Assessment Of Pathologic Response Research Articles

Development of an Interpretable Deep Learning Model for Pathological Tumor Response Assessment After Neoadjuvant Therapy.

Neoadjuvant therapy followed by surgery has become the standard of care for locally advanced esophageal squamous cell carcinoma (ESCC) and accurate pathological response assessment is critical to assess the therapeutic efficacy. However, it can be laborious and inconsistency between different observers may occur. Hence, we aim to develop an interpretable deep-learning model for efficient pathological response assessment following neoadjuvant therapy in ESCC. This retrospective study analyzed 337 ESCC resection specimens from 2020-2021 at the Pudong-Branch (Cohort 1) and 114 from 2021-2022 at the Puxi-Branch (External Cohort 2) of Fudan University Shanghai Cancer Center. Whole slide images (WSIs) from these two cohorts were generated using different scanning machines to test the ability of the model in handling color variations. Four pathologists independently assessed the pathological response. The senior pathologists annotated tumor beds and residual tumor percentages on WSIs to determine consensus labels. Furthermore, 1850 image patches were randomly extracted from Cohort 1 WSIs and binarily classified for tumor viability. A deep-learning model employing knowledge distillation was developed to automatically classify positive patches for each WSI and estimate the viable residual tumor percentages. Spatial heatmaps were output for model explanations and visualizations. The approach achieved high concordance with pathologist consensus, with an R^2 of 0.8437, a RAcc_0.1 of 0.7586, a RAcc_0.3 of 0.9885, which were comparable to two senior pathologists (R^2 of 0.9202/0.9619, RAcc_0.1 of 8506/0.9425, RAcc_0.3 of 1.000/1.000) and surpassing two junior pathologists (R^2 of 0.5592/0.5474, RAcc_0.1 of 0.5287/0.5287, RAcc_0.3 of 0.9080/0.9310). Visualizations enabled the localization of residual viable tumor to augment microscopic assessment. This work illustrates deep learning's potential for assisting pathological response assessment. Spatial heatmaps and patch examples provide intuitive explanations of model predictions, engendering clinical trust and adoption(Code and data will be available at https://github.com/WinnieLaugh/ESCC_Percentage once the paper has been conditionally accepted). Integrating interpretable computational pathology could help enhancethe efficiency and consistency of tumor response assessment and empower precise oncology treatment decisions.

Cytomorphological Disparities in Invasive Breast Cancer Cells following Neoadjuvant Endocrine Therapy and Chemotherapy

Introduction: Neoadjuvant endocrine therapy (NAE) offers a breast-conserving surgery rate and clinical response rate similar to those of neoadjuvant chemotherapy (NAC), while presenting fewer adverse events and lower pathological complete response rates. The assessment of pathological response determines degenerative changes and predicts the prognosis of breast cancer treated with NAC. This study clarified the degenerative changes occurring in breast cancer following NAE. Methods: Our study encompassed two groups: NAE, consisting of 15 patients, and NAC, comprising 18 patients. Tissue samples were obtained from core needle biopsies and surgeries. Nuclear and cell areas were calculated using Autocell analysis. Furthermore, we assessed markers associated with microtubule depolymerization (KIF2A) and initiators of apoptosis (caspase-9). Results: In the NAC group, we observed significant increases in both cytoplasmic and cell areas. These changes in cytoplasm and cells were notably more pronounced in the NAC group compared to the NAE group. After treatment, KIF2A exhibited a decrease, with the magnitude of change being greater in the NET group than in the NAC group. However, no discernible differences were found in caspase-9 expression between the two groups. Conclusion: Our findings indicate that NAE induces condensation in cancer cells via cell cycle arrest or apoptosis. Conversely, NAC leads to cell enlargement due to the absence of microtubule depolymerization. These discrepancies underscore the importance of accounting for these distinctions when establishing criteria for evaluating pathological responses.

Artificial Intelligence–Powered Assessment of Pathologic Response to Neoadjuvant Atezolizumab in Patients With NSCLC: Results From the LCMC3 Study

IntroductionPathologic response (PathR) by histopathologic assessment of resected specimens may be an early clinical end point associated with long-term outcomes with neoadjuvant therapy. Digital pathology may improve the efficiency and precision of PathR assessment. LCMC3 (NCT02927301) evaluated neoadjuvant atezolizumab in patients with resectable NSCLC and reported a 20% major PathR rate. MethodsWe determined PathR in primary tumor resection specimens using guidelines-based visual techniques and developed a convolutional neural network model using the same criteria to digitally measure the percent viable tumor on whole-slide images. Concordance was evaluated between visual determination of percent viable tumor (n = 151) performed by one of the 47 local pathologists and three central pathologists. ResultsFor concordance among visual determination of percent viable tumor, the interclass correlation coefficient was 0.87 (95% confidence interval [CI]: 0.84–0.90). Agreement for visually assessed 10% or less viable tumor (major PathR [MPR]) in the primary tumor was 92.1% (Fleiss kappa = 0.83). Digitally assessed percent viable tumor (n = 136) correlated with visual assessment (Pearson r = 0.73; digital/visual slope = 0.28). Digitally assessed MPR predicted visually assessed MPR with outstanding discrimination (area under receiver operating characteristic curve, 0.98) and was associated with longer disease-free survival (hazard ratio [HR] = 0.30; 95% CI: 0.09–0.97, p = 0.033) and overall survival (HR = 0.14, 95% CI: 0.02–1.06, p = 0.027) versus no MPR. Digitally assessed PathR strongly correlated with visual measurements. ConclusionsArtificial intelligence–powered digital pathology exhibits promise in assisting pathologic assessments in neoadjuvant NSCLC clinical trials. The development of artificial intelligence–powered approaches in clinical settings may aid pathologists in clinical operations, including routine PathR assessments, and subsequently support improved patient care and long-term outcomes.

