Incomplete Pathologic Response Research Articles

Efficacy of PD-1 inhibitor with neoadjuvant chemotherapy in hypopharyngeal and oropharyngeal cancer.

This study is aimed to evaluate the efficacy and safety of PD-1 inhibitors combined with neoadjuvant chemotherapy in patients with locally advanced hypopharyngeal and oropharyngeal cancer prior to surgical resection. This retrospective analysis included 42 patients diagnosed with locally advanced hypopharyngeal and oropharyngeal cancer. The efficacy, safety, survival, and laryngeal preservation rate were evaluated. A total of 42 patients were included in this retrospective analysis, of whom 28 had hypopharyngeal cancer and 14 had oropharyngeal cancer. Of the 42 patients, 14 (33.3%) achieved a pathological complete response (PCR) at the primary site, 20 (47.6%) achieved a major pathological response (MPR), and 8 (19%) had an incomplete pathological response (IPR) at the primary lesion. A PCR at both the primary site and the neck lymph nodes was observed in 9 patients (21.4%). The laryngeal preservation rate was 92.9% (26/28) in patients with hypopharyngeal cancer. The median follow-up time was 10.5 months. The median progression-free survival (PFS) was 26.42 months (95% CI, 23.416-29.424), and the median overall survival (OS) was 27.1 months (95% CI, 24.316-29.884). The 1-year PFS rate was 83.1%, and the 1-year OS rate was 85.9%. Combination therapy with PD-1 inhibitors and neoadjuvant chemotherapy has demonstrated superior efficacy and safety as a preoperative treatment for locally advanced hypopharyngeal and oropharyngeal cancer. Notably, this treatment regimen does not increase the risk of severe postoperative complications and has shown promising results in improving laryngeal preservation rates.

Single-cell profiling of response to neoadjuvant chemo-immunotherapy in surgically resectable esophageal squamous cell carcinoma

BackgroundThe efficacy of neoadjuvant chemo-immunotherapy (NAT) in esophageal squamous cell carcinoma (ESCC) is challenged by the intricate interplay within the tumor microenvironment (TME). Unveiling the immune landscape of ESCC in the context of NAT could shed light on heterogeneity and optimize therapeutic strategies for patients.MethodsWe analyzed single cells from 22 baseline and 24 post-NAT treatment samples of stage II/III ESCC patients to explore the association between the immune landscape and pathological response to neoadjuvant anti-PD-1 combination therapy, including pathological complete response (pCR), major pathological response (MPR), and incomplete pathological response (IPR).ResultsSingle-cell profiling identified 14 major cell subsets of cancer, immune, and stromal cells. Trajectory analysis unveiled an interesting link between cancer cell differentiation and pathological response to NAT. ESCC tumors enriched with less differentiated cancer cells exhibited a potentially favorable pathological response to NAT, while tumors enriched with clusters of more differentiated cancer cells may resist treatment. Deconvolution of transcriptomes in pre-treatment tumors identified gene signatures in response to NAT contributed by specific immune cell populations. Upregulated genes associated with better pathological responses in CD8 + effector T cells primarily involved interferon-gamma (IFNγ) signaling, neutrophil degranulation, and negative regulation of the T cell apoptotic process, whereas downregulated genes were dominated by those in the immune response-activating cell surface receptor signaling pathway. Natural killer cells in pre-treatment tumors from pCR patients showed a similar upregulation of gene expression in response to IFNγ but a downregulation of genes in the neutrophil-mediated immunity pathways. A decreased cellular contexture of regulatory T cells in ESCC TME indicated a potentially favorable pathological response to NAT. Cell–cell communication analysis revealed extensive interactions between CCL5 and its receptor CCR5 in various immune cells of baseline pCR tumors. Immune checkpoint interaction pairs, including CTLA4-CD86, TIGIT-PVR, LGALS9-HAVCR2, and TNFSF4-TNFRSF4, might serve as additional therapeutic targets for ICI therapy in ESCC.ConclusionsThis pioneering study unveiled an intriguing association between cancer cell differentiation and pathological response in esophageal cancer patients, revealing distinct subgroups of tumors for which neoadjuvant chemo-immunotherapy might be effective. We also delineated the immune landscape of ESCC tumors in the context of clinical response to NAT, which provides clinical insights for better understanding how patients respond to the treatment and further identifying novel therapeutic targets for ESCC patients in the future.

Neoadjuvant therapy with chemotherapy and immune checkpoint inhibitor for laryngeal function preservation in locally advanced hypopharyngeal cancer.

