensive surgery could prolong survival; however, multiple randomized trials have demonstrated that greater surgical intervention does not improve survival. Over the past few years, novel therapeutic agents including immune checkpoint inhibitors and molecular-targeted drugs have remarkably improved prognosis of melanoma and potentially reduced the role of surgery. Furthermore, predictive models that integrate clinicopathologic features and gene expression profiling may further optimize patient selection and guidance for surgical de-escalation. In parallel, the use of these agents in adjuvant and neoadjuvant settings highlights the need for multimodal approaches combined with surgery. However, the landmark clinical trials have included few cases of AM, which is rare melanoma subtype in Western populations. Because of its unique molecular alterations, the applicability of findings from Western-based clinical trials to AM remains uncertain, leading to a lack of high-level evidence for this subtype. In this article, we review the available, albeit limited, evidence on surgical management for AM and discuss future perspectives and challenges for optimizing treatment strategies for this distinct melanoma subtype.

Despite advances in immunotherapy, unresectable stage III non-small-cell lung cancer (NSCLC) remains a highly challenging disease, with only around one-third of patients remaining disease-free at 5 years. The PACIFIC trial established consolidation with the anti-PD-L1 antibody durvalumab after concurrent chemoradiotherapy as the standard-of-care approach. Furthermore, the LAURA trial has redefined the treatment of patients with stage III unresectable EGFR-mutant NSCLC, demonstrating unprecedented progression-free survival durations with osimertinib consolidation. Despite these advances, novel approaches are urgently needed. Circulating tumour DNA-based monitoring of minimal residual disease is emerging as a personalized method of tailoring treatment duration and escalation strategies. Novel radiotherapy techniques have the potential to provide synergy with immunotherapy while minimizing toxicities. Additionally, ongoing trials evaluating chemoimmunotherapy combinations adapted from the neoadjuvant setting with the potential for conversion to resectable disease might, in the near future, redefine the boundary of surgical resectability. In this Review, we describe the rapidly evolving field of unresectable stage III NSCLC, providing a state-of-the-art overview that includes challenging topics such as biomarkers, personalization of therapy and the role of immunotherapy rechallenge.

The current status of immunotherapy in colorectal cancer: A systematic review.

Despite receiving standard treatments, patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC) often still face significant risks of disease recurrence or metastasis. In this phase II neoCHANCE-1 study (NCT05517330), we evaluated the efficacy and safety of the dual-targeted blockade of the PD-1 and EGFR pathways in a neoadjuvant setting. The primary endpoint was the major pathological response (MPR) rate. The secondary endpoints included the pathological complete response (pCR) rate, overall response rate (ORR), safety, disease-free survival (DFS), and overall survival (OS). A cohort of 25 patients was subjected to a treatment regimen consisting of tislelizumab for two cycles, concomitant with daily intake of afatinib for six weeks. Among the 23 evaluable patients, eight (35%; 95% CI, 16%-57%) achieved an MPR that met the prespecified endpoint, and four (17%, 95% CI, 5%-39%) achieved a pCR of the primary tumor. The ORR was 48% (12/25, 95% CI: 28%-69%). The most common grade 3-4 adverse events included diarrhea(5/25), hypokalemia(4/25), and rash(3/25). This study highlights the encouraging antitumor activity, manageable toxicity profile, and promising immune activation caused by neoadjuvant tislelizumab plus afatinib treatment of HNSCC, which deserves further investigation.

