Neoadjuvant Therapy Protocols Research Articles

Predictive value of tumor-infiltrating lymphocytes for neoadjuvant therapy response in triple-negative breast cancer: A systematic review and meta-analysis

BACKGROUND The association between tumor-infiltrating lymphocyte (TIL) levels and the response to neoadjuvant therapy (NAT) in patients with triple-negative breast cancer (TNBC) remains unclear. AIM To investigate the predictive potential of TIL levels for the response to NAT in TNBC patients. METHODS A systematic search of the National Center for Biotechnology Information PubMed database was performed to collect relevant published literature prior to August 31, 2023. The correlation between TIL levels and the NAT pathologic complete response (pCR) in TNBC patients was assessed using a systematic review and meta-analysis. Subgroup analysis, sensitivity analysis, and publication bias analysis were also conducted. RESULTS A total of 32 studies were included in this meta-analysis. The overall meta-analysis results indicated that the pCR rate after NAT treatment in TNBC patients in the high TIL subgroup was significantly greater than that in patients in the low TIL subgroup (48.0% vs 27.7%) (risk ratio 2.01; 95% confidence interval 1.77-2.29; P < 0.001, I 2 = 56%). Subgroup analysis revealed that the between-study heterogeneity originated from differences in study design, TIL level cutoffs, and study populations. Publication bias could have existed in the included studies. The meta-analysis based on different NAT protocols revealed that all TNBC patients with high levels of TILs had a greater rate of pCR after NAT treatment in all protocols (all P ≤ 0.01), and there was no significant between-protocol difference in the statistics among the different NAT protocols (P = 0.29). Additionally, sensitivity analysis demonstrated that the overall results of the meta-analysis remained consistent when the included studies were individually excluded. CONCLUSION TILs can serve as a predictor of the response to NAT treatment in TNBC patients. TNBC patients with high levels of TILs exhibit a greater NAT pCR rate than those with low levels of TILs, and this predictive capability is consistent across different NAT regimens.

Treatment of Locally Advanced Rectal Cancer in the Era of Total Neoadjuvant Therapy

Treatment of locally advanced rectal cancer (LARC) involves neoadjuvant chemoradiotherapy plus total mesorectal excision and adjuvant chemotherapy. However, total neoadjuvant therapy (TNT) protocols (ie, preoperative chemotherapy in addition to radiotherapy) may allow better adherence and early treatment of distant micrometastases and may increase pathological complete response (pCR) rates. To assess the efficacy and tolerability of TNT protocols for LARC. MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science Core Collection electronic databases and ClinicalTrials.gov for unpublished studies were searched from inception to March 2, 2024. Randomized clinical trials including adults with LARC who underwent rectal resection as a final treatment were included. Studies including nonoperative treatment (watch-and-wait strategy), treatments other than rectal resection, immunotherapy, or antiangiogenic agents were excluded. Among the initially identified studies, 2.9% met the selection criteria. Two authors independently screened the records and extracted data. Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA)-compliant pairwise and network meta-analyses with a random-effects model were performed in a frequentist framework, and the certainty of evidence was assessed according to the confidence in network meta-analysis approach. The primary outcome was pCR, defined as the absence of residual tumor at pathological assessment after surgery. Secondary outcomes included tolerability, toxic effects, perioperative outcomes, and long-term survival. Of 925 records identified, 27 randomized clinical trials, including 13 413 adults aged 18 years or older (median age, 60.0 years [range, 42.0-63.5 years]; 67.2% male) contributed to the primary network meta-analysis. With regard to pCR, long-course chemoradiotherapy (L-CRT) plus consolidation chemotherapy (relative risk [RR], 1.96; 95% CI, 1.25-3.06), short-course radiotherapy (S-RT) plus consolidation chemotherapy (RR, 1.76; 95% CI, 1.34-2.30), and induction chemotherapy plus L-CRT (RR, 1.57; 95% CI, 1.09-2.25) outperformed standard L-CRT with single-agent fluoropyrimidine-based chemotherapy. Considering 3-year disease-free survival, S-RT plus consolidation chemotherapy (RR, 1.08; 95% CI, 1.01-1.14) and induction chemotherapy plus L-CRT (RR, 1.12; 95% CI, 1.01-1.24) outperformed L-CRT, in spite of an increased 5-year locoregional recurrence rate of S-RT plus consolidation chemotherapy (RR, 1.65; 95% CI, 1.03-2.63). In this systematic review and network meta-analysis, 3 TNT protocols were identified to outperform the current standard of care in terms of pCR rates, with good tolerability and optimal postoperative outcomes, suggesting they should be recognized as first-line treatments.