To evaluate the efficacy and laryngeal function preservation of neoadjuvant treatment with chemotherapy and immune checkpoint inhibitor for locally advanced hypopharyngeal cancer (LAHPC). We retrospectively collected LAHPC patients who were diagnosed between February 2022 and June 2023. The patients received a combination of chemotherapy and immune checkpoint inhibitors as the neoadjuvant therapy. The response to treatment, laryngeal function preservation rate, and short-term survival were assessed. A total of 20 patients were included. Of these patients, 17 (85.0%) had stage IVA-B disease. Ten (50%) and four (20%) patients achieved pathological complete response (PCR) and major pathological response (MPR) to the primary tumor, respectively. In addition, 6 patients had incomplete pathological response (IPR). In the neck, 19 patients had node-positive disease before treatment, and only 5 patients (26.4%) had PCR to regional lymph nodes. Pathologically positive lymph nodes were still observed in 14 (73.6%) patients. Significant downgrading on narrow-band imaging assessment in primary tumors was associated with a higher probability of PCR or MPR than those with IPR (92.9% vs. 33.3%, P=0.014). The overall rate of laryngeal preservation was 95.0%. No severe perioperative complications or perioperative death were found. All patients completed the recommended postoperative radiotherapy/chemoradiotherapy. The median follow-up period was 12.1 months. The 1-year progression-free survival and overall survival were 94.1% and 92.9%, respectively. During the follow-up period, all 19 patients who underwent laryngeal preservation surgery had their laryngeal function preserved. The addition of an immune checkpoint inhibitor to neoadjuvant chemotherapy effectively preserves laryngeal function without increasing complications related to surgery and postoperative radiotherapy in LAHPC.

Characterization of BCL-X L , MCL-1, and BAX Protein Expression in Response to Neoadjuvant Chemotherapy in Breast Cancer.

The use of chemotherapy has improved the overall treatment of breast cancer, which is frequently administered in the form of neoadjuvant chemotherapy (NAC). Apoptosis is an established cell stress response to NAC in preclinical models; however, there is limited understanding of its role in clinical cancer, specifically, its contribution to favorable pathologic responses in breast cancer therapy. Here, we aimed to characterize the change in protein expression of 3 apoptosis-associated biomarkers, namely, BCL-X L , MCL-1, and BAX in breast cancer in response to NAC. For this, we utilized a set of 68 matched invasive breast cancer FFPE samples that were collected before (pre) and after (post) the exposure to NAC therapy that were characterized by incomplete pathologic response. Immunohistochemistry (IHC) analysis suggested that most of the samples show a decrease in the protein expression of all 3 markers following exposure to NAC as 90%, 69%, and 76% of the matched samples exhibited a decrease in expression for BCL-X L , MCL-1, and BAX, respectively. The median H-score of BCL-X L post-NAC was 150/300 compared with 225/300 pre-NAC ( P value <0.0001). The median H-score of MCL-1 declined from 200 pre-NAC to 160 post-NAC ( P value <0.0001). The median H-score of BAX protein expression decreased from 260 pre-NAC to 190 post-NAC ( P value <0.0001). There was no statistically significant association between the expression of these markers and stage, grade, and hormone receptor profiling (luminal status). Collectively, our data indicate that the expression of apoptosis regulatory proteins changes following exposure to NAC in breast cancer tissue, developing a partial pathologic response.

Circulating tumour mutation detection in triple-negative breast cancer as an adjunct to tissue response assessment

Circulating tumour DNA (ctDNA) detection via liquid biopsy is an emerging alternative to tissue biopsy, but its potential in treatment response monitoring and prognosis in triple negative breast cancer (TNBC) is not yet well understood. Here we determined the prevalence of actionable mutations detectable in ctDNA using a clinically validated cancer gene panel assay in patients with TNBC, without recurrence at the time of study entry. Sequencing of plasma DNA and validation of variants from 130 TNBC patients collected within 7 months of primary treatment completion revealed that 7.7% had detectable residual disease with a hotspot panel. Among neoadjuvant treated patients, we observed a trend where patients with incomplete pathologic response and positive ctDNA within 7 months of treatment completion were at much higher risk of reduced progression free survival. We propose that a high risk subset of early TNBC patients treated in neoadjuvant therapy protocols may be identifiable by combining tissue response and sensitive ctDNA detection.

NOXA expression is downregulated in human breast cancer undergoing incomplete pathological response and senescence after neoadjuvant chemotherapy

Neoadjuvant chemotherapy (NAC) is a frequently utilized approach to treat locally advanced breast cancer, but, unfortunately, a subset of tumors fails to undergo complete pathological response. Apoptosis and therapy-induced senescence (TIS) are both cell stress mechanisms but their exact role in mediating the pathological response to NAC is not fully elucidated. We investigated the change in expression of PAMIP1, the gene encoding for the pro-apoptotic protein, NOXA, following NAC in two breast cancer gene datasets, and the change in NOXA protein expression in response to NAC in 55 matched patient samples (pre- and post-NAC). PAMIP1 expression significantly declined in post-NAC in the two sets, and in our cohort, 75% of the samples exhibited a downregulation in NOXA post-NAC. Matched samples that showed a decline in NOXA post-NAC were examined for TIS based on a signature of downregulated expression of Lamin-B1 and Ki-67 and increased p16INK4a, and the majority exhibited a decrease in Lamin B1 (66%) and Ki-67 (80%), and increased p16INK4a (49%). Since our cohort consisted of patients that did not develop complete pathological response, such findings have clinical implications on the role of TIS and NOXA downregulation in mediating suboptimal responses to the currently established NAC.

Frequency of axillary nodal complete pathological response of breast cancer patients in neoadjuvant chemotherapy setting: A cross-sectional study.

