Excellent Pathologic Response Research Articles

Resectability versus Operability in Early-Stage Non-Small Cell Lung Cancer.

With increased detection of early-stage non-small cell lung cancer (NSCLC) owing to screening, determining optimal management increasingly hinges on assessing resectability and operability. Resectability refers to the feasibility of achieving microscopically negative margins based on tumour size, location and degree of local invasion and achieving an anatomical lobar resection. Operability reflects the patient's tolerance for resection based on comorbidities, cardiopulmonary reserve and frailty. Standardized criteria help guide these assessments, but application variability contributes to practice inconsistencies. This review synthesizes a strategic approach to evaluating resectability and operability in contemporary practice. Standardization promises reduced care variability and optimized patient selection to maximize curative outcomes in this new era of early detection. Recent pivotal trials demonstrate equivalency of sublobar resection to lobectomy for small, peripheral, node-negative NSCLC, expanding options for parenchymal preservation in borderline surgical candidates. Furthermore, recent phase 3 trials have highlighted the benefit of chemoimmunotherapy as a neoadjuvant treatment with an excellent pathological response and a down staging of the tumour, improving the resectability of the early-stage NSCLC. A good assessment of the operability and resectability is paramount in order to offer the best course of treatment for our patients. European and American societies have issued recommendations to help clinicians assess the cardiopulmonary function and predict the extension of pulmonary resection that could afford the patient. This operability assessment is closely linked with the evaluated tumour resectability which will determine the extension of pulmonary resection that is needed for the patient in order to achieve a good oncological outcome. Some major progresses have been done recently to improve the operability and resectability of patients. For instance, prehabilitation program allows better postoperative morbidity. Some studies have shown a potential good oncological outcome with sublobar resection expending access to surgery for patient with reduced lung function. Some others have identified the neoadjuvant immunochemotherapy as a potential solution for downstaging tumours. Work-up of early-stage NSCLC is a key moment and has to be done thoroughly and in full knowledge of the recent findings in order to propose the most appropriate treatment for the patient.

Induction Chemotherapy and Toripalimab for Larynx Preservation in Resectable Locally Advanced Laryngeal/Hypopharyngeal Carcinoma: Preliminary Results of INSIGHT Study

Previous studies have demonstrated excellent pathological response of induction PD-1 inhibitor with chemotherapy for locally advanced head and neck cancer. To our knowledge, there is scarce evidence on induction chemotherapy (ICT) and PD-1 inhibitor in organ preservation for patients (pts) with laryngeal/hypopharyngeal carcinoma. Hence, the aim of this study is to evaluate the efficacy and toxicities of ICT and PD-1inhibitor (Toripalimab) followed by radiotherapy or surgery, for pts with resectable locally advanced laryngeal/hypopharyngeal carcinoma. This isa single-arm phase II study. Pts with histopathologic confirmed, resectable locally advanced laryngeal/hypopharyngeal squamous cell carcinoma and ECOG PS 0-1 were eligible. Three cycles of ICT (paclitaxel 175 mg/m d1, cisplatin 25 mg/m d1-3) combined with PD-1 inhibitor (Toripalimab 240 mg d0) were given. Response assessment (RECIST 1.1) was performed post-ICT. Patients with complete response (CR)/partial response (PR) of primary tumor received concurrent chemoradiation, followed by maintenance therapy of Toripalimab for eight cycles. Otherwise, patients were referred to surgery, followed by adjuvant radiation (RT)/chemoradiation (CRT), and then maintenance therapy of Toripalimab. The primary endpoint is larynx-preservation (LP) rate at 3 months post-RT. Forty-two patients were planned. Based on a two-stage Fleming design (one-sided α:10%, power: 80%), if at least 22 patients attained LP of the first 27 patients in stage I or at least thirty-two pts attained LP of the 42 patients at the end of stage II, the null hypothesis would be rejected. The cohort would enroll 15 more pts in stage II if 19-21 pts in stage I observed LP, and the study would be terminated if the number of pts with LP were less than 18 in stage I. A total of 27 pts were enrolled. By the cut-off date Feb 8, 2023, all reached at least 3 months of follow-up post-RT. Median age was 63 (53-74) years with 92.6% male. Hypopharyngeal cancer accounted for 66.7%. There were 74.1% who were T3 to T4, and 77.7% were N2 to N3. Six cases had primary invasion of esophagus and five pts underwent pretreatment tracheostomy. ORR of ICT was 85.2%. Afterward, 21 pts were treated with concurrent CRT, while 6 pts received surgery of primary tumor. At 3 months post-RT, 23 pts attained organ preservation and the LP rate was 85.2%. With a median follow-up of 13.5 months, 1-year OS rate, PFS rate and LP survival rate was 83.1%, 79.5% and 79.4%, respectively. During ICT, 22.2% of pts experienced grade 3-4 treatment-related AEs (TRAEs). The most common grade 3-4 TRAEs were nausea and neutrophil count decreased. The primary endpoint LP rate was met. In this cohort of extensive locally advanced laryngeal/hypopharyngeal carcinoma, ICT and Toripalimab followed by radiotherapy or surgery resulted in satisfactory short-term LP rate and encouraging survival.

Induction chemotherapy and toripalimab for larynx preservation in resectable locally advanced laryngeal/hypopharyngeal carcinoma: Preliminary results of INSIGHT study.