Utilizing quantitative pathologic analysis of digitized images of rectal cancer (RC) to predict response to neoadjuvant therapy (NAT).

200 Background: We developed and validated a quantitative segmentation algorithm (QuantCRC) to predict disease recurrence in stage I-III colorectal cancer patients (pts) based on the analysis of digitized hematoxylin and eosin (H+E) stained pathology slides. In this study, we aim to determine if QuantCRC analysis on pre-treated RC biopsies can predict pathological complete response (pCR) after NAT which include total neoadjuvant therapy (TNT), chemoradiation (CRT) and others. Methods: Stage II-IV RC pts treated with curative intent modalities between 2005-2023 at Mayo Clinic and University of Pittsburgh were evaluated. Eligible pts had pre and post-treatment tissue available for analysis. Clinical characteristics, treatment, and outcome data were extracted from the medical record. QuantCRC extracted 15 features: %tumor, %stroma, tumor:stroma ratio, %TB/PDC, %mucin, %necrosis, %high-grade, %signet ring cells, tumor-infiltrating lymphocytes (TILs) per cm2 of a tumor, %immature stroma (tumor bed), %inflammatory stroma (tumor bed), %mature stroma (tumor bed), %immature (stromal region), %inflammatory (stromal region), and %mature (stromal region). The associations between the QuantCRC features and pCR were evaluated using Wilcoxon rank-sum tests and logistic regression models while adjusting for primary tumor location and NAT. Results: The identified 288 pts had the following demographics: median age 60, 59% male, 52% distal tumor, 42% TNT. Pts who achieved pCR had smaller pre-treatment tumors (p=0.03), higher TILS, and lower %immature (stroma) (Table 1). After multivariable adjustment, higher TILS and lower %immature (stroma) remain to be significantly associated with a higher likelihood of pCR. A higher %mature (stroma) and %mature stroma (tumor bed) were also identified, in multivariable models, to be associated with a higher rate of pCR. NAT protocol and tumor location (proximal vs. distal) were not associated with pCR. Conclusions: The ability to integrate pathological features with AI may allow for personalized treatment. Using this technology, we recognize that patients who harbor a more mature stromal archetype and inflammatory tumor predisposition, are more likely to achieve pCR to conventional NAT. These pathological features are not currently incorporated into risk stratification in RC. Additional validation and integration into current risk stratification methods is warranted. [Table: see text]

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.

Outcomes Following Recent and Distant Neoadjuvant Radiation in Rectal Cancer: An Institutional Retrospective Review and Analysis of NSQIP

BackgroundNeoadjuvant chemoradiotherapy (nCRT) is the standard of care in locally advanced rectal cancer (LARC). However, radiation therapy is thought to increase operative difficulty due to induction of fibrosis. Total neoadjuvant therapy (TNT) protocols increase the time between completion of radiation and surgical resection which may lead to increased operative difficulty and complications. MethodsA single institution retrospective review of patients ≥18 years with LARC undergoing nCRT from 2015 to 2022. Patients were dichotomized in 2 cohorts: <90 days from radiation to surgery (recent radiation), and ≥90 days from radiation to surgery (distant radiation). Institutional data was compared to National Surgical Quality Improvement Program (NSQIP) rectal cancer data from 2016 to 2020. Outcomes included intraoperative complications, 30-day morbidity, and oncologic outcomes. ResultsOne hundred forty-six institutional patients included, 120 had recent radiation, 26 had distant radiation. Thirty-day morbidity and intraoperative complications did not differ. There was greater radial margin positivity (7% vs. 24%), fewer lymph nodes harvested (17 ± 5 vs. 15 ± 6), and a lower rate of complete mesorectal dissection (88% vs. 65%,) in distant radiation patients 3059 patients were included in NSQIP analysis, 2029 completed radiation <90 days before surgery and 1030 without radiation 90 days before surgery. Patients without radiation 90 days preoperatively had more radial margin positivity (9.2% vs. 4.6%), organ space infection (8.6% vs. 6.4%), and pneumonia (2.2% vs. 0.9%). ConclusionThe present study suggests that increased time between radiation and surgery results in more challenging dissection with less complete mesorectal dissection and increased radial margin positivity without increasing technical complications.