Association between pathologic response and survival after neoadjuvant therapy in lung cancer

Neoadjuvant immunotherapy plus chemotherapy improves event-free survival (EFS) and pathologic complete response (0% residual viable tumor (RVT) in primary tumor (PT) and lymph nodes (LNs)), and is approved for treatment of resectable lung cancer. Pathologic response assessment after neoadjuvant therapy is the potential analog to radiographic response for advanced disease. However, %RVT thresholds beyond pathologic complete response and major pathologic response (≤10% RVT) have not been explored. Pathologic response was prospectively assessed in the randomized, phase 3 CheckMate 816 trial (NCT02998528), which evaluated neoadjuvant nivolumab (anti-programmed death protein 1) plus chemotherapy in patients with resectable lung cancer. RVT, regression and necrosis were quantified (0–100%) in PT and LNs using a pan-tumor scoring system and tested for association with EFS in a prespecified exploratory analysis. Regardless of LN involvement, EFS improved with 0% versus >0% RVT-PT (hazard ratio = 0.18). RVT-PT predicted EFS for nivolumab plus chemotherapy (area under the curve = 0.74); 2-year EFS rates were 90%, 60%, 57% and 39% for patients with 0–5%, >5–30%, >30–80% and >80% RVT, respectively. Each 1% RVT associated with a 0.017 hazard ratio increase for EFS. Combining pathologic response from PT and LNs helped differentiate outcomes. When compared with radiographic response and circulating tumor DNA clearance, %RVT best approximated EFS. These findings support pathologic response as an emerging survival surrogate. Further assessment of the full spectrum of %RVT in lung cancer and other tumor types is warranted. ClinicalTrials.gov registration: NCT02998528.

Pembrolizumab, Radiotherapy, and Chemotherapy in Neoadjuvant Treatment of Malignant Esophago-Gastric Diseases (PROCEED): Assessment of Pathologic Response in a Prospective, Phase II Single-Arm Trial

A standard treatment paradigm for locally advanced, resectable, non-metastatic esophageal or gastric adenocarcinomas (EGA) is neoadjuvant chemoradiation (CRT) followed by surgical resection. Historical pathologic complete response (pCR) rate after CRT with carboplatin/paclitaxel per the CROSS trial was 23%. The efficacy of immune checkpoint inhibition in the adjuvant setting has since been demonstrated in this patient population. The primary objective of this trial was to investigate whether neoadjuvant CRT combined with pembrolizumab improves pCR compared to the historical control of CRT alone. Single-institution, prospective phase II trial (NCT03064490) evaluating the efficacy and safety of neoadjuvant pembrolizumab combined with CRT followed by adjuvant pembrolizumab in patients with locally advanced operable EGA. CRT (45 Gy in 25 fractions with concurrent, weekly carboplatin [AUC 2] and paclitaxel [50mg/m2 of BSA]) with three cycles of pembrolizumab were administered as neoadjuvant therapy. Patients also received three cycles of adjuvant pembrolizumab after surgical resection. Baseline characteristics were collected. Pathologic response was scored from 0-3 based on tumor regression grading (TRG), with 0 indicating a complete response, 1 indicating marked response (<10% residual disease), 2 indicating partial response, and 3 indicating poor or no response. The percentage of patients with pCR and major pathologic response (MPR, score of 0-1) are described. Accrual of this trial is now complete, with 35 patients with cT2-3N0-2M0 EGA enrolled from 10/10/2017-10/07/2022. 89% of enrolled patients are male, and 94% are white. 97% of patients have an esophageal primary. One patient withdrew from the study prior to completing neoadjuvant therapy due to a severe drug reaction. Two other patients did not undergo surgery, one due to preference and the other due to development of metastatic disease. Of 32 remaining eligible patients, 28 have completed neoadjuvant therapy and surgical resection to date. 100% of patients underwent IMRT/VMAT. 27/28 (97%) patients underwent R0 resection. 10/28 (35.7%: 95% CI: 17%, 53%) patients achieved a pCR, and 14/28 (50%: 95% CI: 31%, 68%) patients achieved an MPR. Patients undergoing neoadjuvant CRT combined with pembrolizumab for EGA experienced a higher rate of pCR/MPR compared to historical controls treated with CRT alone. This phase II trial demonstrates the efficacy of this treatment paradigm, which warrants assessment in future prospective studies.