Pathological complete response (pCR) occurs in about 20-30% of patients undergoing systemic neoadjuvant therapy. This leads to the idea of sparing the patient the morbidity associated with axillary surgery. "Wait and watch" policy for cancers which achieve complete pathological response on neoadjuvant systemic therapy is a well-established practice in various cancers like the esophagus, rectum and larynx. This has led to organ preservation protocols being practiced worldwide for these cancers without affecting the overall survival of the patient. We believe patients undergoing a complete pathological response in the breast may be spared axillary surgery. Axillary surgery leads to morbidity and extra financial burden with no added advantage in survival. A total of 326 patients with breast cancer who had received neoadjuvant systemic chemotherapy from 2015 to 2020 were included in our retrospective study. Final histopathology of the breast and axillary surgery was noted to report the frequency of complete pathological response. The frequency of positive nodal disease with respect to stage, grade and type of cancer was measured. Among 326 patients, our study showed that 53% of patients with complete pathological response in breast also had complete response in the axilla compared to 43% with incomplete pathological response. No significant difference was found for age, menopausal status, initial tumor size when patients with complete pathological response were compared to non or partial responders. The rate of complete pathological response was higher in patients with clinically node negative patients after NACT, hormone negative, HER2 positive and triple negative population. Our results indicated that 53% of the patients who developed complete pathological response in the breast underwent needless axillary procedure. Axillary surgery can be staged after the breast surgery if residual tumor is present on the histopathological specimen. In case of pCR, omission of axillary surgery can be considered. However, a larger population, multi-centric studies are needed for treatment guidelines.

Machine Learning-Based Radiomic Features on Pre-Ablation MRI as Predictors of Pathologic Response in Patients with Hepatocellular Carcinoma Who Underwent Hepatic Transplant

The aim was to investigate the role of pre-ablation tumor radiomics in predicting pathologic treatment response in patients with early-stage hepatocellular carcinoma (HCC) who underwent liver transplant. Using data collected from 2005-2015, we included adult patients who (1) had a contrast-enhanced MRI within 3 months prior to ablation therapy and (2) underwent liver transplantation. Demographics were obtained for each patient. The treated hepatic tumor volume was manually segmented on the arterial phase T1 MRI images. A vector with 112 radiomic features (shape, first-order, and texture) was extracted from each tumor. Feature selection was employed through minimum redundancy and maximum relevance using a training set. A random forest model was developed based on top radiomic and demographic features. Model performance was evaluated by ROC analysis. SHAP plots were constructed in order to visualize feature importance in model predictions. Ninety-seven patients (117 tumors, 31 (32%) microwave ablation, 66 (68%) radiofrequency ablation) were included. The mean model for end-stage liver disease (MELD) score was 10.5 ± 3. The mean follow-up time was 336.2 ± 179 days. Complete response on pathology review was achieved in 62% of patients at the time of transplant. Incomplete pathologic response was associated with four features: two first-order and two GLRM features using univariate logistic regression analysis (p < 0.05). The random forest model included two radiomic features (diagnostics maximum and first-order maximum) and four clinical features (pre-procedure creatinine, pre-procedure albumin, age, and gender) achieving an AUC of 0.83, a sensitivity of 82%, a specificity of 67%, a PPV of 69%, and an NPV of 80%. Pre-ablation MRI radiomics could act as a valuable imaging biomarker for the prediction of tumor pathologic response in patients with HCC.

Electrochemical therapy (EChT) of cancer tumor with an external anode, a way to achieve pathological complete response

There is a critical need for re-evaluation of electrochemical therapy (EChT) approaches of solid tumors to address the challenges of the currently used method: incomplete pathological response. The coexistence of anode and cathode in the tumor region resulted in acid-alkaline mixation (buffered pH) when the electrodes are so near each other (d < 1cm), and in the non-affected lesions when the electrodes are far from each other (d > 1cm), both have resulted in intact tumoral lesions in EChT field. Here, we presented a designation model study of EChT with an external anode out of the tumor and filled the tumor with dense distribution of cathode electrodes to completely destroy the tumoral lesions without any remaining vital tumoral residues. Anode was located in a biological ionic gel chamber (located on top of the skin) which mediates the ionic interface between the external anode and intratumoral cathode. Our newly reported method can solve the lack of a comprehensive therapeutic guideline for any solid tumors. A remarkable increase in the efficiency of EChT without any over-treating was achieved by alkaline therapy of the tumor (without any limitation in locating cathodic needles all over the tumor) and an external acidic region on top of the skin in a cylindrical gel chamber. We found that the destructive volumes and treating ability of mice tumors by this newly represented method were more significant than the conventional EChT method in fewer therapy sessions and no damage to the skin (both anode and cathode electrodes inside the tumor) (P < 0.05). Results of this study applied to mouse model tumors shed new light on returning attraction to EChT as a valuable complementary method for treating different types of solid breast tumors.

Altered genome‑wide hydroxymethylation analysis for neoadjuvant chemoradiotherapy followed by surgery in esophageal cancer.