Abstract Background Immune checkpoint inhibitor treatment in non-small cell lung cancer (NSCLC) expands to early stages of disease. The neoadjuvant setting allows to investigate the mechanism-of-action of immune therapy using molecular imaging and tissue analysis. We investigated the safety and feasibility of programmed cell death ligand-1 (PD-L1) PET-imaging with 89Zr-labeled avelumab and neoadjuvant avelumab treatment in resectable NSCLC. Secondly, [89Zr]Zr-DFO-avelumab accumulation was correlated with features of the tumor immune microenvironment and pathological response. Methods This phase I-II study (NCT03514719) enrolled 20 patients with stage Ia-IIIa NSCLC who received 2 cycles of avelumab (10mg/kg Q2W) prior to surgery. In the imaging optimization part, [89Zr]Zr-DFO-avelumab PET was performed with protein doses of 2mg, 10mg or 50mg avelumab and imaging at day 2 and 4 post-injection. Subsequent patients were scanned with 10mg [89Zr]Zr-DFO-avelumab at day 4. Tracer-accumulation was correlated to PD-L1 expression and immune cell densities on pretreatment biopsies. Results [89Zr]Zr-DFO-avelumab PET/CT was successfully performed in 23/24 patients. 19/20 patients started neoadjuvant avelumab treatment, with no delays or conversions of surgical procedures. Six patients showed pathologic response, including two major pathologic responses. [89Zr]Zr-DFO-avelumab tumor-accumulation was not correlated to PD-L1 expression, but did correlate with regulatory T-cell density (r=0.72, p=0.030) and pathologic response (r=0.56, p=0.036); and was inversely correlated with CD303+ plasmacytoid dendritic cell density (r=-0.72, p=0.030). SUVpeak on baseline [18F]FDG-PET correlated with pretreatment PD-L1 expression but not with [89Zr]Zr-DFO-avelumab accumulation nor with pathologic response. Conclusion [89Zr]Zr-DFO-avelumab PET imaging is a safe and feasible approach in early-stage NSCLC. Higher [89Zr]Zr-DFO-avelumab tumor-accumulation at baseline strongly correlates with features of a suppressive tumor immune environment and response to neoadjuvant avelumab.

Targeted therapy in non-small cell lung cancer (NSCLC) is now often included as first-line treatment in the neoadjuvant and adjuvant settings. Delays in optimizing treatments based on biomarker status can affect outcomes. Therefore, we assessed the turnaround time (TAT) of reflex biomarker testing for all NSCLCs clinical stage 1B and greater. A next-generation sequencing (NGS) and PD-L1 immunohistochemistry reflex protocol for NSCLC clinical stage 1B and greater was implemented. Turnaround time intervals between procedure date, pathology sign-out, date received in the molecular laboratory, and date of NGS sign-out were calculated. Median and IQR of each interval before and after implementation of the reflex protocol were calculated and compared using the Mann-Whitney U test. In total, 492 lung cancer NGS cases were identified, 351 before and 141 after implementation of the reflex protocol. The prereflex cases, after exclusion of biomarker testing ordered on older blocks and outside consults (n = 165), demonstrated a 22-day median time from procedure to NGS sign-out (range, 11-70 days; IQR, 9; mean, 24 days), compared to a 20-day median time (range, 13-54 days; IQR, 4.5; mean, 21 days) postimplementation (n = 120) (P < .000103). Reduction in median TAT from procedure to NGS sign-out was statistically significant after implementation of reflex biomarker testing in NSCLC samples.

Locally advanced oral squamous cell carcinoma (OSCC) is associated with poor survival outcomes, particularly in resource-limited settings, where treatment delays are prevalent. Oral metronomic chemotherapy (OMCT) utilising methotrexate and celecoxib is a potentially low-toxicity, cost-effective alternative in the neoadjuvant setting. Thirteen patients diagnosed with stage 3 or 4 resectable OSCC were enrolled in this study. Each participant received one month of OMCT prior to surgical intervention and continued OMCT as maintenance therapy following treatment. The expression levels of PTGS2, VEGFA, VEGFB, KDR, CXCR1, and CXCR2 were analysed both before and after OMCT administration. Additionally, organ function and patient survival were evaluated to determine the efficacy and toxicity of treatment. PTGS2, VEGFA, VEGFB, and KDR were significantly upregulated in the tumour tissues at baseline. Post-OMCT, VEGFA, VEGFB, and KDR were significantly downregulated, whereas PTGS2 expression increased. No significant changes were observed in CXCR1 and CXCR2 expression. Liver, renal, and thyroid functions remained within normal limits. No adverse events were reported. The median overall survival was 22.1 months, and the median disease-free survival was 20 months. Upregulation of PTGS2, VEGFA, and VEGFB was correlated with improved outcomes. OMCT has the potential to manage disease progression in patients with OSCC awaiting surgical intervention. It is characterised by low toxicity and may exert anti-angiogenic effects through modulation of the VEGF pathway. Further large-scale trials are necessary to substantiate these findings and to establish optimal treatment strategies. The study was also registered in the Clinical Trials Registry of India (registration number: CTRI/2021/01/030256).