386. ROLE OF RECURRENT NERVE LYMPHADENECTOMY THROUGH MINIMALLY INVASIVE SURGERY IN THE TREATMENT OF OESOPHAGEAL CANCER

Abstract Background With the development of neoadjuvant therapy protocols and the advances in minimally invasive surgery, an increasing number of patients are undergoing surgery of oesophageal cancer. Lymphatic involvement is one of the most important independent prognostic factors. There is enough evidence to support that the greater the lymphadenectomy, the better survival rates. Our aim is to present the results of our series, in which partial or total recurrent nerve lymphadenectomy was performed during oncological oesophagectomies. Methods Retrospective observational study that includes all patients that were operated on for oesophageal cancer from January 2019 to January 2023. All surgeries were performed by the same specialized team. Quantitative variables are described as mean and standard deviation, and qualitative variables as absolute number and percentage. The univariate methods used were Pearson’s X2 or Student’s t test for independent samples. We used logistic regression models to study prognostic factors influencing survival. The IBM SPSS Statistics 22 programme was chosen for data analysis. Results 59 patients were operated during this period through minimally invasive approach, including recurrent nerve lymphadenectomy. Anatomopathological results showed 6 (10.2%) patients with recurrent lymph node involvement, 2 (3.4%) with right-sided positive nodes, 3 (5.1%) with left-sided ones and 1 (1.7%) with bilateral invasion. Analysis by subgroups showed that 20% of tumours larger than T2 had recurrent nerve lymph node metastasis. There were 18 (30.5%) recurrent nerve injuries, all of which were transient except for 3 (5.1%) that required scheduled surgery. A statistically significant relationship was found between the number of affected nodes and disease-free survival time (p-value = 0.045). Conclusions Mediastinal and recurrent nerve lymphadenectomy in oesophageal cancer increases the number of total positive lymph nodes obtained after surgery, allowing for a better adequacy of adjuvant treatment and corelating positively with disease-free survival time. Complications derived from these procedures are similar in number to standard lymphadenectomy and most of them can be managed by conservative treatment.

Abstract P4-03-19: Expected real-world impact of escalation and de-escalation of Her2-directed therapy in breast cancer patients receiving neoadjvuant therapy

Abstract Background: For patients with palpable, early stage, Her2+ breast cancer, neoadjuvant therapy (NAT) is the preferred approach to curative treatment. While Trastuzumab (T) is standardly included in NAT protocols globally, there is variable ability to escalate or potentially de-escalate therapy due to perceived cost/benefit of additional Her2 targeting therapies, such as Pertuzumab (P) in the early stage setting. The impact of neoadjuvant Pertuzumab (NeoP) does have potentially significant impact on the need for therapeutic interventions in the setting of recurrence. It is challenging to estimate the real world impact financially on escalated therapy in the neoadjuvant setting and likewise the long-term effects of cost of recurrent therapy. We wanted to assess and estimate the impact of NeoP addition to T in British Columbian patients with Her2+ early breast cancer, and estimate incremental impact on short and long-term costs to our cancer system. Methods: Utilizing quality assurance database prospectively updated at BC Cancer Vancouver, we extracted cases of patients with Her2+ breast cancer who received NAT between 2012 – 2021 to provide real world estimations of prevalence of cases and estimated annual costs. Descriptive statistics were utilized to calculate rate of pCR in patients receiving neoadjuvant her2 directed therapy. Expected rates of improvement in pCR with the addition of NeoP were extracted from meta-analyses of Her2 directed therapy in the neoadjuvant setting. The publicly available national pCODR Ecomonic Guidance Reports were utilized to identify cost per cycle per patient of Pertuzumab, Trastuzumab, TDM-1 and chemotherapy in the Canadian healthcare system. The additional cost of NeoP per centre, per year, was compared to the current cost of non-Pertuzumab containing neoadjvuant regimen. Based on recurrence data collected from the database, the expected impact of NeoP on rate of recurrence and subsequent need for Her2 directed therapy in the metastatic setting was calculated. Results: 347 patients with HER2+ breast cancer received neoadjuvant T + chemotherapy at the BC Cancer Vancouver Centre between May 2012 and May 2022. 137 patients (39.5%) achieved pCR and 210 (60.5%) did not achieve pCR. Of those who did not achieve pCR, 12% recurred and 6% died, compared to only 5% and 1% respectively in the group that did achieve pCR. Based on a risk ratio of 1.57, we calculated the expected rate of pCR in our real world cohort would have increased from 39.5% to 62.3% with the availability of NeoP routinely. For each year of data in our cohort, an average of 40 patients with Her2 positive disease were treated with neoadjvant therapy. Using modeling based on our real world cohort we predicted an added cost of $669,920 to provide neoadjuvant pertuzuamb at one Canadian Cancer centre per year. Based on extraction of data from current state, where adjvuant TDM-1 is provided for 13 cycles in the setting of no PCR, the adjuvant TDM-1 costs were estimated to be $1, 729, 151 without NeoP and $1,067377 with NeoP. The cost difference for addition of NeoP in the treatment of early Her2+ breast cancer at one Canadian Centre per year was calculated as $8,146 increase in cost. In patients who had recurrence in our cohort we observed a shorter median survival than expected with most patients succumbing to their recurrence within a 2-3 year period. We expanded our modeling to assess the incremental impact on estimated cost of treatment for those who may recur. We estimated a cost saving of $85,054 per centre, per year, related to decrease in risk of recurrence of Her2+ breast cancer in those who receive NeoP. Conclusion: While the additional cost per centre of adding NeoP was $8146, the subsequent decrease in expected rate of recurrence resulted in a cost savings of $85,054. Citation Format: Andrew Mollenthiel, Aidan Morris, Corke Lauren, Christine Simmons. Expected real-world impact of escalation and de-escalation of Her2-directed therapy in breast cancer patients receiving neoadjvuant therapy. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-03-19.