Esophageal cancer has high incidence rate in China. Neoadjuvant chemoradiotherapy (nCRT) has become the standard treatment for esophageal squamous cell carcinoma (ESCC). However, there are few reliable epigenetic parameters for patients with ESCC undergoing neoadjuvant therapy. Genomic extract from tumor tissue was amplified and sequenced using the Illumina HiSeq4000 to quantify genes associated methylation or hydromethylation in 12 patients with ESCC undergoing nCRT. The genome-wide hydroxymethylation were analyzed by methylated and hydroxymethylated DNA immunoprecipitation sequencing by MACS2 software and UCSC RefSeq database. Abnormal DNA methylation was statistically different between nCRT-well (showed a pathological complete response to nCRT) and nCRT-poor (showed incomplete pathological response to nCRT) patients. Levels of ten-eleven translocation 1, 2 and 3 mRNA and protein were higher in tumor tissue in nCRT-well group patients than in nCRT-poor group patients. Illumina HiSeq 4000 sequencing identified 2925 hypo-differentially hydroxymethylated region (DhMRs) and 292 hyper-DhMRs in promoter between nCRT-well and nCRT-poor patients. Biological processes associated with hyper-DhMRs included 'snRNA processing', 'hormone-mediated signaling pathway' and 'cellular response'. Metabolic processes were associated with hypo-DhMRs. These data may explain the functional response to nCRT in patients with abnormal promoter of methylation gene-associated mRNA expression. The present results implied that hyper-DhMRs and hypo-DhMRs affect molecular pathways, such as hippo and Notch signaling pathways, highlighting epigenetic modifications associated with clinical response to nCRT in patients with esophageal cancer.

Concurrent Olaparib and Radiotherapy in Patients With Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) cells are sensitive to poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors used as radiosensitizers. Whether combining PARP inhibitors with radiotherapy in patients with TNBC would enhance the biological effectiveness of the irradiation and improve locoregional control is unclear. To assess the safety and tolerability of PARP inhibition with olaparib used concurrently with radiotherapy in patients with TNBC with residual disease after neoadjuvant chemotherapy. This phase 1 prospective dose-escalation trial (Olaparib and Radiation Therapy for TNBC [RadioPARP] trial) using a time-to-event continual reassessment method was performed from September 2017 to November 2019, with follow-up until November 2021. Participants had an incomplete pathologic response after neoadjuvant chemotherapy or unresectable TNBC despite previous neoadjuvant chemotherapy, an Eastern Cooperative Oncology Group Performance Status score of 0 or 1, and adequate organ functions. Olaparib was administered orally in the form of tablets and given at increasing doses (50 mg, 100 mg, 150 mg, or 200 mg twice daily). Olaparib therapy was started 1 week before radiotherapy and was continued concomitantly with radiotherapy. After breast-conserving surgery, a total dose of 50.4 Gy was delivered to the whole breast, with a 63-Gy simultaneously integrated boost to the tumor bed for patients younger than 60 years. After radical mastectomy or for unresectable tumors despite neoadjuvant chemotherapy, a total dose of 50.0 Gy was delivered to the chest wall (after mastectomy) or to the whole breast (for unresectable tumors). Regional lymph node stations could be treated with a total dose of 50.0 Gy to 50.4 Gy in cases of node-positive disease. Main outcomes were the safety and tolerability of PARP inhibition with radiotherapy for early-stage, high-risk TNBC. Secondary outcomes included overall survival (OS) and event-free survival (EFS). Among the 24 patients included in the trial (100% female; median age, 46 years [range, 25-74 years]), no dose-limiting toxic effects were observed, and olaparib was escalated to 200 mg twice daily without reaching the maximum tolerated dose. No late treatment-related grade 3 or greater toxic effect was observed, and the maximum observed treatment-related toxic effects at the 2-year follow-up were grade 2 breast pain, fibrosis, and deformity in 1 patient (4.2%). Three-year OS and EFS were 83% (95% CI, 70%-100%) and 65% (95% CI, 48%-88%), respectively. Homologous recombination status was not associated with OS or EFS. The findings of this phase 1 dose-escalation trial suggest that PARP inhibition with olaparib concurrently with radiotherapy for early-stage, high-risk TNBC is well tolerated and should continue to be evaluated in further clinical trials. ClinicalTrials.gov Identifier: NCT03109080.

A tumor immune microenvironment-related integrated signature can predict the pathological response and prognosis of esophageal squamous cell carcinoma following neoadjuvant chemoradiotherapy: A multicenter study in China

BackgroundCurrently, there are insufficient indicators for the reliable assessment of treatment response following neoadjuvant chemoradiotherapy (nCRT) in patients with esophageal squamous cell carcinoma (ESCC). Considering the essential role of protein-coding and non-coding RNAs in gene regulation and cellular processes, we systematically explored the molecular features and clinical significance of mRNA and lncRNA in 249 pretreatment biopsies from four hospitals in three districts with a high incidence of ESCC patients in China. MethodsDuring the discovery phrase, 13 differentially expressed genes were identified and validated between samples with a complete pathological response (pCR) and those with an incomplete pathological response (<pCR). Subsequently, we constructed a predictive mRNA and lncRNA signature (SERPINE1, LINC00592, and PRKAG2-AS1) using Fisher's linear discriminant analysis (FLDA) with stepwise variant-selection, followed by validation of its predictive ability in both internal and external cohorts. ResultsOur signature showed great value in predicting the response to nCRT among ESCC samples and acted as an independent predictive indicator, in addition to demonstrating great potential in estimating patient prognosis. Interestingly, we found that patients with a high signature score had lower PD-L1 and IDO1 expression levels but higher CD8+ T cells infiltration, suggesting that PD-L1 and IDO1 are negatively correlated with a high signature score and further associated with pCR and a better prognosis. ConclusionThe present study identified a promising three-gene-based predictive signature that has powerful clinical implications for the identification of pCR and a good prognosis among patients with ESCC. Further immune-related exploration may provide an opportunity for future therapeutic combination.