BackgroundThe addition of immunotherapy in the neoadjuvant setting is showing promising results for HER2- and triple-negative breast cancer patients, but pathological complete response is observed only in a fraction of patients. The aim of the present work was to investigate if ARIADNE, an algorithmic strategy to analyze gene expression data from bioptic samples based on epithelial-mesenchymal phenotypes, can predict the response to immunotherapy in HER2- patients.MethodsWe considered gene expression data for HER2-breast cancer patients treated with pembrolizumab in addition to chemotherapy (n = 69) and with chemotherapy alone (n = 179) from the I-SPY 2 trial. We stratified patients in two risk groups (low/high risk) according to the score of the ARIADNE algorithm and studied an additional cytokine signature. To better understand the significance of our results, we studied the interactions among genes in the PD-L1 pathway and analyzed single-cell data from TNBC patients treated with pembrolizumab.ResultsOur results show that ARIADNE predicts differential response to immunotherapy: the high-risk group has a pathological complete response (pCR) rate of 26% as compared with 62% for the low-risk group (OR 4.7, with 1.68–11.32 95% CI and p < 0.01). We also find significant correlations between a cytokine score and the rate of pCR. The ability of ARIADNE to predict pCR is associated with regulatory activity within the PD-L1 pathway. Comparison between ARIADNE and other immunological genomic signatures shows no correlations. The study of single-cell data showed that patients responding to immunotherapy display a larger number of exhausted T-cells than non-responders.ConclusionsOur analysis shows that ARIADNE is predictive of the response to immunotherapy, but not to chemotherapy, in HER2- patients.

The Formulary Management Expert Committee (FMEC) recommends that pertuzumab in combination with trastuzumab and chemotherapy be reimbursed for the treatment of adults with early-stage HER2-positive breast cancer in the neoadjuvant setting, provided certain conditions are met. Pertuzumab in combination with trastuzumab and chemotherapy may be initiated in adult patients for the neoadjuvant treatment of early-stage HER2-positive breast cancer if all of the following conditions are met: it is locally advanced, inflammatory or early-stage breast cancer (&gt; 2 cm or node positive) and there is no evidence of metastasis. A price reduction for pertuzumab may be required.

Evolving Neoadjuvant, Adjuvant, and Concurrent Systemic Therapy Strategies in Head and Neck Squamous Carcinoma.

Acute presentations in neoadjuvant chemotherapy/immune checkpoint inhibition for triple negative breast cancer: experiences and impact from real-world data.

Hormonal treatment of aggressive angiomyxoma.

Hepatocellular carcinoma and liver transplant: What about neo- and adjuvant immunotherapy.