HPB P36 The influence of sarcopenia and systemic inflammation on survival in resected pancreatic cancer

Abstract Background Sarcopenia, cachexia and systemic inflammation are early hallmarks of pancreatic cancer (PC) which hamper systemic therapy and accelerate the terminal stages of the disease. The significant impact of sarcopenia on survival in PC has been demonstrated in numerous meta-analyses using standardised thresholds to define body composition measurements. We sought to determine the influence of sarcopenia and systemic inflammation on survival in our cohort of resected PC patients. We also interrogated the impact of the introduction of neoadjuvant therapy (NAT) protocols on survival, body composition and systemic inflammation. Finally we investigated the use of varying thresholds to define sarcopenia and the impact of this on survival. Methods Analysis of a prospectively maintained database of resected patients with PC accrued through the tertiary West of Scotland Pancreatic Unit was undertaken. Patients with cancer types other than pancreatic ductal adenocarcinoma were excluded. Body composition analysis was carried out using cross-sectional measurements of skeletal muscle area, skeletal muscle density and visceral fat area at the L3 level from pre-treatment or pre-operative CT scan using Slice-o-Matic software (Tomovision, Montreal). Disease-specific survival was used with Log-rank test for survival differences. Results 188 patients underwent resection between 2008–2020. 44.1% received NAT and 65.9% were resected up-front. Using Prado / Martin cutoffs of skeletal muscle index (SMI) to define sarcopenia demonstrated no significant survival difference in either cohort. Visceral obesity and myosteatosis (defined by Doyle / Martin) also demonstrated no significant survival difference. Modified thresholds tailored to our cohort were used and a median survival difference of 34.5 vs 23.1 months was identified (p &amp;lt; 0.001). Similarly for modified BMI-specific thresholds a median survival difference of 35.2 vs 22.8 months was identified (p &amp;lt; 0.001). On further analysis of the NAT cohort, 60.2% of patients exhibited gain in SMI with treatment and 39.8% of patients exhibited loss of SMI. There was a tendency towards poorer survival in the latter group however this was not significant. On further stratification of cohorts in to NAT and up-front resection it was revealed that the predictive effect of sarcopenia was entirely the effect of the up-front resected cohort, with little difference in survival between sarcopenic and non-sarcopenic groups in the NAT cohort. Median survival in all patients (NAT and up-front resection combined) increased from 27.4 months to 32.6 months (p = 0.016) with the introduction of NAT protocols in 2013. Conclusions Defining sarcopenia using modified thresholds tailored specifically to our cohort of patients demonstrates the significant impact of sarcopenia on survival in resected PC. The introduction of NAT protocols in 2013 has had a significant impact on survival, an effect which may be due to the selection of smaller tumours for up-front resection. Further work is needed as part of intention-to-treat analysis to identify patients who undergo NAT who do not progress to resection. Analysis of this cohort will validate our findings and shed further light on the impact of neoadjuvant therapy on sarcopenia and body composition. This analysis is ongoing and further novel data will be presented in September should this abstract be accepted.

Towards Patient-Specific Optimization of Neoadjuvant Treatment Protocols for Breast Cancer Based on Image-Guided Fluid Dynamics.

This study establishes a fluid dynamics model personalized with patient-specific imaging data to optimize neoadjuvant therapy (i.e., doxorubicin) protocols for breast cancers. Ten patients recruited at the University of Chicago were included in this study. Quantitative dynamic contrast-enhanced and diffusion weighted magnetic resonance imaging data are leveraged to estimate patient-specific hemodynamic properties, which are then used to constrain the mechanism-based drug delivery model. Then, computer simulations of this model yield the subsequent drug distribution throughout the breast. By systematically varying the dosing schedule, we identify an optimized regimen for each patient using the maximum safe therapeutic duration (MSTD), which is a metric balancing treatment efficacy and toxicity. With an individually optimized dose (range = 12.11-15.11 mg/m2 per injection), a 3-week regimen consisting of a uniform daily injection significantly outperforms all other scheduling strategies (P < 0.001). In particular, the optimal protocol is predicted to significantly outperform the standard protocol (P < 0.001), improving the MSTD by an average factor of 9.93 (range = 6.63 to 14.17). A clinical-mathematical framework was developed by integrating quantitative MRI data, advanced image processing, and computational fluid dynamics to predict the efficacy and toxicity of neoadjuvant therapy protocols, thus enabling the rational identification of an optimal therapeutic regimen on a patient-specific basis. Our clinical-computational approach has the potential to enable optimization of therapeutic regimens on a patient-specific basis and provide guidance for prospective clinical trials aimed at refining neoadjuvant therapy protocols for breast cancers.