Pathologic response to neoadjuvant chemotherapy in ovarian cancer and its association with outcome: A surrogate marker of survival

ObjectiveWe aimed to validate whether pathologic response (pR) to neoadjuvant chemotherapy (NACT) using a three-tier chemotherapy response score (CRS) is associated with clinical outcome in ovarian cancer (OC) and could be used as surrogate marker for survival. MethodsWe conducted a retrospective study of OC patients with FIGO stage III/IV disease who received NACT and graded response as no or minimal (CRS 1), partial (CRS 2), or complete/near-complete (CRS 3) pR using tissue specimens obtained from omentum. Uni- and multivariate survival analyses were performed accounting for age, FIGO stage, debulking and BRCA status as well as neoadjuvant use of bevacizumab. ResultsCRSs 1, 2 and 3 were found in 41(31%), 62 (47%) and 30 (22%) of the 133 examined cases. Response to NACT was associated with significantly improved progression-free (PFS, p < 0.001) and overall survival (OS, p = 0.011). Complete/ near-complete pathologic response (CRS3) was associated with improved PFS (median 24.8 vs. 12.5 months, unadjusted HR 0.28 [95%CI 0.15–0.54], p < 0.001; adjusted hazard ration (aHR) 0.31 [95% CI 0.14–0.72], p = 0.007) and OS (median 63.3 vs. 32.1 months, unadjusted HR 0.27 [95%CI 0.10–0.68], p = 0.006; aHR 0.32 [95% CI 0.09–1.11], p = 0.072) when compared to no or minimal response (CRS1). ConclusionsWe validate a three-tier CRS for assessment of pathologic response to NACT in OC and demonstrate its prognostic independence of BRCA status or neoadjuvant bevacizumab use. Improving pR rates may be a useful goal of NACT in OC with the expectation of improved survival. The CRS may be a useful endpoint in clinical trials in OC.

International Association for the Study of Lung Cancer Study of Reproducibility in Assessment of Pathologic Response in Resected Lung Cancers After Neoadjuvant Therapy

IntroductionPathologic response has been proposed as an early clinical trial end point of survival after neoadjuvant treatment in clinical trials of NSCLC. The International Association for the Study of Lung Cancer (IASLC) published recommendations for pathologic evaluation of resected lung cancers after neoadjuvant therapy. The aim of this study was to assess pathologic response interobserver reproducibility using IASLC criteria. MethodsAn international panel of 11 pulmonary pathologists reviewed hematoxylin and eosin–stained slides from the lung tumors of resected NSCLC from 84 patients who received neoadjuvant immune checkpoint inhibitors in six clinical trials. Pathologic response was assessed for percent viable tumor, necrosis, and stroma. For each slide, tumor bed area was measured microscopically, and pre-embedded formulas calculated unweighted and weighted major pathologic response (MPR) averages to reflect variable tumor bed proportion. ResultsUnanimous agreement among pathologists for MPR was observed in 68 patients (81%), and inter-rater agreement (IRA) was 0.84 (95% confidence interval [CI]: 0.76–0.92) and 0.86 (95% CI: 0.79–0.93) for unweighted and weighted averages, respectively. Overall, unweighted and weighted methods did not reveal significant differences in the classification of MPR. The highest concordance by both methods was observed for cases with more than 95% viable tumor (IRA = 0.98, 95% CI: 0.96–1) and 0% viable tumor (IRA = 0.94, 95% CI: 0.89–0.98). The most common reasons for discrepancies included interpretations of tumor bed, presence of prominent stromal inflammation, distinction between reactive and neoplastic pneumocytes, and assessment of invasive mucinous adenocarcinoma. ConclusionsOur study revealed excellent reliability in cases with no residual viable tumor and good reliability for MPR with the IASLC recommended less than or equal to 10% cutoff for viable tumor after neoadjuvant therapy.

The assessment of pathological response to neoadjuvant chemotherapy in muscle-invasive bladder cancer patients with DCE-MRI and DWI: a systematic review and meta-analysis.