BackgroundNon-small cell lung cancer (NSCLC) is the second most common cancer globally and a leading cause of cancer-related mortality. Although 5-year survival rates remain lower than those of other cancer types, significant improvements have been observed in recent years, largely due to the introduction of immunotherapy and targeted therapies. Recently, immune checkpoint inhibitors (ICIs) have been approved for use in combination with standard double-platinum chemotherapy in the neoadjuvant setting for resectable NSCLC, improving outcomes and extending time to recurrence. However, neoadjuvant therapy (NAT) can lead to declines in pulmonary function and cardiorespiratory fitness (CRF), thereby increasing the risk of postoperative complications. This study aims to evaluate the effects of multimodal prehabilitation on maintaining CRF and enhancing surgical resilience in patients with NSCLC undergoing neoadjuvant chemoimmunotherapy.MethodsAmbispective cohort study to evaluate the feasibility and preliminary efficacy of multimodal prehabilitation in patients with NSCLC undergoing NAT with chemoimmunotherapy. Eligible patients will be recruited from tertiary cancer centres in Spain and France. The intervention will include: (I) a supervised exercise training conducted twice weekly through the duration of NAT until surgery; (II) a nutritional assessment with a personalized dietary plan; and (III) psychological support. Additional services (such as smoking cessation counselling) will be provided if needed. The primary outcome will be changes in peak oxygen uptake (VO2peak), measured via cardiopulmonary exercise test (CPET) before and after NAT. Secondary outcomes will include: (I) feasibility (recruitment rate, treatment completion rate, adherence and training compliance); (II) functional capacity; (III) mood; (IV) treatment-related toxicity and adverse events; (V) postoperative outcomes (complications and length of hospital stay); and (VI) postoperative recovery of functional capacity.DiscussionThis trial aims to provide data on efficacy, safety, and feasibility to support the implementation of prehabilitation for patients with resectable NSCLC undergoing NAT.Trial RegistrationClinicalTrials.gov; NCT05636969.

BackgroundSmall-cell lung cancer (SCLC) is a highly aggressive form of lung cancer. The emergence of chemoimmunotherapy has changed the mode of SCLC treatment. However, in limited-stage SCLC (LS-SCLC), the effectiveness and safety of chemoimmunotherapy in the neoadjuvant setting for LS-SCLC are not well-established. To address this gap, we conducted a study to evaluate neoadjuvant chemoimmunotherapy in LS-SCLC.MethodsA retrospective study was conducted on patients from Beijing Chest Hospital, Capital Medical University, who underwent etoposide-based chemotherapy with programmed death-ligand 1/programmed death 1 (PD-L1/PD-1) inhibitors (neoCIT group) or without (neoCT group) prior to surgery for LS-SCLC between April 2019 and March 2023. The primary endpoints were to evaluate the major pathological response (MPR) and the pathological complete response (pCR). Secondary endpoints comprised event-free survival (EFS), overall survival (OS), and safety.ResultsA total of 31 patients with stage IIB-IIIB LS-SCLC were included, comprising 16 cases in the neoCIT group and 15 patients in the neoCT group. A pCR was observed in eight cases [50.0%; 95% confidence interval (CI): 28.0 to 72.0] within the neoCIT group, compared to one patient (6.7%; 95% CI: 0.3 to 29.8) in the neoCT group (odds ratio, 14.00; 95% CI: 1.71 to 164.20; P=0.02). An MPR was observed in 14 cases (87.5%; 95% CI: 64.0 to 97.8) within the neoCIT group, while three patients (20.0%; 95% CI: 7.0 to 45.2) were noted in the neoCT group, yielding an odds ratio of 28.00 (95% CI: 4.23 to 150.50; P<0.001). The median EFS was not achieved with neoCIT, while it was 19.0 months with neoCT (hazard ratio, 0.15; 95% CI: 0.04 to 0.62). The median OS was not reached for neoCIT, while it was 39.0 months for neoCT (hazard ratio, 0.23; 95% CI: 0.06 to 0.95). Grade 3 or 4 adverse events were observed in five patients in the neoCIT group (30.0%) and five in the control group (33.3%).ConclusionsOur study underscores the potential of neoadjuvant chemoimmunotherapy in resectable SCLC patients. The significant improvements in pCR, MPR, EFS, and OS compared to neoadjuvant chemotherapy alone offer a promising outlook for the future management of LS-SCLC.