Neoadjuvant (preoperative) chemoradiotherapy of advanced rectal tumors

Introduction: There have been significant changes in the treatment protocol for rectal tumors in recent decades, greatly reducing the rate of local recurrence and distant metastasis, thereby increasing overall survival. Method: We performed a retrospective processing and statistical analysis of the data of 362 patients with rectal cancer who underwent local neoadjuvant chemoradiotherapy and then underwent surgical treatment between 1 January 2010 and 31 December 2017 at the Institute of Surgery of the University of Debrecen. We compared the response rate and overall survival results of our patients with local neoadjuvant treatment to the outcomes of total neoadjuvant treatment reported by the recent large international studies. Results: We experienced complete pathological regression in 8.6% of our patients. After neoadjuvant therapy, 10.7% of our patients experienced distant metastasis at the time of the operation or within 3 months period thereafter. In our study, the rate of response to the neoadjuvant treatment was a prognostic factor independent of the stage at di-agnosis and recognition. The groups with better response produced significantly better survival results. Conclusion: The total neoadjuvant treatment doubled the number of patients with complete pathological response, and the incidence of distant metastasis was by 7% lower in both recent international studies compared to the local neoadjuvant group. 85% of our patients were T3-4N+ stage at the time of recognition. Given the 10.7% rate of dis- tant metastases detected at the time of surgery or within 3 months in our patient population, we can state that ap- proximately half of our patients would have benefited from the administration of total neoadjuvant therapy which produced better outcomes. Based on this conclusion, we decided to introduce the total neoadjuvant therapy protocol in our department for treatment of patients with advanced rectal tumors.

Total neoadjuvant therapy for pancreatic adenocarcinoma increases probability for a complete pathologic response

BackgroundMultiple neoadjuvant therapy protocols have been proposed in the treatment of pancreatic adenocarcinoma, including chemotherapy (CT), chemoradiation (CRT), and total neoadjuvant therapy (TNT), defined as a CT plus CRT. A pathologic complete response (pCR) can be achieved in a minority of cases. We hypothesize that TNT is more likely to confer pCR than other neoadjuvant therapies, which may improve overall survival (OS). MethodsA retrospective review of the National Cancer Database (NCDB) from 2006 to 2016 was performed, identifying patients who underwent any neoadjuvant therapy followed by definitive pancreatic resection for locally advanced or borderline resectable pancreatic adenocarcinoma. A pathologic complete response was defined as down-staging from any clinical stage to pathologic stage 0. ResultsA total of 5402 patients who received neoadjuvant therapy followed by resection were identified. 177 patients (3.3%) achieved a pCR. Of the patients who achieved a pCR, 57 received CT, 41 CRT and 79 received TNT. On multivariate analysis, TNT was more likely to confer a pCR than CRT (OR 1.67, CI 1.13–2.46, p = 0.0103) or CT (OR 2.61, CI 1.83–3.71, p < 0.0001). Patients who achieved pCR had a significantly higher OS, with median survival of 64.9 months, compared to 21.6 months in patients who did not achieve pCR (p < 0.0001). ConclusionTNT may be more likely to achieve a pCR than CT or CRT. Patients who achieve a pCR have a significant OS benefit as compared to those who have residual disease. TNT should be considered for patients requiring neoadjuvant therapy, as it may increase the likelihood of achieving a pCR, thus potentially improving OS.