6068 Background: Previous studies have demonstrated excellent pathological response of induction PD-1 inhibitor with chemotherapy for locally advanced head and neck cancer. To our knowledge, there is scarce evidence on induction chemotherapy (ICT) and PD-1 inhibitor in organ preservation for patients (pts) with laryngeal/hypopharyngeal carcinoma. Hence, the aim of this study is to evaluate the efficacy and toxicities of ICT and PD-1 inhibitor (Toripalimab) followed by radiotherapy or surgery, for pts with resectable locally advanced laryngeal/hypopharyngeal carcinoma. Methods: This is a single-arm phase II study. Pts with histopathologic confirmed, resectable locally advanced laryngeal/hypopharyngeal squamous cell carcinoma and ECOG PS 0-1 were eligible. Three cycles of ICT (paclitaxel 175mg/m2 d1, cisplatin 25mg/m2 d1-3) combined with PD-1 inhibitor (Toripalimab 240mg d0) were given. Response assessment (RECIST 1.1) was performed post-ICT. Pts with complete response (CR)/partial response (PR) of primary tumor received concurrent chemoradiation, followed by maintenance therapy of Toripalimab for eight cycles. Otherwise, pts were referred to surgery, followed by adjuvant radiation (RT)/chemoradiation (CRT), and then maintenance therapy of Toripalimab. The primary endpoint is larynx-preservation (LP) rate at 3 months post-RT. Forty-two pts were planned. Based on a two-stage Fleming design (one-sided α:10%, power: 80%), if at least 22 pts attained LP of the first 27 pts in stage I or at least 32 pts attained LP of the 42 pts at the end of stage II, the null hypothesis would be rejected. The cohort would enroll 15 more pts in stage II if 19-21 pts in stage I observed LP, and the study would be terminated if the number of pts with LP were less than 18 in stage I. Results: A total of 27 pts were enrolled. By the cut-off date Feb 8th, 2023, all reached at least 3 months of follow-up post-RT. Median age was 63 (53-74) years with 92.6% male. Hypopharyngeal cancer accounted for 66.7%. 74.1% were T3 to T4, and 77.7% were N2 to N3. Six cases had primary invasion of esophagus and five pts underwent pretreatment tracheostomy. ORR of ICT was 85.2%. Afterwards, 21 pts were treated with concurrent CRT, while 6 pts received surgery of primary tumor. At 3 months post-RT, 23 pts attained organ preservation and the LP rate was 85.2%. With a median follow-up of 13.5 months, 1-year OS rate, PFS rate and LP survival rate was 83.1%, 79.5% and 79.4%, respectively. During ICT, 22.2% of pts experienced grade 3-4 treatment-related AEs (TRAEs). The most common grade 3-4 TRAEs were nausea and neutrophil count decreased. Conclusions: The primary endpoint LP rate was met. In this cohort of extensive locally advanced laryngeal/hypopharyngeal carcinoma, ICT and Toripalimab followed by radiotherapy or surgery resulted in satisfactory short-term LP rate and encouraging survival. Clinical trial information: NCT04995120 .

The Role of miR-375-3p, miR-210-3p and Let-7e-5p in the Pathological Response of Breast Cancer Patients to Neoadjuvant Therapy.

Background and Objectives: Prediction of response to therapy remains a continuing challenge in treating breast cancer, especially for identifying molecular tissue markers that best characterize resistant tumours. Microribonucleic acids (miRNA), known as master modulators of tumour phenotype, could be helpful candidates for predicting drug resistance. We aimed to assess the association of miR-375-3p, miR-210-3p and let-7e-5p in breast cancer tissues with pathological response to neoadjuvant therapy (NAT) and clinicopathological data. Material and methods: Sixty female patients diagnosed with invasive breast cancer at The Oncology Institute “Ion Chiricuță”, Cluj-Napoca, Romania (IOCN) were included in this study. Before patients received any treatment, fresh breast tissue biopsies were collected through core biopsy under echographic guidance and processed for total RNA extraction and miRNA quantification. The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) database was used as an independent external validation cohort. Results: miR-375-3p expression was associated with more differentiated tumours, hormone receptor presence and lymphatic invasion. According to the Miller–Payne system, a higher miR-375-3p expression was calculated for patients that presented with intermediate versus (vs.) no pathological response. Higher miR-210-3p expression was associated with an improved response to NAT in both Miller–Payne and RCB evaluation systems. Several druggable mRNA targets were correlated with miR-375-3p and miR-210-3p expression, with upstream analysis using the IPA knowledge base revealing a list of possible chemical and biological targeting drugs. Regarding let-7e-5p, no significant association was noticed with any of the analysed clinicopathological data. Conclusions: Our results suggest that tumours with higher levels of miR-375-3p are more sensitive to neoadjuvant therapy compared to resistant tumours and that higher miR-210-3p expression in responsive tumours could indicate an excellent pathological response.

Primary analysis of MUKDEN 01: A multicenter, single-arm, prospective, phase 2 study of neoadjuvant treatment with pyrotinib and letrozole plus dalpiciclib in triple-positive breast cancer.