Abstract 1255: Identification of predictive biomarkers for neoadjuvant chemotherapy response in invasive breast cancer Latino patients

Abstract Purpose: Breast cancer (BC) is the leading cause of morbidity and mortality in women in Colombia, constituting a major public health issue. Importantly, not all breast cancer patients respond to neoadjuvant chemotherapy (NAC), leading to an incomplete pathological response and suggesting that there are tumor characteristics that may explain the differences in response. The overarching goal of this study is to identify gene expression profiles associated with an incomplete pathological response to NAC in Colombian women with invasive BC. Design: An integrative transcriptome analysis using Illumina high-throughput RNA sequencing was performed from 63 baseline and post-NAC (follow-up) paraffin-embedded samples from 46 different female patients with locally advanced BC (stage IIB to IIIC) treated at the Colombian National Cancer Institute. Gene expression data were obtained from 42 baseline and 21 follow-up samples. Two comparison analyses were conducted to identify differentially expressed genes (DEGs) first comparing baseline vs follow-up samples from nonresponders to NAC and second comparing to baseline samples from nonresponders vs responders to NAC. Additionally, enrichment analyses were performed in both comparative analyses. Results: From 46 patients included, 20 had a pathological complete response (pCR), while 26 did not show pCR. By investigating the gene expression profiling, 1546 significantly DEGs and 174 DEGs were identified among non-responders and Baseline analyses, respectively. From these analyses, 24 DEGs were found in common and apoptosis as the only shared enrichment pathway (p=0.001). In both analyses, Histone associated genes were downregulated in nonresponders (Histone 3, p=0,001 and Histone 2B, p&amp;lt;0,001). In addition, downregulation of Granzyme B and perforin were also found differentially expressed in apoptosis network pathways. CD8+ naïve T-cells, hematopoietic stem cells, Macrophages, Macrophages M1, Neurons, Th1 cells, activated dendritic cells and pro B cells were defined by the xCell algorithm and showed statistically significant association with non-response to NAC. Conclusions: Changes in histones and tumor microenvironment cell populations elicits local immune response, which contributed to therapeutic efficacy. Downregulation of Granzyme B and perforin could block mechanism of resistance to carcinogenesis, leading to non-response to NAC. Furthermore, patients with tumors containing higher gene signatures of these DEGs may benefit from NAC. Additional validations are needed to confirm these data. If confirmed, these data may be relevant in elucidating the mechanisms that lead to therapy resistance as well as in selecting patients that will benefit from NAC in Latino (Colombian) patients. Citation Format: Hedda Michelle Guevara-Nieto, Rafael Parra-Medina, Juan Carlos Mejia-Henao, Patricia Eugenia López-Correa, José Ismael Guío-Avila, Sandra Diaz-Casas, Jone Garai, Jovanny Zabaleta, Liliana López-Kleine, Alba Lucia Cómbita. Identification of predictive biomarkers for neoadjuvant chemotherapy response in invasive breast cancer Latino patients [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 1255.

Lymph node yield after rectal resection is a predictor of survival among patients with node-negative rectal adenocarcinoma

BackgroundPathologic review of at least 12 lymph nodes is recommended by the American Joint Committee on Cancer following surgical resection of rectal cancer. However, implications of lymph node yield on prognosis are unclear. This study evaluates the impact of lymph node yield on survival among pathologic node-negative patients who received appropriate neoadjuvant chemoradiation. MethodsThe National Cancer Database from 2010 to 2016 was queried for clinical stage II and III rectal adenocarcinoma with neoadjuvant chemoradiation, resection of the primary tumor, negative surgical margins, and pN0M0 pathologic stage. Data were analyzed with χ2, student’s t test, or Mann-Whitney U test as appropriate. Propensity score matching controlled for clinicodemographic variation. Survival was estimated with Kaplan-Meier curves and Cox hazards analysis. ResultsInadequate lymph node yield (1–11 nodes on pathology) led to a 29% increased risk of mortality compared to adequate lymph node yield (≥12 nodes on pathology). Among patients with an incomplete pathologic complete response to neoadjuvant therapy, 5-year survival was estimated to be 73% for inadequate lymph node yield and 78% for adequate lymph node yield (P = .002). Among patients with a complete pathologic response, 5-year survival estimated to be 82% for inadequate lymph node yield and 90% for adequate lymph node yield (P = .006). Among patients with inadequate lymph node yield and complete pathologic response, 5-year survival improved with the use of adjuvant chemotherapy (90.4%), compared to those without adjuvant chemotherapy (78.5%, P < .001). ConclusionThese findings suggest an inadequate lymph node yield can negatively impact survival, despite negative nodal status and a pathologic complete response to neoadjuvant therapy.