Abstract PS13-44: Identifying relevant parameters that characterize the early response to NAT in breast cancer patients using a novel personalized mechanistic model integrating in vitro and in vivo imaging data

Abstract The early determination of response to neoadjuvant therapy (NAT) in triple-negative breast cancer would enable the treating oncologist to adapt the therapeutic regimen of a non-responding patient (e.g., by changing dosage, dose schedule, prescribed drugs), and thereby improve treatment outcomes while avoiding unnecessary toxicities. To address this challenge, we propose to use personalized, in silico forecasts of tumor response to therapeutic regimens via a mechanistic mathematical model calibrated with patient-specific longitudinal multi-parametric magnetic resonance imaging (MRI) data acquired early in the course of NAT. Here, we extend our mechanistic model to include a new term describing the synergistic effects of NAT drug combinations and identify the driving parameters involved in its formulation by means of a sensitivity analysis. Our model describes tumor cell dynamics as a combination of proliferation, which is regulated by a logistic term, and mobility, which is described as a diffusion process constrained by the local tumor-induced mechanical stress. Tumor cell density is extracted from diffusion-weighted MRI data, while tissue mechanical properties are defined from segmented T1-weighted MRI data. We adjust the tumor proliferation rate in response to NAT drug combinations with a recent model of drug synergy, MuSyC, which accounts for distinct types of synergistic drug effects (synergy of potency vs. synergy of efficacy). We also consider the heterogeneous intratumoral delivery of drugs by means of perfusion maps estimated from dynamic contrast-enhanced MRI data. We use Sobol’s method for the sensitivity analysis of two different tumors - one well-perfused and one poorly-perfused. We simulate a four-cycle NAT protocol in which NAT drugs are delivered every 14 days, and assess the total effect (ST) of each parameter on the mean relative difference of tumor cell density with respect to a control simulation of tumor growth without NAT. Sensitivity analysis results directly depend on the definition of the parameter space, which we construct by combining two approaches. First, we experimentally constrain parameter ranges using time-resolved, high-throughput, automated microscopy assays to capture the changes in proliferation rates of various breast cancer lines (HCC1143, SUM149, MDAMB231, and MDAMB468) caused by two standard drug combinations: paclitaxel with carboplatin and doxorubicin with perfosfamide (metabolic derivative of the pro-drug cyclophosphamide), and fitting the MuSyC model to these data. Second, we scale the resulting in vitro parameter ranges to clinically-relevant in vivo ranges by running an in silico study with our mechanistic model of breast cancer growth and NAT response. Our results show that, out of the ten parameters involved in the synergy term, three have a dominant role in the dynamics of breast cancer during NAT (ST &amp;gt; 0.1): synergistic potency, the maximal change in tumor cell proliferation by the slowest decaying drug, and its concentration producing half of maximal effects. The other parameters have marginal (0.02 &amp;lt; ST &amp;lt; 0.1) to negligible effect (ST &amp;lt; 0.02). Ongoing studies are assessing the ability of our mechanistic model to forecast NAT response over a small patient cohort after patient-specific calibration of the driving parameters identified in the present study. Citation Format: Guillermo Lorenzo, Angela M. Jarrett, Christian T. Meyer, Darren R. Tyson, Vito Quaranta, Thomas E. Yankeelov. Identifying relevant parameters that characterize the early response to NAT in breast cancer patients using a novel personalized mechanistic model integrating in vitro and in vivo imaging data [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS13-44.

Opportunity and challenge of neoadjuvant treatment in triple negative breast cancer

Triple negative breast cancer (TNBC) is a special type of breast cancer. At present, the major treatment for TNBC is chemotherapy. Neoadjuvant therapy and obtained pathology completed response could bring the TNBC patients better prognosis. The most used TNBC chemotherapy protocols are established on the basis of anthracycline and taxane. Through the thorough knowledge of molecular mechanism of TNBC, neoadjuvant therapy protocols have optimized, including the use of platinum, immune checkpoint inhibitors and poly-ADP-ribose polymerase inhibitors, and assumed positive outcome for TNBC patients.

PS02.126: NEOADJUVANT CHEMORADIOTHERAPY IN ESOPHAGEAL TUMORS: REAL LIFE BEYOND STUDY PROTOCOLS

Abstract Background Neoadjuvant therapy is in common clinical practice in the treatment of patients with esophageal cancer. In our department a phase 2 clinical trial was conducted for a neoadjuvant chemoradiotherapy protocol in patients under 75 with ECOG grade 0–2. At the end of the study, which led to encouraging results, the criteria for inclusion of patients in a neoadjuvant therapy protocol were extended. The aim of this work is to compare the results of the historical group of selected patients (protocol group) with the group of patients treated at the end of the study (real life group). Methods two groups of patients were considered: a historical group from 2003 to 2011 and a more recent group, from 2012 to 2018. The patients of the historical group (protocol group) were selected according to the precise inclusion criteria. The recent group (real life group) includes all patients who, by extension of disease and by comorbidity, could enter into a multimodal strategy in an intention to treat perspective. these two groups were compared for: protocol type, protocol completion, surgery rate, surgery radicality, pathological response and survival. Results In the real life group, 99 patients were referred to protocols different from the protocol considered standard in our department, because they were deemed not able to tolerate the treatment; the rate of completion of intention to treat strategy was 84,5 in the protocol group compared to 80,5 of the real life group (P = 0.326). Rate of radicality were 93,9 vs 92,4 in the protocol group vs to the real life group (P = 0.311). PCR was 49,6 and 35,9 respectively (P = 0.001). 5y disease relate survival was 51,3% for protocol group compared to 42,8 of the real life group in operated on patients (P = 0.467). Considering patient in the real life group that would have been within the inclusion criteria of the protocol group, R0 was 92,9, CPR 35,5 and 5y DRS 49,6 (P = 0581). Conclusion multimodal therapy is certainly the standard of care in these patients, but real life is not as bright as we would like to believe Disclosure All authors have declared no conflicts of interest.