588 Background: Despite the use of multiple lines of targeted therapy has revolutionized treatment for HER2-positive breast cancer, these methods still have limited efficacy for triple-positive breast cancer (TPBC), which calls for persistent exploration for optimized treatment strategy. This MUKDEN-01 prospective trial aimed to evaluate the efficacy of oral, chemo-sparing neoadjuvant therapy with pyrotinib, letrozole and dalpiciclib, which also meet the need for treatment convenience under COVID-19 pandemic, for patients with TPBC. Methods: The MUKDEN 01 was an investigator-initiated, multicentre, single arm, prospective phase II trial, which was performed at twelve hospitals in China(NCT04486911). Treatment-naïve patients with stage II-III tumors that according to the AJCC 8th edition criteria were eligible. Patients were treated with each cycle of 4 weeks with oral administration of pyrotinib 320 mg, and letrozole 2.5mg once daily for 4 weeks, and dalpiciclib 125 mg once daily for three weeks, followed by one week off, for five cycles. The primary endpoint was pathological complete response (pCR) in the breast and axilla (ypT0/is ypN0). Secondary endpoints included pCR in the breast (ypT0/is). residual cancer burden (RCB) score, Ki67 index change at surgery compared with baseline, and safety. Safety was analyzed in all patients, who received treatment. The study is still ongoing, and the enrollment has been completed. Results: Between June 20, 2020 and Sep. 6, 2021, 68 patients were screened for eligibility and 61 patients were recruited into this first stage of study. After surgery, 18 (29.5%, 95% CI 18.5-42.6) out of 61 patients achieving tpCR(ypT0/is ypN0), 21 (34.4%, 95% CI 22.7-47.7) patients achieved bpCR(ypT0/is). The patients with excellent pathologic response (RCB 0-1) to the combined therapy accounted for 54.1% (33/61, 95% CI 40.9-66.9). Mean Ki67 expression was reduced from 38.7% (95%CI: 31.3-46.0) at baseline to 19.3% (95% CI:13.6-25.0; p=0.0001) in the surgical samples. The most frequent grade 3 AE were neutropenia (35 [57%]), leukopenia (13 [21%]), diarrhea (9 [15%]) and oral mucositis (4 [7%]). There were five grade 4 neutropenia (8%) and one grade 4 increased AST (2%), but without other SAE and death throughout the study. Conclusions: Neoadjuvant therapy with pyrotinib, letrozole and dalpiciclib yielded a pCR rate comparable to standard chemotherapy plus dual HER2 blockade in TPBC patients. The combined therapy was also well-tolerated and provided a chemo-sparing neoadjuvant approach for TPBC patients. To our knowledge, this is the first study to evaluate the therapeutic efficacy of a chemo-free neoadjuvant treatment with HER2 TKI pyrotinib and letrozole plus CDK4/6 inhibitor dalpiciclib for TPBC patients. Further validation in a large-scale randomized controlled trial is warranted. Clinical trial information: NCT04486911.

The ratio of CD8\u2009+\u2009lymphocytes to tumor-infiltrating suppressive FOXP3\u2009+\u2009effector regulatory T cells is associated with treatment response in invasive breast cancer

PurposeFOXP3 + and CD8 + are recognized markers of tumor-infiltrating lymphocytes (TILs) for breast cancer. FOXP3 + TILs are composed of effector Tregs (eTregs) and other subpopulations that are classified by their differences in suppressive function. In this prospective study, we evaluated Treg subpopulations and CD8 + TILs in breast cancer.Methods84 patients with breast cancer were enrolled. Fresh TILs were extracted andTregs were classified into eTregs (CD4+FOXP3highCD45RA−), other FOXP3+ Treg subsets (naïve and non-Tregs), and total CD8+CD4− TILs using flow cytometry. The suppression strength of each Treg subpopulation was analyzed. The association between TIL subpopulations, clinicopathological characteristics, and response to chemotherapy was evaluated.ResultsThe mean CD8/eTreg ratio value was 7.86 (interquartile range: 4.08–12.80). The proliferation function of eTregs was significantly suppressed compared with that of the other subpopulations (proliferation rates: control: 89.3%, + naiiveTreg: 64.2%, + non-Treg: 78.2% vs eTreg 1.93%; all P < 0.05). The patients with high with a high CD8 + /eTreg ratio achieved excellent pathological complete response (pCR) rate of neoadjuvant chemotherapy (90.2%) and the CD8/eTreg ratio were independent predictive factors for pCR (odds ratio:18.7(confidence interval 1.25–279) P < 0.05). A detailed assessment of the CD8/eTreg ratio for each patient who underwent NAC revealed that high CD8/eTreg ratio showed a significantly higher pCR rate compared to patients with a low CD8/FOXP3 ratio (39.6% vs 13.3, P < 0.05) in triple negative subtype patients with stromal TILs < 50%.ConclusionsA high CD8/eTreg ratio enhances pCR rate in patients with invasive breast cancer.

Pathological response following neoadjuvant immunotherapy in mismatch repair-deficient/microsatellite instability-high locally advanced, non-metastatic colorectal cancer.

This case series demonstrates an excellent pathological response to neoadjuvant checkpoint inhibitor (CPI) therapy in patients with mismatch repair-deficient (dMMR) colorectal cancer, which has translated into exemplary short-term oncological outcomes. As well as validating the utility of neoadjuvant CPI therapy in dMMR colorectal cancer, it also opens the door to future study of limited resection in patients with tumours that would otherwise require multivisceral resection.

Pragmatic use of short-course radiotherapy, chemotherapy and surgery for stage IV rectal cancer with locally advanced or symptomatic primary tumours.