The purpose of this meta-analysis was to determine the value of dynamic contrast-enhanced-MRI (DCE-MRI) and diffusion-weighted imaging (DWI) in evaluating the pathological response of muscle invasive bladder cancer (MIBC) to neoadjuvant chemotherapy (NAC), and further indirectly compare the diagnostic performance of DCE-MRI and DWI. Literatures associated to DCE-MRI and DWI in the evaluation of pathological response of MIBC to NAC were searched from PubMed, Cochrane Library, web of science, and EMBASE databases. The quality assessment of diagnostic accuracy studies 2 tool was used to assess the quality of studies. Pooled sensitivity (SE), specificity (SP), positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and the area under the receiver operating characteristic curves (AUC) with their 95% confidence intervals (CIs) were calculated to evaluate the diagnostic performance of DCE-MRI and DWI in predicting the pathological response to NAC in patients with MIBC. There were 11 studies involved, 6 of which only underwent DCE- MRI examination, 4 of which only underwent DWI examination, and 1 of which underwent both DCE- MRI and DWI examination. The pooled SE, SP, PLR, NLR, DOR of DCE-MRI were 0.88 (95% CI: 0.78-0.93), 0.88 (95% CI: 0.67-0.96), 7.4 (95% CI: 2.3-24.2), 0.14 (95% CI: 0.07-0.27), and 53 (95% CI: 10-288), respectively. The pooled SE, SP, PLR, NLR, DOR of DWI were 0.83 (95% CI: 0.75-0.88), 0.88 (95% CI: 0.81-0.93), 7.1 (95% CI: 4.3-11.7), 0.20 (95% CI: 0.14-0.28), and 36 (95% CI:18-73), respectively. The AUCs of SROC curve for DCE-MRI and DWI were 0.93 (95% CI: 0.91-0.95) and 0.92 (95% CI: 0.89-0.94), respectively. There were no significant differences between DWI and DCE-MRI for SE, SP, and AUC. This meta-analysis demonstrated high diagnostic performance of both DCE-MRI and DWI in predicting the pathological response to NAC in MIBC. DWI might be a potential substitute for DCE-MRI, with no significant difference in diagnostic performance between the two. However, caution should be taken when applying our results, as our results were based on indirect comparison. No previous studies have comprehensively analysed the value of DCE-MRI and DWI in evaluating the pathological response to NAC in MIBC. According to the current study, both DCE-MRI and DWI yielded high diagnostic performance, with the AUCs of 0.93 and 0.92, respectively. Indirect comparison no significant difference in the diagnostic performanceof DCE-MRI and DWI.

Immune-checkpoint inhibition for resectable non-small-cell lung cancer - opportunities and challenges.

Therapeutic strategies harnessing the immune system to eliminate tumour cells have been successfully used for several cancer types, including in patients with advanced-stage non-small-cell lung cancer (NSCLC). In these patients, immune-checkpoint inhibitors (ICIs) can provide durable responses and improve overall survival either as monotherapy, or combined with chemotherapy or other immunotherapeutic agents. However, the implementation of ICIs in early stage NSCLC has been hampered by the continuous struggle to develop robust end points to assess their efficacy in this setting, especially those enabling a fast and reproducible evaluation of the clinical activity of neoadjuvant strategies. Several trials are testing ICIs, alone or in combination with chemotherapy, in early stage NSCLC as an adjuvant, neoadjuvant or perioperative approach. As a novelty, most trials in the neoadjuvant setting have adopted pathological response as a primary end point. ICIs have been approved for use in the neoadjuvant and adjuvant settings on the basis of event-free survival and disease-free survival benefit, respectively; however, the correlation of these end points with overall survival remains unclear in these settings. Unresolved challenges for the optimal use of ICIs with curative intent include concerns about their applicability in daily clinical practice and about improving patient selection based on predictive biomarkers or assessment of pathological response and minimal residual disease. In this Review, we discuss the rationale, available strategies and current trial landscape for the implementation of ICIs in patients with resectable NSCLC, and we further elaborate on future approaches to optimize their clinical benefit.

The Current State of Neoadjuvant Therapy in Resectable Advanced Stage Melanoma.

The advent of effective immunotherapy and targeted therapy has significantly improved outcomes in advanced-stage resectable melanoma. Currently, the mainstay of treatment of malignant melanoma is surgery followed by adjuvant systemic therapies. However, recent studies have shown a potential role for neoadjuvant therapy in the treatment of advanced-stage resectable melanoma. Mechanistically, neoadjuvant immunotherapy may yield a more robust response than adjuvant immunotherapy, as the primary tumor serves as an antigen in this setting rather than only micrometastatic disease after the index procedure. Additionally, targeted therapy has been shown to yield effective neoadjuvant cytoreduction, and oncolytic viruses may also increase the immunogenicity of primary tumors. Effective neoadjuvant therapy may serve to decrease tumor size and thus reduce the extent of required surgery and thus morbidity. It also allows for assessment of pathologic response, facilitating prognostication as well as tailoring future therapy. The current literature consistently supports that neoadjuvant therapy, even as little as one dose, is associated with improved outcomes and is well-tolerated. Some patients with a complete pathological response may even avoid surgery completely. These results challenge the current paradigm of a surgery-first approach and provide further evidence supporting neoadjuvant therapy in advanced-stage resectable melanoma. Further research into the optimal treatment schedule and dose timing is warranted, as is the continued investigation of novel therapies and combinations of therapies.