The ever-evolving role of pathologists in the management of breast cancer with neoadjuvant treatment: recommendations based on the Spanish clinical experience

PurposeTo compare the current international standards for neoadjuvant systemic therapy (NAST) protocols, and establish consensus recommendations by Spanish breast pathologists; and to look into the Spanish reality of defining pathological complete response in daily practice.Materials and methodsA modified Delphi technique was used to gain consensus among a panel of 46 experts with regard to important issues about NAST specimens, with the objective of standardize handling and analysis of these breast cancer specimens. In addition, a survey was conducted among 174 pathologists to explore the Spanish reality of post-NAST breast cancer specimens handling.ResultsOur survey shows that pathologists in Spain follow the same guidelines as their international colleagues and face the same problems and controversies. Among the experts, 94.1% agreed on the recommendation for a pre-treatment evaluation with a core needle biopsy, and 100% of experts agreed on the need of having properly indicated information for the post-NAST surgical specimens. However, only 82.7% of them receive properly labelled specimens and even less receive specimens where markers are identified and the degree of clinical/radiological response is mentioned. Among participants 59.9% were familiar with the residual cancer burden system for post-NAST response quantification, but only 16.1% used it regularly.ConclusionsActive participation on breast cancer multidisciplinary teams, optimal usage of core needle biopsy for timely and standardized procedures for the diagnostic analysis, and accurate diagnosis of pathological complete response and complete evaluation of the response to NAST need to become the standard practice when handling breast cancer specimens in Spain.

Principles of esophageal cancer surgery, including surgical approaches and optimal node dissection (2- vs. 3-field).

Surgery for esophageal carcinoma and carcinoma of the gastro-esophageal junction (GEJ) is considered as one of the most complex and challenging interventions on the digestive tract. This is due to the intimate relations with vital structures in the chest and the tendency of early lymphatic dissemination via a dense and complex submucosal network. This review article discusses the different aspects of surgical access routes in the light of the ever-evolving techniques, in particular the minimally invasive esophagectomy (MIE). The aspects of surgical approach are inextricably linked to the still ongoing debate on extent of lymphadenectomy, a debate that is obtaining a new dimension in view of the widely applied neoadjuvant therapy protocols as well as in view of the increasing importance of quality of life aspects after surgery. Finally, the authors provide a practical and patient tailored approach as applied in their center.

Hilar Cholangiocarcinoma: No Longer Hopeless

Cholangiocarcinoma affecting the bifurcation of the common hepatic duct is a devastating disease. Surgical resection is standard therapy, but tumor involvement of vascular and biliary structures in the hilus of the liver often preclude a margin-free resection with preservation of viable liver. During the 1980s, it was thought that liver transplantation would overcome the aforementioned barriers to resection and achieve success in the treatment of unresectable hilar cholangiocarcinoma. The entire tumor can be removed with the liver, including involved vascular and biliary structures, which are simply replaced by implantation of a donor liver. Unfortunately, liver transplantation did not achieve results good enough to justify use of scarce donor livers [1], and hilar cholangiocarcinoma became recognized as a contraindication for liver transplantation. The University of Nebraska attempted to overcome the limitations of transplantation by treating patients with high dose brachytherapy prior to transplantation [2]. Complications from the brachytherapy were prohibitive, but there was an excellent tumor response. Our team at Mayo Clinic Rochester refined this approach and cautiously moved forward with a neoadjuvant therapy protocol that included high-dose external beam therapy, lower dose brachytherapy, and chemosensitization with 5-FU. We proposed that liver transplantation—after careful selection of patients with early stage disease, neoadjuvant therapy, and operative staging—could achieve reasonable survival. We reported our initial results with treatment of 19 patients between 1993 and 2000 [3]. Twelve underwent transplantation with 100 % survival at a median follow-up of 44 months. Since that time, other centers have implemented identical or similar protocols and achieved comparable success. The United Network for Organ Sharing (UNOS) adopted the Mayo Clinic approach, including diagnostic and selection criteria, for MELD (Model for End-stage Liver Disease) exception guidelines [4] and policies. Most commercial insurance plans will cover this treatment, and the CMS (Center for Medicare Services) recently agreed to provide reimbursement as well. In this issue of Digestive Diseases and Sciences, Salgia et al. [5] from the University of Michigan report their findings from a study of the US experience with liver transplantation for cholangiocarcinoma using the US Scientific Registry of Transplant Recipients (SRTR) database. They associate an improvement in patient survival after transplantation with publication of the initial results from Mayo Clinic Rochester in 2000. Their key findings are: (1) national results with liver transplantation for cholangiocarcinoma showed significant improvement after 2000; (2) there were no differences in survival between UNOS regions; (3) the number of transplants for cholangiocarcinoma increased after 2000. They also report that survival was favorably associated with acute cellular rejection. These findings validate the Mayo Clinic protocol, highlight the value of a national registry study, and also demonstrate the limitations of a registry study. Does this report validate the Mayo Clinic protocol? The authors report a significant improvement in survival after 2000 (Figure 4), the time of publication of our initial results. Their study included 595 patients registered for transplantation and 359 transplanted with a diagnosis of cholangiocarcinoma between October 1987 and May 2008. During that time, Mayo Clinic Rochester registered 163 C. B. Rosen (&) Division of Transplantation Surgery, Mayo Clinic, Rochester, MN, USA e-mail: Rosen.Charles@mayo.edu