We assessed management of patients with de novo metastatic rectal cancer, referred for radiotherapy to the rectum, who were candidates for short-course radiotherapy (SCRT) and chemotherapy, followed by resection of all disease. We assessed surgical outcomes, overall survival (OS) and progression-free survival (PFS). Retrospective review of patients meeting criteria: (i) treatment with SCRT to rectum; (ii) locally advanced primary rectal cancer; and (iii) resectable distant metastases at diagnosis. Data were collected from charts, correspondence and electronic patient records. OS and PFS were calculated using the Kaplan-Meier method. Between 2016 and 2020, 48 patients with stage IV rectal cancer at diagnosis were treated with SCRT. Only 15 patients (31%) had resectable metastatic disease and were intended for SCRT (25 Gy/5#), then chemotherapy, followed by resection of all sites of disease and are included in our study. 12 of the 15 surgical candidates (80%) had rectal surgery as planned, and 11 of the 15 (73%) had resection of the rectal primary and all metastatic disease. One patient had a pathological complete response (pCR), and 50% of surgical patients had a Mandard TRG of 1 or 2. Median PFS and OS for the 15 surgical candidates were 12.6 and 25.2 months, respectively, with a median FU of 21.2 months. For this cohort of patients, our treatment paradigm is pragmatic and results in excellent pathological response. However, the effectiveness of this approach should be the subject of future prospective studies.

196P - The tolerability and efficacy of FOLFIRINOX in gastro-oesophageal carcinoma

Background5-FU based regimens represent the gold standard of therapy for gastroesophageal carcinomas. Options include Cisplatin-5FU doublets, FOLFOX and FOLFIRI, and in the neo-adjuvant setting FLOT is emerging as a popular choice for those with good performance status. We identified two cohorts of patients who received m-FOLFIRINOX as first line treatment of gastroesophageal carcinoma; patients undergoing neo-adjuvant therapy in whom FLOT was thought to be too toxic, and those with extensive metastatic disease where it was thought that they would not be fit enough for second line therapy. In these settings there is a theoretical advantage to FOLFIRINOX as it exploits the synergy between Oxaliplatin and Irinotecan; Oxaliplatin forms platinum-DNA adducts and Irinotecan prevents the repair of these adducts impeding the development of platinum resistance. We prospectively evaluated our single institution use of FOLFIRINOX in both neo-adjuvant and advanced treatment of gastro-oesophageal carcinomas. Methods14 patients with oesophageal, gastro-oesophageal junction or stomach carcinoma gave informed consent to treatment with FOLFIRINOX. Five of these patients had extensive metastatic disease at diagnosis. Response to treatment was recorded via combined CT/PET scanning, endoscopy reports, tumour markers and pathology. ResultsAll nine patients being treated neo-adjuvantly displayed a good metabolic response prior to surgical resection. Of note was one patient who received only two cycles, however achieved reduction in his tumour from T3N2 to T2N0, which was then completely resected. For the five patients with extensive disease, all showed complete metabolic responses on PET, after having an average of 10.6 cycles each of FOLFIRINOX treatment. Only one patient relapsed 6 months after completing treatment, who subsequently responded to FOLFIRINOX retreatment, and died 23 months after diagnosis. ConclusionsFOLFIRINOX appears to be highly effective in the treatment of early stage and metastatic gastro-oesophageal adenocarcinomas, as well as showing an excellent pathological response rate which aids surgical resection. This case series suggest that the regimen should be formally trialled, comparing tolerability and efficacy against FLOT. Legal entity responsible for the studySt John Of God Hospital Subiaco. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Abstract ES7-3: Indications for radiation treatments after neoadjuvant chemotherapy while awaiting the results of clinical trials

Abstract Using systemic therapy prior to surgery has become an accepted standard for patients with lymph node-positive disease at presentation. Studies demonstrate that this approach can eradicate the disease in lymph nodes prior to local-regional interventions. This occurs particularly frequently for patients with HER2/neu-positive disease and to a relevant degree for those with triple negative disease. Patients with an excellent pathological response to treatment have improved outcomes compared to those with extensive residual disease. However, it is less clear whether local-regional therapies can be diminished or omitted in patients with an excellent pathological response. Accordingly, such questions are currently being investigated in phase III clinical trials. Unfortunately, local-regional therapeutic trials require long-term outcome data, particularly for the endpoints of distant disease control and overall survival. Therefore, the ongoing studies addressing whether regional lymph node radiation can be omitted in selected patients after neoadjuvant chemotherapy will not provide clinically useful information in the near term. This is unfortunate because such questions arise with a high degree of frequency in oncology practices. This topic has also become increasingly important because completed clinical trials indicate that regional lymph node radiation combined with treatment of the chest wall/breast improves the outcome of patients with pathologically positive lymph node(s) and who are treated with surgery first followed by adjuvant systemic therapy. While the sequencing of chemotherapy and surgery does not affect the risk of local-regional recurrence for populations of patients, it does affect an individual patient's risk. For example, patients with clinically stage II, lymph node-positive disease (who do not receive radiation) will have lower risk of local-regional recurrence if they achieve a pathological complete response to neoadjuvant chemotherapy compared to those with residual positive lymph nodes. This is also true for patients with clinical stage III disease, although patients with locally advance breast cancer have a high enough risk for local recurrence even with a complete pathological response to warrant adjuvant radiation. Based on the data outlined above, the current standard outside the setting of clinical protocols is to recommend regional lymph node radiation with chest wall/breast radiation for all patients with residual positive lymph nodes after neoadjuvant chemotherapy and all patients who present with clinically stage III disease. For patients with stage II disease who achieve a pathological complete response, the available evidence suggests that their predicted local regional recurrence risk without regional or postmastectomy radiation is 10% or less. Therefore the benefit from radiation is likely low and it is reasonable weigh out these small potential benefits in the context of associated treatment morbidities and costs. It is also important to further consider additional local-regional risk factors such as patient age, tumor biology, plans for prolonged systemic therapies, and other pathological factors at presentation in making radiation treatment decisions for such patients. Citation Format: Buchholz T. Indications for radiation treatments after neoadjuvant chemotherapy while awaiting the results of clinical trials [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr ES7-3.