Pembrolizumab, radiotherapy, and chemotherapy in neoadjuvant treatment of malignant esophago-gastric diseases (PROCEED): Assessment of pathologic response and toxicity in a prospective, phase II single-arm trial.

4062 Background: A standard treatment paradigm for locally advanced, resectable, non-metastatic esophageal or gastric adenocarcinomas (EGA) is neoadjuvant chemoradiation (CRT) followed by surgery. Historical pathologic complete response (pCR) rates after CRT with carboplatin/paclitaxel in the CROSS trial are low at 23%. Efficacy of adjuvant immunotherapy has since been shown in this patient population. The main objectives of this trial were to investigate whether neoadjuvant CRT + pembrolizumab improves pCR compared to the historical control of CRT alone, and also determine the associated acute and post-surgical toxicity of this approach. Methods: Single-institution, prospective phase II trial (NCT03064490) evaluating the efficacy and safety of neoadjuvant pembrolizumab + CRT followed by adjuvant pembrolizumab in patients with locally advanced operable EGA. CRT (45 Gy/25 fractions with concurrent weekly carboplatin [AUC 2] and paclitaxel [50 mg/m2 of BSA]) with 3 cycles of pembrolizumab was administered as neoadjuvant therapy. Patients also received 3 cycles of adjuvant pembrolizumab after surgical resection if they did not experience ≥Grade 3 (G3) toxicity during neoadjuvant treatment. Baseline characteristics were collected. Pathologic response was scored from 0-3 per tumor regression grading. The percentage of patients with pCR (score of 0) are described. Acute toxicities are defined per CTCAE v4 and include relevant events occurring within 90 days after treatment. Results: Accrual is complete, with 35 patients with cT2-3N0-2M0 EGA enrolled from 10/10/2017-10/07/2022. 28/32 patients have completed neoadjuvant therapy and surgical resection. 89% of enrolled patients are male, and 94% are white. 97% have an esophageal primary, and 97% underwent R0 resection. 10/28 (35.7%: 95% CI: 17%, 53%) patients achieved a pCR. 22/32 patients have experienced treatment-related ≥G3 non-hematologic toxicity to date (94.2% G3, 5.8% G4). 18 patients experienced ≥G3 toxicity related to neoadjuvant therapy, with 53 events overall, the majority being GI (24.5%) or metabolic/nutritional disorders (24.5%). 10 patients experienced ≥G3 toxicity related to surgery, with 16 events overall, the majority being procedural complications (31.3%) and infectious disorders (31.3%). Conclusions: Patients undergoing neoadjuvant CRT + pembrolizumab for EGA experienced higher rates of pCR and acceptable rates of treatment-related toxicity compared to historical controls. This phase II trial demonstrates the safety and efficacy of this treatment paradigm, which warrants assessment in future prospective studies. Clinical trial information: NCT03064490 .

Comparative study of pathological response evaluation systems after neoadjuvant chemotherapy for breast cancer: developing predictive models of multimodal ultrasound features including shear wave elastography combined with puncture pathology.

This study created a predictive preoperative nomogram dependent on multimodal ultrasound characteristics and primary lesion biopsy results for various pathologic response assessment systems following neoadjuvant chemotherapy (NAC). This retrospective study included 145 breast cancer patients treated at Gansu Cancer Hospital between January 2021 and June 2022 who underwent shear wave elastography (SWE) prior to completing NAC. Intra- and peritumoral SWE features, including maximum (Emax), mean (Emean), minimum (Emin), and standard deviation (Esd) elasticity, were measured individually and linked with the Miller-Payne grading system and residual cancer burden (RCB) class. Univariate analysis was used for conventional ultrasound and puncture pathology. Binary logistic regression analysis was used to screen for independent risk factors and to develop a prediction model. Intratumor Emean and peritumoral Esd differed significantly from the Miller-Payne grade [intratumor Emean: r=0.129, 95% confidence interval (CI): -0.002 to 0.260; P=0.042; peritumoral Esd: r=0.126, 95% CI: -0.010 to 0.254; P=0.047], RCB class (intratumor Emean: r=-0.184, 95% CI: -0.318 to -0.047; P=0.004; peritumoral Esd: r=-0.139, 95% CI: -0.265 to 0.000; P=0.029) and RCB score components (r=-0.277 to -0.139; P=0.001-0.041). Two prediction model nomograms-pathologic complete response (pCR)/non-pCR and good responder/nonresponder-for the RCB class were developed using binary logistic regression analysis for all significant variables in SWE, conventional ultrasound, and puncture results. The area under the receiver operating characteristic curve for the pCR/non-pCR and good responder/nonresponder models was 0.855 (95% CI: 0.787-0.922) and 0.845 (95% CI: 0.780-0.910), respectively. According to the calibration curve, the nomogram had excellent internal consistency between estimated and actual values. The preoperative nomogram can effectively guide clinicians to predict pathological response of breast cancer after NAC and has the potential to guide individualized treatment.