PD-L1 expression in breast invasive ductal carcinoma with incomplete pathological response to neoadjuvant chemotherapy.

Objectives:To investigate the expression of programmed death-ligand 1 (PD-L1) in breast cancer in association with incomplete pathological response (PR) to neoadjuvant chemotherapy (NAC).MethodsPD-L1 expression was evaluated using immunohistochemistry in post-operative, post-NAC samples of 60 patients (n = 60) diagnosed with breast invasive ductal carcinoma with incomplete PR to NAC, including 31 matched pre-NAC and post-NAC samples (n = 31). PD-L1 protein expression was assessed using three scoring approaches, including the tumor proportion score (TPS), the immune cell score (ICS), and the combined tumor and immune cell score (combined positive score, CPS) with a 1% cut-off.ResultsIn the post-operative, post-NAC samples (n = 60), positive expression rate of PD-L1 was observed in 18.3% (11/60) of cases by TPS, 31.7% (19/60) by ICS, and 25% (15/60) by CPS. In matched samples, positive expression rate of PD-L1 was observed in 19.3% (6/31) of patients by TPS, 51.6% (16/31) by ICS, and 19.3% (6/31) by CPS in pre-NAC specimens, while it was observed in 22.6% (7/31) of matched post-NAC samples by TPS, 22.6% (7/31) by ICS, and 19.3% (6/31) by CPS. In the matched samples, there was a significant decrease in PD-L1 immunoexpression using ICS in post-NAC specimens (McNemar’s, p = 0.020), while no significant differences were found using TPS and CPS between pre- and post-NAC samples (p = 1.000, p = 0.617; respectively). PD-L1 immunoexpression determined by TPS or CPS was only significantly associated with ER status (p = 0.022, p = 0.021; respectively), but not with other clinicopathological variables. We could not establish a correlation between PD-L1 expression and the overall survival rate (p > 0.05). There were no significant differences in the tumor infiltrating lymphocytes count between the paired pre- and post-NAC samples (t = 0.581, p = 0.563 or Wilcoxon’s Signed Rank test; z = -0.625, p = 0.529).ConclusionOur findings indicate that PD-L1 protein expression in infiltrating immune cells was significantly reduced in breast tumors that developed incomplete PR following the exposure to NAC.

Induction chemotherapy with capecitabine and oxaliplatin followed by chemoradiotherapy before surgery in patients with locally advanced rectal cancer

BackgroundLocally advanced rectal cancer (LARC) has a high incidence of local and distant relapse even after adequate treatment. The emerging role of neoadjuvant induction chemotherapy may allow initial down staging of the primary tumor, less toxicity and early treatment of micrometastatic disease followed by chemoradiation with the hope of increased complete response rates before surgery ObjectivesTo identify the effect of induction chemotherapy before concurrent chemoradiation (CCRTH) in locally advanced rectal cancer in terms of response and toxicity. Primary end point is assessment of pathological complete response rate after surgery. Secondary end points are disease free survival (DFS) and overall survival (OS) after 3 years follow up. Patients and MethodsPatients with MRI based criteria for staging high-risk LARC (T4 tumors, tumors within 2 mm of mesorectal fascia, T3 tumors at or below levators and T2–4 with LN +ve tumors) were included. Thirty-five patients were recruited. Patients received 12 weeks of induction capecitabine/oxaliplatin followed by concomitant capecitabine and conventional 3D-conformal radiotherapy. Surgery was done at least 6 weeks later . ResultsFive patients (20.8%) had a pathological complete response (TRG 0) (ypT0N0). Another three patients (12.5%) had near complete pathological response (TRG 1). Regarding OS and pathological complete response corrlelation, it was statistically not significant in relation to patients with incomplete pathological response (p = 1). ConclusionInduction chemotherapy could be a promising option for better response rates either clinical or pathological for high risk LARC patients with acceptable toxicity.

Development and Assessment of a Clinical Calculator for Estimating the Likelihood of Recurrence and Survival Among Patients With Locally Advanced Rectal Cancer Treated With Chemotherapy, Radiotherapy, and Surgery