Precision neoadjuvant therapy (P-NAT): A planned interim analysis of a randomized, TNBC enrolling trial to confirm molecular profiling improves survival (ARTEMIS).

518Background: ARTEMIS is a double blind, randomized trial to determine if P-NAT impacts rates of excellent pathologic response [Residual Cancer Burden (RCB) 0-I]. P-NAT used a CLIA-certified chemo...

Down-staging depth score to predict outcomes in locally advanced rectal cancer achieving ypI stage after neoadjuvant chemo-radiotherapy versus de novo stage pI cohort: A propensity score-matched analysis.

Prognosis of patients with locally advanced rectal cancer (LARC) but achieving ypT1-2N0 stage after neoadjuvant concurrent chemo-radiotherapy (CRT) has been shown to be favorable. This study aims to determine whether the long-term outcome of ypT1-2N0 cases can be comparable to that of pT1-2N0 cohort that received definitive surgery for early disease. From January 2008 to December 2013, 449 consecutive patients with rectal cancer were treated and their outcome maintained in a database. Patients with LARC underwent total mesorectal excision (TME) surgery at 4-8 weeks after completion of CRT, and those achieving stage ypI were identified as a group. As a comparison, stage pI group pertains to patients whose initially limited disease was not upstaged after TME surgery alone. After propensity score matching (PSM), comparisons of local regional control (LC), distant metastasis-free survival (DMFS), disease-free survival (DFS) and overall survival (OS) were performed using Kaplan-Meier analysis and log-rank test between ypI and pI groups. Down-staging depth score (DDS), a novel method of evaluating CRT response, was used for subset analysis. Of the 449 patients, 168 matched cases were generated for analysis. Five-year LC, DMFS, DFS and OS for stage pI vs. ypI groups were 96.7% vs. 96.4% (P=0.796), 92.7% vs. 73.6% (P=0.025), 91.2% vs. 73.6% (P=0.080) and 93.1% vs. 72.3% (P=0.040), respectively. In the DDS-favorable subset of the ypI group, LC, DMFS, DFS and OS resulted in no significant differences in comparison with the pI group (P=0.384, 0.368, 0.277 and 0.458, respectively). LC was comparable in both groups; however, distant metastasis developed more frequently in down-staged LARC than de novo early stage cases, reflecting the need to improve the efficacy of systemic treatment despite excellent pathologic response. DDS can be an indicator to identify a subset of the ypI group whose long-term oncologic outcomes are as good as those of stage pI cohort.

Abstract OT3-2-05: Improving outcomes in triple-negative breast cancer (TNBC) using molecular triaging and diagnostic imaging to guide neoadjuvant therapy

Abstract BACKGROUND: Known disparities exist in patients with TNBC treated using neoadjuvant chemotherapy (NACT) with 30-50% having excellent response to treatment (pCR/RCB-I) and good survival prognosis, while 50-70% demonstrate marked residual disease (RCB-II-III) with significantly worse prognosis. Lack of response early into NACT also indicates a low chance (5%) of achieving pCR. Thus, it is important to develop diagnostic platforms predictive of pCR, in order to direct patients with responsive disease toward standard NACT and non-responsive disease toward experimental therapies within clinical trials. TRIAL DESIGN This study will determine the impact of predicting response to NACT using both molecular and imaging diagnostics and will determine if offering a clinical trial of selected targeted therapy will impact outcomes (as measured by pCR and RCB) in predicted non-responsive disease. An algorithm that incorporates pre-defined genomic signatures will determine predicted sensitivity to chemotherapy (JAMA, 2011; 305:1873-81). All patients will undergo biopsy of the primary tumor for molecular analyses, but will then be randomized 2:1 to know these results (Arm A) versus not (Arm B). All patients will begin anthracycline-based NACT with diagnostic imaging to assess response after 4 cycles. Patients who fit molecular/imaging criteria for non-responsive disease will be offered a clinical trial based upon molecular profiling (Arm A) or based upon physician/patient choice (Arm B). Patients who fit criteria for responsive disease in either arm will continue with taxane based NACT. ELIGIBILITY CRITERIA INCLUSION: Candidate for biopsy of the primary tumor site; tumor size &amp;gt; 1.5 cm diameter; TNBC by standard pathologic assays; &amp;gt;18 years of age; LVEF &amp;gt; 50%; adequate organ and bone marrow function EXCLUSION: Stage IV disease; history of invasive cancer within 5 years; excisional biopsy of the primary tumor; biopsy site changes that limit response assessment; medically unfit for chemotherapy; prior anthracycline; &amp;gt;grade II neuropathy; Zubrod performance status of &amp;gt;2; history of serious cardiac event PRIMARY AIM Primary Aim: to prospectively determine the impact of implementation of a research platform that includes molecular (genomic) testing from a primary tumor biopsy to predict response, and diagnostic imaging to assess response to standard NACT in patients with localized invasive TNBC. Secondary Aims: compare rates of clinical trial enrollment between study arms, compare DFS, integrated "prospective-retrospective" biomarker analysis, correlative science studies to identify therapeutic targets for resistant disease STATISTICAL METHODS AND TARGET ACCRUAL Success will be defined as an improvement in the rate of excellent pathologic response (pCR/RCB-I) from 50%--&amp;gt;64% using the triaging platform. A maximum of 360 patients will be randomized 2:1 to the experimental arm vs. the control arm using a group sequential design with one-sided O’Brien-Fleming boundaries, with up to two equally spaced binding interim tests for both futility and superiority and one final test, having an overall Type I error .05 and power .80 to detect a response rate improvement from a null rate of .50 to a target value of .642. Citation Format: Stacy Moulder-Thompson, Wei Yang, Naoto T Ueno, Joe Ensor, Vicente Valero, Ricardo Alvarez, Jennifer Litton, Rashmi Murthy, Nuhad Ibrahim, Banu Arun, Beth Mittendorf, Kelly Hunt, Funda Meric-Bernstam, Helen Piwnica-Worms, Rosalind Candelaria, Debu Tripathy, Fraser Symmans. Improving outcomes in triple-negative breast cancer (TNBC) using molecular triaging and diagnostic imaging to guide neoadjuvant therapy [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT3-2-05.