Biopsy-Guided Pathological Response Assessment in Breast Cancer is Insufficient: Additional Pathology Findings of the MICRA Trial

BackgroundNeoadjuvant systemic treatment (NST) leads to pathologic complete response (pCR) in 10–89% of breast cancer patients depending on subtype. The added value of surgery is uncertain in patients who reach pCR; however, current imaging and biopsy techniques aiming to predict pCR are not accurate enough. This study aims to quantify the residual disease remaining after NST in patients with a favorable response on MRI and residual disease missed with biopsies.MethodsIn the MICRA trial, patients with a favorable response to NST on MRI underwent ultrasound-guided post-NST 14G biopsies followed by surgery. We analyzed pathology reports of the biopsies and the surgical specimens. Primary outcome was the extent of residual invasive disease among molecular subtypes, and secondary outcome was the extent of missed residual invasive disease.ResultsWe included 167 patients. Surgical specimen showed residual invasive disease in 69 (41%) patients. The median size of residual invasive disease was 18 mm (interquartile range [IQR] 12–30) in hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) patients, 8 mm (IQR 3–15) in HR+/HER2-positive (HER2+) patients, 4 mm (IQR 2–9) in HR-negative (HR−)/HER2+ patients, and 5 mm (IQR 2–11) in triple-negative (TN) patients. Residual invasive disease was missed in all subtypes varying from 4 to 7 mm.ConclusionAlthough the extent of residual invasive disease is small in TN and HER2+ subtypes, substantial residual invasive disease is left behind in all subtypes with 14G biopsies. This may hamper local control and limits adjuvant systemic treatment options. Therefore, surgical excision remains obligatory until accuracy of imaging and biopsy techniques improve.

Different pathological response and histological features following neoadjuvant chemotherapy or chemo-immunotherapy in resected non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer incidence and mortality worldwide. Neoadjuvant chemo-immunotherapy has led to clinical benefits in resectable NSCLC in comparison to chemo-therapy alone. Major pathological response (MPR) and pathological complete response (pCR) have been used as surrogates of neoadjuvant therapy response and clinical outcomes. However, the factors affecting the pathological response are still controversial. Therefore, in this study we retrospectively examined MPR and pCR in two different cohorts of NSCLC patients, 14 treated by chemotherapy and 12 by chemo-immunotherapy in the neoadjuvant setting. In resected tumor specimens, different histological characteristics were evaluated: necrosis, fibrosis, inflammation, presence of organizing pneumonia, granuloma, cholesterol cleft, and reactive epithelial alterations. In addition, we evaluated how MPR impacts on event-free survival (EFS) and overall survival (OS). In a small group of patients treated by chemo-immunotherapy, a gene expression analysis of the Hippo pathway was performed both in preoperative biopsies and matched post-surgical specimens. We observed a better pathological response in the chemo-immunotherapy treated cohort: 6/12 patients (50.0%) achieved a MPR ≤10% and 1/12 (8.3%) achieved pCR both on primary tumor and on lymph nodes. On the contrary, no patient treated with chemotherapy alone achieved pCR or MPR ≤10%. A higher amount of stroma in the neoplastic bed was observed in patients treated with immuno-chemotherapy. Moreover, patients achieving better MPR (including pCR) had significantly improved overall survival (OS) and event-free survival (EFS). After neoadjuvant chemo-immunotherapy, residual tumors showed a remarkable upregulation of genes consistent with the activation of YAP/TAZ. Also, alternative checkpoint, such as CTLA-4, were enhanced. Our findings showed that neoadjuvant chemo-immunotherapy treatment improves MPR and pCR thus resulting in better EFS and OS. Moreover, a combined treatment could induce different morphological and molecular changes in comparison to chemotherapy alone, thus giving new insights in the assessment of pathological response.

PP01.39 Infrastructure for Interobserver Variability Assessment of Pathologic Response (PR), in Surgical Resection Specimens Following Neoadjuvant Immune Check Point Inhibitor (ICI) Therapies in Early Stage NSCLC

PP01.39 Infrastructure for Interobserver Variability Assessment of Pathologic Response (PR), in Surgical Resection Specimens Following Neoadjuvant Immune Check Point Inhibitor (ICI) Therapies in Early Stage NSCLC

PP01.53 Pathologic Response Assessment Tool – Architecting a Cloud-Based Tool to Streamline Logistics for Shipping, Tracking, Scoring, and Reporting

Immune checkpoint inhibitor (ICI) therapies given in the neoadjuvant setting have been approved for early-stage NSCLC. Pathologic response (PR) in the surgical specimen could be an early clinical indicator of better outcome. However, there is a need to standardize PR assessment. Therefore, IASLC and MDACC have collaborated to conduct an inter-observer PR assessment study using specimens from NSCLC patients treated with ICI based regimens in 6 different clinical trials. In order to collect and store the PR scores from the global pathologists an online tool (cloud-based secured password protected website) had to be created.