Impact of FDG-PET and -PET/CT Imaging in the Clinical Decision-Making of Ovarian Carcinoma: An Evidence-Based Approach

The most definitive role of fluorodeoxyglucose (FDG)-PET/computed tomography (CT) at present is surveillance and detecting recurrence in patients who have completed primary therapy but demonstrate a rising serum tumor marker (e.g., CA-125 levels). In this scenario, PET/CT demonstrates high sensitivity and accuracy in detecting lesions that are otherwise challenging, and appears superior (with less interobserver variability) compared with CT alone. Despite the fact that peritoneal deposits may be missed by PET/CT, the overall performance is better than CT alone. FDG-PET does not play a significant additional role in the primary diagnosis of ovarian cancers; however, the role of combined PET/CT modality has recently begun to be re-explored for initial disease staging, particularly because PET/CT can pick up small unsuspected lesions and thereby provide a better disease assessment of the whole body in a single examination. The baseline PET/CT also subserves an important role for future monitoring of therapy response. Therapy monitoring by PET could help to optimize neoadjuvant therapy protocols and to avoid ineffective therapy in nonresponders early in its course, although PET/CT has cost-effectiveness issues that need further evaluation. The prognostic value of FDG-PET/CT has been investigated in the following areas: in the preoperative setting to predict optimal cytoreduction; to assess the value of a positive FDG-PET following primary surgery; and when employed as a replacement for second-look laparotomy following completion of primary surgery and chemotherapy. The data, although promising, are still sparse in all the three domains for a definite recommendation.

Lebertransplantation beim hilären Cholangiokarzinom

Local non-resectable, hilar cholangiocarcinoma can be cured by performing a liver transplantation. The initially poor results after transplantation have significantly improved since neoadjuvant therapy protocols have been established. Therefore, hilar cholangiocarcinoma is now an accepted indication for liver transplantation in selected patients. This article summarizes the current state, recommendations and results of liver transplantation for these patients.

Predicting response to neoadjuvant therapy in esophageal cancer

Despite improvements in preoperative staging, surgical techniques and postoperative care, the 5-year survival rate of patients with locally advanced esophageal cancer remains only approximately 15–40%. Therefore, multimodality treatment options have been widely promoted in the therapy of this malignant disease. However, recent meta-analyses evaluating randomized trials of neoadjuvant therapy protocols prior to surgery for patients with advanced esophageal cancer showed only modest improvement of survival for the whole treatment group. Among these patients, those with excellent histopathologic response seem to benefit greatly from neoadjuvant regimens. Therefore, predictive markers to allow individualization of multimodality therapy in locally advanced esophageal cancer are needed to identify those who will benefit the most. Unfortunately, there is still a great lack of markers for response assessment in patients with esophageal cancer undergoing multimodality therapy. Endoscopy, endoscopic biopsies, computed tomography and endoscopic ultrasound do not seem to provide reliable information for assessing the response to neoadjuvant therapy. Whether 18F-fluorodeoxyglucose-PET can effectively characterize responders in neoadjuvant therapy protocols remains controversial. Finally, although results of mostly retrospective studies on molecular factors for response assessment in esophageal cancer patients are promising, these markers do not yet provide a reliable and cost-effective molecular tool for utilization in clinical practice.