592P - Relationship of Ugt1A and Abc Genetic Variants to Toxicity and Response in Preoperative Chemoradiation (Crt) with Concurrent Irinotecan for Locally Advanced Rectal Cancer (Larc)

ABSTRACT Aim: Germline homozygosity for UDP glucuronosyltransferase (UGT)1A1*28 has been associated with increased haematological and gastrointestinal toxicity to irinotecan. The influence of UGT1A and drug transporter gene ABC genetic variants on the toxicity of and response to CRT including concurrent irinotecan has not been studied. Methods: Blood was collected retrospectively from 96 surviving patients (pts) (71%) of 135 who had undergone surgery in the NWCOG-2 phase I/II trial in which pts with LARC received preoperative CRT (45 Gy in 25 fractions in 5 weeks) using concurrent capecitabine (650mg/m2 bid PO 7 days/week) and irinotecan (weekly at 60mg/m2 IV weeks 1-4). Germline DNA was tested for variants UGT1A1*6, *27, *28, *60 and *93, UGT1A7*3 and 622T > C and UGT1A9*22 using fragment size analysis and Taqman allelic discrimination assay. The ability of these variants, their common haplotypes (inferred with R package haplo.stats) and transporter gene ABCB1 and ABCC2 variants, to predict treatment toxicity and histological response was examined. Results: Overall commonest grade (gr) 3/4 toxicities were diarrhoea (n = 18), neutropenia (n = 7) and fatigue (n = 7). No association was seen between any individual variants and serious toxicity. Carriage of at least one haplotype III (all reference UGT1A alleles with the exception of UGT1A7*3 (387T > G)) significantly increased the risk of gr 3/4 diarrhoea (OR 6.03, 95% CI 1.79-21.85, p = 0.001). There was no association of ABC variants with serious toxicity. Overall 41 pts (43%) showed an excellent pathological response (EPR: either ypCR or microfoci). Individuals with one or two variant alleles of UGT1A7*3 had a significantly increased EPR rate (TG = 48%, OR 8.89, 95%CI 1.1-414.60, p = 0.04 and GG = 46%, OR 8.28, 95% CI 1.0-391.40, p = 0.04) compared to those with only reference alleles (TT = 9%). Conclusions: No association was seen between individual UGT1 genotypic variants (including UGT1A1*28) and serious toxicity. However the presence of the UGT1A7*3 variant as part of a haplotype with all other reference alleles significantly increased diarrhoea and as an individual variant increased EPR. Disclosure: All authors have declared no conflicts of interest.

Abstract P6-06-37: Predicting improvements in survival based on improvements in pathologic response rate to neoadjuvant chemotherapy in different breast cancer subtypes

Abstract Background: Individuals with excellent pathologic response (complete response or minimal residual cancer burden, pCR+RCB-I) to neoadjuvant chemotherapy have prolonged survival, and several chemotherapy regimens have resulted in improved pathologic response rates. However, how to estimate expected improvements in disease free survival (DFS) in a clinical trial based on improvement in pathologic response remains uncertain. The purpose of this study was to develop a statistical tool to estimate improvements in DFS based in improvements in pCR/RCB-I in triple negative (TNBC) and HR+/HER2- breast cancer subtypes. Methods: 387 clinical stage II (73%) and III (23%) breast cancers who received neoadjuvant T/FAC chemotherapy at MD Anderson Cancer Center were included in this analysis (N = 127 TNBC, N = 260 HR+/HER2-). Patients received adjuvant endocrine therapy if HR+. To evaluate the association between pCR rate and survival we used within-subtype stratified bootstrap analysis with biased resampling from the two response groups (pCR and RCB-I) to generate 500 bootstrapped populations with a range of different response rates. Survival was based on the Kaplan-Meier estimator with its variance obtained from the bootstrap standard error. Power was estimated as the probability of no overlap in the 95% log confidence intervals of survival in 500 bootstrap replicates of populations of different sizes and response rates. Results: Excellent pathologic response (pCR or RCB-I), was observed in 50% and 23% in the TNBC and ER+/HER2- cohorts respectively. The median follow-up was 7.6 years (range 0.1 to 13.4 years); 48 and 59 relapses occurred in the TNBC and HR+ subtypes, respectively. Bootstrap analysis showed a linear dependence of the 5-year DFS on the pCR/RCB-I rate, with a slope of 0.472 for TNBC suggesting a 4.7% improvement in DFS for every 10% increase in response rate. A more modest slope of 0.129 was observed for ER+/HER2- cancers. The sample size of a randomized 2-arm study required to show with 80% power a statistically significant improvement in 5-year DFS that corresponds to 75% response rate compared to baseline response rate of 50% and 23% in TNBC and ER+/HER2- would be 1144 and 1688 cases respectively. We are providing an open-access web-based calculator to estimate improvements in DFS and for sample size calculations for randomized clinical trials with combined endpoints of pCR/RCB-I and survival. Conclusions: We observed a linear increase in DFS with increase in pathologic response rate in the evaluated cohort. The slope depends on breast cancer subtype - it is greater in TNBC than in ER+ cancers - and expected to be influenced by the stage distribution in the study population. These results could help provide a basis for powering studies with combined response and survival endpoints. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-06-37.