Concomitant Use of Biopsy Clips and Wire Localization in Invasive Breast Cancer is Associated With Successful Clip Retrieval

IntroductionSurgical management of the axilla in patients with clinically node-positive breast cancer has shifted to less invasive surgical approaches, such as sentinel lymph node dissection (SLND) and targeted axillary dissection (TAD). Successful retrieval of the biopsy clip marking the lymph node of interest is crucial for assessment of pathologic response and locoregional disease control. MethodsWe performed a retrospective review of patients ≥18 years old with invasive breast cancer and biopsy-proven axillary LN involvement, who underwent LN clip placement from January 2012 to July 2017 at Johns Hopkins Hospital. ResultsOf the 128 eligible patients, the median age at diagnosis was 51.5 years (range, 23-92 years) with predominately stage T2-3 disease (54.7% T2, 42.2% T3), of ductal histology (76.6%), and located in the upper outer quadrant (42.2%). Among the 63.3% (81) of patients who received neoadjuvant systemic therapy, 43.2% (35) had a partial response and 30.9% (25) had a complete response. Axillary procedures performed consisted of 36.7% (47) SLND/TAD, 53.9% (69) ALND, and 9.4% (12) SLND/TAD with conversion to ALND. The clipped LN was successfully retrieved in 63.8% (30) of SLND/TADs, 39.1% (27) of ALNDs, and 58.3% (7) of SLND/TADs followed by ALND. Pre-operative node localization by wire and/or skin markings was performed for 16.4% (21) of patients. Among these, 90.5% (19) of clipped LNs were successfully retrieved, compared to 42.1% (45) retrieved in axillary procedures without preoperative node localization. ConclusionUse of preoperative targeted node localization improved rate of clipped LN retrieval across all three types of axillary procedures.

NAUTIKA1: A Multicenter Phase II Study with a PD-L1+ Cohort of Patients Receiving Atezolizumab (Atezo) with Low-Dose Stereotactic Body Radiation Therapy (SBRT) as Neoadjuvant Therapy for Resectable Stage IB-III NSCLC

<h3>Purpose/Objective(s)</h3> Despite complete surgical resections, cure rates in early-stage NSCLC remain modest. Neoadjuvant and adjuvant chemotherapy (chemo) trials have shown a 5-year overall survival (OS) benefit of 5% in patients (pts) with resectable disease. Developing new treatment strategies to increase cure rates following resection remains critical. Phase III trials including IMpower030, Checkmate 816, AEGEAN, Keynote-671, and Checkmate 77T, tested checkpoint inhibitors (CPIs) in combination with chemo. Checkmate 816 met the primary endpoint with a pathological complete response (pCR) rate of 24% and event-free survival (EFS) in pts with resectable stage IB-IIIA NSCLC. Despite the positive results with CPI + chemo, chemo-free options are still needed for some patients. Preclinical and clinical data in advanced NSCLC indicate that low-dose SBRT may be a potent immunomodulator, enhancing immune response facilitated by CPIs (Demaria et al, 2015; Formenti et al, 2018; Theelen et al, 2019). In a Phase II study, neoadjuvant durvalumab combined with low-dose SBRT (8 Gy × 3) was well tolerated and associated with a major pathologic response (MPR) rate of 53% (Altorki et al, 2021). Given the evidence for atezo antitumor activity in early-stage NSCLC, as seen in LCMC3 (Lee et al, 2020) and IMpower010 (which led to FDA approval of atezo as adjuvant treatment following resection and platinum-based chemo in pts with stage II-IIIA NSCLC, who have PD-L1 expression on ≥1% of tumor cells), NAUTIKA1 now includes a PD-L1+ cohort to explore neoadjuvant atezo with low-dose SBRT. <h3>Materials/Methods</h3> NAUTIKA1 (NCT04302025) PD-L1+ cohort will enroll pts with resectable stage IB-IIIA or select IIIB (T3N2 only) NSCLC (8th edition AJCC TNM staging). Pts must have PD-L1+ status (defined as expression in ≥1% tumor cells by any FDA-approved PD-L1 assay) performed in a Clinical Laboratory Improvement Amendments–certified laboratory. Pts will receive up to 4 cycles of neoadjuvant atezo in combination with low-dose SBRT (8 Gy × 3) in the first cycle, followed by surgical resection and standard-of-care adjuvant treatment. The primary efficacy objective is to evaluate pCR, defined as lack of any viable tumor cells on local pathology review of H&E slides from the lung cancer resection specimen, including all sampled regional lymph nodes. Secondary objectives include investigator-assessed radiographic response, MPR, disease-free survival, EFS, OS, nodal downstaging and circulating tumor DNA clearance. The safety objective includes evaluation of the incidence and severity of adverse events. Exploratory endpoints include correlation of pre- and post-treatment tissue and blood biomarkers with clinical outcome mechanisms of immune escape, as well as evaluation of artificial intelligence–powered digital pathologic response assessment. <h3>Results</h3> TBD <h3>Conclusion</h3> TBD