Predicting outcomes in patients receiving neoadjuvant therapy for rectal cancer is challenging because of tumor downstaging. Validated clinical calculators that can estimate recurrence-free survival (RFS) and overall survival (OS) among patients with rectal cancer who have received multimodal therapy are needed. To develop and validate clinical calculators providing estimates of rectal cancer recurrence and survival that are better for individualized decision-making than the American Joint Committee on Cancer (AJCC) staging system or the neoadjuvant rectal (NAR) score. This prognostic study developed risk models, graphically represented as nomograms, for patients with incomplete pathological response using Cox proportional hazards and multivariable regression analyses with restricted cubic splines. Because patients with complete pathological response to neoadjuvant therapy had uniformly favorable outcomes, their predictions were obtained separately. The study included 1400 patients with stage II or III rectal cancer who received treatment with chemotherapy, radiotherapy, and surgery at 2 comprehensive cancer centers (Memorial Sloan Kettering [MSK] Cancer Center and Siteman Cancer Center [SCC]) between January 1, 1998, and December 31, 2017. Patients from the MSK cohort received chemoradiation, surgery, and adjuvant chemotherapy from January 1, 1998, to December 31, 2014; these patients were randomly assigned to either a model training group or an internal validation group. Models were externally validated using data from the SCC cohort, who received either chemoradiation, surgery, and adjuvant chemotherapy (chemoradiotherapy group) or short-course radiotherapy, consolidation chemotherapy, and surgery (total neoadjuvant therapy with short-course radiotherapy group) from January 1, 2009, to December 31, 2017. Data were analyzed from March 1, 2020, to January 10, 2021. Chemotherapy, radiotherapy, chemoradiotherapy, and surgery. Recurrence-free survival and OS were the outcome measures, and the discriminatory performance of the clinical calculators was measured with concordance index and calibration plots. The ability of the clinical calculators to predict RFS and OS was compared with that of the AJCC staging system and the NAR score. The models for RFS and OS among patients with incomplete pathological response included postoperative pathological tumor category, number of positive lymph nodes, tumor distance from anal verge, and large- and small-vessel venous and perineural invasion; age was included in the risk model for OS. The final clinical calculators provided RFS and OS estimates derived from Kaplan-Meier curves for patients with complete pathological response and from risk models for patients with incomplete pathological response. Among 1400 total patients with locally advanced rectal cancer, the median age was 57.8 years (range, 18.0-91.9 years), and 863 patients (61.6%) were male, with tumors at a median distance of 6.7 cm (range, 0-15.0 cm) from the anal verge. The MSK cohort comprised 1069 patients; of those, 710 were assigned to the model training group and 359 were assigned to the internal validation group. The SCC cohort comprised 331 patients; of those, 200 were assigned to the chemoradiotherapy group and 131 were assigned to the total neoadjuvant therapy with short-course radiotherapy group. The concordance indices in the MSK validation data set were 0.70 (95% CI, 0.65-0.76) for RFS and 0.73 (95% CI, 0.65-0.80) for OS. In the external SCC data set, the concordance indices in the chemoradiotherapy group were 0.71 (95% CI, 0.62-0.81) for RFS and 0.72 (95% CI, 0.59-0.85) for OS; the concordance indices in the total neoadjuvant therapy with short-course radiotherapy group were 0.62 (95% CI, 0.49-0.75) for RFS and 0.67 (95% CI, 0.46-0.84) for OS. Calibration plots confirmed good agreement between predicted and observed events. These results compared favorably with predictions based on the AJCC staging system (concordance indices for MSK validation: RFS = 0.69 [95% CI, 0.64-0.74]; OS = 0.67 [95% CI, 0.58-0.75]) and the NAR score (concordance indices for MSK validation: RFS = 0.56 [95% CI, 0.50-0.63]; OS = 0.56 [95% CI, 0.46-0.66]). Furthermore, the clinical calculators provided more individualized outcome estimates compared with the categorical schemas (eg, estimated RFS for patients with AJCC stage IIIB disease ranged from 7% to 68%). In this prognostic study, clinical calculators were developed and validated; these calculators provided more individualized estimates of the likelihood of RFS and OS than the AJCC staging system or the NAR score among patients with rectal cancer who received multimodal treatment. The calculators were easy to use and applicable to both short- and long-course radiotherapy regimens, and they may be used to inform surveillance strategies and facilitate future clinical trials and statistical power calculations.

MRI radiomics features of mesorectal fat can predict response to neoadjuvant chemoradiation therapy and tumor recurrence in patients with locally advanced rectal cancer.

To interrogate the mesorectal fat using MRI radiomics feature analysis in order to predict clinical outcomes in patients with locally advanced rectal cancer. This retrospective study included patients who underwent neoadjuvant chemoradiotherapy for locally advanced rectal cancer from 2009 to 2015. Three radiologists independently segmented mesorectal fat on baseline T2-weighted axial MRI. Radiomics features were extracted from segmented volumes and calculated using CERR software, with adaptive synthetic sampling being employed to combat large class imbalances. Outcome variables included pathologic complete response (pCR), local recurrence, distant recurrence, clinical T-category (cT), post-treatment T category (ypT), and post-treatment N category (ypN). A maximum of eight most important features were selected for model development using support vector machines and fivefold cross-validation to predict each outcome parameter via elastic net regularization. Diagnostic metrics of the final models were calculated, including sensitivity, specificity, PPV, NPV, accuracy, and AUC. The study included 236 patients (54 ± 12 years, 135 men). The AUC, sensitivity, specificity, PPV, NPV, and accuracy for each clinical outcome were as follows: for pCR, 0.89, 78.0%, 85.1%, 52.5%, 94.9%, 83.9%; for local recurrence, 0.79, 68.3%, 80.7%, 46.7%, 91.2%, 78.3%; for distant recurrence, 0.87, 80.0%, 88.4%, 58.3%, 95.6%, 87.0%; for cT, 0.80, 85.8%, 56.5%, 89.1%, 49.1%, 80.1%; for ypN, 0.74, 65.0%, 80.1%, 52.7%, 87.0%, 76.3%; and for ypT, 0.86, 81.3%, 84.2%, 96.4%, 46.4%, 81.8%. Radiomics features of mesorectal fat can predict pathological complete response and local and distant recurrence, as well as post-treatment T and N categories. • Mesorectal fat contains important prognostic information in patients with locally advanced rectal cancer (LARC). • Radiomics features of mesorectal fat were significantly different between those who achieved complete vs incomplete pathologic response (accuracy 83.9%, 95% CI: 78.6-88.4%). • Radiomics features of mesorectal fat were significantly different between those who did vs did not develop local or distant recurrence (accuracy 78.3%, 95% CI: 72.0-83.7% and 87.0%, 95% CI: 81.6-91.2% respectively).