Abstract P6-05-05: Gene expression signatures of effector immune cell abundance are significantly associated with pathologic breast tumor response in the neoadjuvant setting

Abstract Background Neoadjuvant chemotherapy for early breast cancer leads to significant clinical response rates of 70-90%, with only 10-20% complete pathologic responses (pCR). The biological and clinical factors that determine the degree of pCR are incompletely understood and most investigated are drug choice, proliferation index, intrinsic subtypes and host-therapy interactions. Mounting evidence indicates that the patient's immune system contributes to tumor regression and can be modulated by therapies. Investigations using immunohistochemical approaches confirmed that immune cell infiltrate on pre-treatment or post-treatment tumor biopsies are associated with greater frequency of pCR. The cell types most frequently observed with this association are effector tumor infiltrating lymphocytes (TILs) such as cytotoxic T cells, natural killer cells and B cells suggesting a strong link between infiltrating immune cell abundance and anti-tumor immunogenicity. More recently, we and others have shown that the relative abundance of TIL in breast cancer can be quantified by intratumoral transcript levels of coordinately expressed, immune cell-specific genes. Through expression microarray analysis, we recently discovered three separate immune gene signatures, or metagenes, that appear to reflect the relative abundance of distinct tumor-infiltrating leukocyte populations. These metagenes, referred as the B/P (B-cell/Plasma cell), T/NK (T-cell/Natural Killer cell) and M/D (Monocyte/Dendritic cell) immune metagenes, were significantly associated with the distant metastasis-free survival of patients with highly proliferative cancer of the Basal-like, HER2-Enriched and Luminal B subtypes, in particular. Aim Given the histopathological evidence that TIL abundance is predictive of neoadjuvant treatment efficacy, we evaluated the therapy-predictive potential of the prognostic immune metagenes. We hypothesized that the pre-chemotherapy immune gene signatures would be significantly predictive of tumor responses. Methods In a multi-institutional, meta-cohort analysis of 701 breast tumor patients receiving neoadjuvant chemotherapy, gene expression profiles of tumor biopsies were investigated to determine the relationships between immune metagenes, tumor proliferative capacity, and molecular breast tumor subtypes. Results We used multiple logistic regression to investigate the predictive value of the immune signatures. In a univariate analysis the B/P, T/NK and M/D immune metagenes were statistically significantly associated with excellent pathologic response as defined by residual cancer burden scores ((B/P (odds ratio (95% CI) 1.6 (1.3, 1.9), T/NK 1.6 (1.2, 2.0), M/D 1.7 (1.3, 2.1)). In multivariate analysis, B/P and M/D metagenes remained significant after adjustment for intrinsic subtype and proliferation (B/P 1.25 (1.01, 1.54), M/D 1.4 (1.03, 1.90). Conclusions Gene expression signatures of infiltrating immune cells carry both prognostic and therapy-predictive value. Furthermore, our work highlights a less described role for myeloid derived antigen presenting cells that could explain the variability of pathologic response to neoadjuvant chemotherapy. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-05-05.

First report of the correlation of PET Response Criteria in Solid Tumors (PERCIST) criteria and pathologic change in patients with rectal cancer treated with neoadjuvant radiation.

261 Background: High-dose-rate endorectal brachytherapy (Endo-HDR) is a promising technique using a short course of radiation therapy in the neoadjuvant setting for rectal cancer. While clinical exam and standard imaging (CT and MRI) suggest outstanding radiation response in these patients, they cannot reliably predict pathologic complete response (pCR) or high tumor regression grade (TRG). In this study, we investigate the utility of PERCIST criteria to predict pathologic change. Methods: We treated nine patients on a prospective clinical trial investigating Endo-HDR as a single agent neoadjuvant therapy (6.5 Gy x 4 fractions, total dose of 26 Gy) for stage II-III rectal cancer patients. A pre-radiation PET/CT scan was compared to a post-treatment PET/CT scan performed one month following the completion of radiation. All nine patients proceeded to surgical resection with the pathologic specimen analyzed for residual disease. TRG (Mandard et al.) was used to quantify response to treatment. A 50% decrease in SUVpeak by PERCIST criteria was correlated with a TRG 1 or 2 (none or minimal residual cancer cells on the final pathologic specimen). Results: As demonstrated in our table, 3/5 (60%) of patients achieving a TRG 1 or 2 had a SUVpeak that decreased by 50% or more; contrarily, zero of 4 (0%) of patients without a TRG 1 or 2 had a SUVpeak of 50% or more. Despite a trend, the small patient sample limited statistical significance (p=0.17). A minimum decrease of 50% in SUVpeak resulted in a positive predictive value of 100%, a negative predictive value of 67%, a specificity of 100%, and a sensitivity of 60% for predicting TRG 1 or 2. Conclusions: Our results demonstrate the first report of utilizing PERCIST criteria in rectal cancer treated with neoadjuvant Endo-HDR. Reliable clinical predictors following Endo-HDR for excellent pathologic response may identify patients in whom a non-operative rectal cancer treatment is possible. [Table: see text]

High pathologic response rate of hepatic colorectal cancer metastases (HCRM) following neoadjuvant bevacizumab (Bev)-based treatment (tx).