Abstract 463: Highly accurate machine learning assessment of immune-related pathologic response criteria (irPRC) scoring in patients with non-small cell lung carcinoma (NSCLC) treated with neoadjuvant anti-PD-1-based therapies

Abstract Pathological complete response (no residual viable tumor, RVT) and/or major pathologic response (≤10% RVT) are now primary or secondary endpoints for a large proportion of clinical trials studying neoadjuvant immunotherapeutic regimens. We previously developed a scoring system for assessing pathologic response after immunotherapy, termed irPRC (Cottrell et al. Ann Oncol 2018). By these criteria, %RVT is assessed by dividing RVT by the sum of the surface area on the slide composed of RVT + necrosis + regression bed– the latter feature is where the tumor used to be and is characterized by fibroinflammatory stroma that is distinct from tumoral stroma. We have previously reported high inter-observer reproducibility for pathologic response assessment following immunotherapy. However, these assessments involve performing evaluations that are currently outside the scope of routine surgical pathology training and may be time-consuming. To date, these assessments have primarily been performed by academic pathologists who have seen the largest number of these cases as a part of clinical trials. A machine learning (ML)-powered assessment of irPRC would allow for faster, standardized evaluation and expanded access to patients treated outside of large academic centers. We trained a supervised convolutional neural network to assess pathologic response using irPRC on n=92 H&amp;E-stained slides from patients with advanced, resectable NSCLC treated with neoadjuvant anti-PD-1 +/- anti-CTLA-4 at a single institution. The ML algorithm was trained based on ground-truth manual annotations by pathologists on whole slide digital scans and tested using leave-one-out cross validation. Each of ~830,000 image tiles was classified into one of four classes: tumor, necrosis, immune-mediated regression, or background lung tissue. Receiver operating curves showed that the algorithm exhibited high accuracy for predicting the various tissue classes with an area under the curve of 0.95, 0.96, 0.90, and 0.90 for the four classes, respectively. %RVT was calculated by dividing the surface area of RVT by total tumor bed surface area (RVT + necrosis + regression). There was a strong positive correlation between the machine assessed RVT and the human assessed RVT at both the slide level and case level (aggregate %RVT based on surface area from all slides for a given patient), Pearson’s r=0.95 and r=0.99, respectively. Here, we demonstrate that a ML algorithm performs as well as an experienced pathologist assessment in scoring pathologic response. These findings will need to be validated in larger studies. Additionally, the association of pathologic response with longer term patient outcomes will be evaluated as survival data matures to determine whether pathologic response is a robust surrogate of survival. Citation Format: Julie E. Stein, Vinay Pulim, Tricia R. Cottrell, Patrick M. Forde, Janis M. Taube. Highly accurate machine learning assessment of immune-related pathologic response criteria (irPRC) scoring in patients with non-small cell lung carcinoma (NSCLC) treated with neoadjuvant anti-PD-1-based therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 463.

Pathological Response and Immune Biomarker Assessment in Non-Small-Cell Lung Carcinoma Receiving Neoadjuvant Immune Checkpoint Inhibitors.

Simple SummaryRecently, the U.S. Food and Drug Administration (FDA) approved neoadjuvant immunotherapy plus chemotherapy for the treatment of resectable non-small-cell lung carcinoma (NSCLC) due to the clinical benefits reported in several clinical trials. In these settings, the pathological assessment of the tumor bed to quantify a pathological response has been used as a surrogate method of clinical benefit to neoadjuvant therapy. In addition, several clinical trials are including the assessment of tissue-, blood-, or host-based biomarkers to predict therapy response and to monitor the response to neoadjuvant treatment. In this manuscript, we provide an overview of current recommendations for the evaluation of pathological response and describe potential biomarkers used in clinical trials of neoadjuvant immunotherapy in resectable NSCLC.Lung cancer is the leading cause of cancer incidence and mortality worldwide. Adjuvant and neoadjuvant chemotherapy have been used in the perioperative setting of non-small-cell carcinoma (NSCLC); however, the five-year survival rate only improves by about 5%. Neoadjuvant treatment with immune checkpoint inhibitors (ICIs) has become significant due to improved survival in advanced NSCLC patients treated with immunotherapy agents. The assessment of pathology response has been proposed as a surrogate indicator of the benefits of neaodjuvant therapy. An outline of recommendations has been published by the International Association for the Study of Lung Cancer (IASLC) for the evaluation of pathologic response (PR). However, recent studies indicate that evaluations of immune-related changes are distinct in surgical resected samples from patients treated with immunotherapy. Several clinical trials of neoadjuvant immunotherapy in resectable NSCLC have included the study of biomarkers that can predict the response of therapy and monitor the response to treatment. In this review, we provide relevant information on the current recommendations of the assessment of pathological responses in surgical resected NSCLC tumors treated with neoadjuvant immunotherapy, and we describe current and potential biomarkers to predict the benefits of neoadjuvant immunotherapy in patients with resectable NSCLC.