Camrelizumab plus chemotherapy as neoadjuvant therapy for resectable, locally advanced esophageal squamous cell carcinoma (NIC-ESCC2019): A multicenter, open-label, single-arm, phase 2 study.

4028 Background: Despite multidisciplinary therapies, prognosis of pts with resectable esophageal squamous cell carcinoma (ESCC) remains poor. Combining PD-1 blockade to neoadjuvant chemotherapy might be a feasible and effective strategy. Camrelizumab (an anti-PD-1 antibody) was approved for advanced or metastatic ESCC in the second-line setting and showed improved anti-tumor activity and survival benefit when combined with chemotherapy in multiple advanced tumors. Methods: In this NIC-ESCC2019 phase 2 study, histologically or cytologically confirmed ESCC pts (stage II-IVA) were enrolled to receive two cycles of neoadjuvant chemoimmunotherapy (NIC) with camrelizumab (200 mg on day 1) plus nab-paclitaxel (260 mg/m² in total on day 1 and day 8) and cisplatin (75 mg/m² in total on days 1-3) of each 21-day cycle, followed by esophagectomy. The primary endpoint was complete pathologic response (CPR) rate in the primary tumor. Besides, we also explored the relationship between the tumor genomic profile or primary-tumor microenvironment and the pathological response. Results: Between Jan 17, 2020 and Dec 8, 2020, 56 pts were enrolled. 51 pts underwent surgical resection, and all had complete tumor resection. CPR was achieved in 18 (35.3%; 95% CI, 21.7%-48.9%) pts; 12 (23.5%) pts had major pathologic response (MPR), and 21 (41.2%) had incomplete pathological response (IPR). Of note, 16 (31.4%) pts achieved CPR in both primary tumor and lymph nodes. The objective response rate was 66.7% (95% CI, 40.0-70.4). No in-hospital mortality occurred. The most common treatment-related adverse events (TRAEs) were decreased WBC (20 [36%] of 56 pts), vomiting (19 [34%]), and alopecia (18 [32%]). Grade 3 TRAEs only occurred in 6 (11%) pts, and there were no grade 4 or 5 TRAEs. The most common immune-related AEs included grade 1-2 rash maculo-papular (7 [13%]) and reactive cutaneous capillary endothelial proliferation (5 [9%]). Presence of mutations in CREBBP and KMT2D at treatment-naïve time-point was correlated with non-response group (IPR and stable disease) (CREBBP, p = 0.046; KMT2D, p = 0.047). Among the immune populations, CD8+, CD8+PD-1+ and CD8+PD-L1+ T cells increased significantly after two doses of NIC, especially in the CPR+MPR group (CD8+, p = 0.013; CD8+PD-1+, p &lt; 0.001; CD8+PD-L1+, p = 0.068). Conclusions: The addition of camrelizumab to neoadjuvant chemotherapy in ESCC demonstrated promising efficacy with acceptable toxicity, supporting the further investigation in a randomized phase 3 clinical trial. Clinical trial information: NCT04225364. [Table: see text]

Expression of therapy-induced senescence markers in breast cancer samples upon incomplete response to neoadjuvant chemotherapy.

Senescence is a cell stress response induced by replicative, oxidative, oncogenic, and genotoxic stresses. Tumor cells undergo senescence in response to several cancer therapeutics in vitro (Therapy-Induced Senescence, TIS), including agents utilized as neoadjuvant chemotherapy (NAC) in the treatment of invasive breast cancer. TIS has been proposed to contribute to adverse therapy outcomes including relapse. However, there is limited evidence on the induction of senescence in response to NAC in clinical cancer and its contribution to disease outcomes. In this work, the expression of three senescence-associated markers (p21CIP1, H3K9Me3 (histone H3 lysine 9 trimethylation), and Lamin B1) was investigated in breast cancer samples that developed partial or incomplete pathological response to NAC (n=37). Accordingly, 40.54% of all samples showed marker expression consistent with a senescence-like phenotype, while the remainders were either negative or inconclusive for senescence (2.70 and 56.8%, respectively). Moreover, analysis of core-needle biopsies revealed minimal changes in p21CIP1 and H3K9Me3, but significant changes in Lamin B1 expression levels following NAC, highlighting a more predictive role of Lamin B1 in senescence detection. However, our analysis did not establish an association between TIS and cancer relapse as only three patients (8.1%) with a senescence-like profile developed short-term recurrent disease. Our analysis indicates that identification of TIS in tumor samples requires large-scale transcriptomic and protein marker analyses and extended clinical follow-up. Better understanding of in vivo senescence should elucidate its contribution to therapy outcomes and pave the way for the utilization of senolytic approaches as potential adjuvant cancer therapy.