529 Background: Pathologic response of HCRM to neoadjuvant tx is associated to better outcome. In retrospective analyses Bev-based tx improved tumor regression grade (TRG), while cetuximab (Cmab) increased RECIST response and R0 resections in prospective studies. The aim of this analysis was to assess the effect of Bev vs Cmab-based tx in terms of HCRM pathological response and outcome. Methods: Fifty-eight pts with HCRM were resected at National cancer Institute of Milan from 2007 to 2012 following Bev (n=30) or Cmab (n=28) based neoadjuvant tx. Pathological response was classified from TRG 1 for pathological complete response (pCR), to TRG5 for no response; TRG 1-3, for histological response; TRG 4-5 for scarce/no response (Rubbia-Brandt L, Ann Oncol 2007). Results: KRAS missing in 9 pts (3 Bev/6 Cmab), mutated in 18 pts (60%) in Bev vs 4 (14%) in Cmab group.Median number of resected metastases: 4.6 vs 3.9; mean TRG: 2.9 (2.2-4) in Bev vs 3.8 (3-5) in Cmab group (p=0.04 at Kruskal-Wallis test). Pathological response rate was higher for Bev vs Cmab (70% vs 39%; p=0.037 at Chi-square test). Bev also increased pCRs (20% vs 0%, p=0.024 at Fisher’s test). With generalized estimating equation for all resected nodules, mean TRG was lower in Bev vs Cmab group: 2.6 (2-4) vs 3.7 (3-4), p&lt;0.001. At univariate analysis, no PFS and OS difference was observed according to tx. Multivariable Cox models shown below: Conclusions: Bev-based tx obtained an excellent pathological response rate, despite the high proportion of KRAS mutated tumors, and further prospective confirmation of these data is planned. [Table: see text]

Accelerated methotrexate, vinblastine, doxorubicin, and cisplatin (AMVAC) as neoadjuvant chemotherapy for patients with muscle‐invasive transitional cell carcinoma of the bladder

Meta-analysis data demonstrate a 5% absolute survival benefit for neoadjuvant chemotherapy (NAC) using cisplatin-based combination regimens in the radical treatment of muscle-invasive bladder cancer (MIBC). However, there are no randomized, controlled trial data on the optimum regimen. Accelerated methotrexate, vinblastine, doxorubicin, and cisplatin (AMVAC) is a dose-intense regimen that has the potential to minimize delays to definitive, potentially curative therapy. A retrospective analysis is presented of the efficacy and toxicity of AMVAC as NAC in patients with MIBC and its impact on the patient pathway. Eighty consecutive patients with MIBC were treated with AMVAC as NAC by 2 UK multidisciplinary uro-oncology teams. Three or 4 cycles of AMVAC (methotrexate 30 mg/m(2) , vinblastine 3 mg/m(2) , doxorubicin 30 mg/m(2) , and cisplatin 70 mg/m(2) ) were given at 2-week intervals, with granulocyte colony-stimulating factor support, prior to either radical surgery or radical radiotherapy. All planned cycles of chemotherapy were completed, without dose reduction or delay in 84% of patients. All 80 patients subsequently received their planned definitive therapy. Grade 3/4 toxicities were seen in 26% of the 42% of patients for whom toxicity data are available, including 12% grade 3/4 neutropenia. Pathological complete response to AMVAC was seen in 43% of 60 surgical patients. Objective radiological local response was seen in 83% of 57 evaluable patients. Two-year disease-free and overall survival were 65% and 77%, respectively. AMVAC is safe and appears to be a well-tolerated and effective NAC regimen for MIBC. It minimizes delays to definitive treatment and produces excellent pathological and radiological response rates. It is an appropriate comparator for future randomized trials.

A genomic predictor of response and survival following taxane-anthracycline chemotherapy for invasive breast cancer.

Prediction of high probability of survival from standard cancer treatments is fundamental for individualized cancer treatment strategies. To develop a predictor of response and survival from chemotherapy for newly diagnosed invasive breast cancer. Prospective multicenter study conducted from June 2000 to March 2010 at the M. D. Anderson Cancer Center to develop and test genomic predictors for neoadjuvant chemotherapy. Patients were those with newly diagnosed ERBB2 (HER2 or HER2/neu)-negative breast cancer treated with chemotherapy containing sequential taxane and anthracycline-based regimens (then endocrine therapy if estrogen receptor [ER]-positive). Different predictive signatures for resistance and response to preoperative (neoadjuvant) chemotherapy (stratified according to ER status) were developed from gene expression microarrays of newly diagnosed breast cancer (310 patients). Breast cancer treatment sensitivity was then predicted using the combination of signatures for (1) sensitivity to endocrine therapy, (2) chemoresistance, and (3) chemosensitivity, with independent validation (198 patients) and comparison with other reported genomic predictors of chemotherapy response. Distant relapse-free survival (DRFS) if predicted treatment sensitive and absolute risk reduction ([ARR], difference in DRFS between 2 predicted groups) at median follow-up (3 years). Patients in the independent validation cohort (99% clinical stage II-III) who were predicted to be treatment sensitive (28%) had 56% (95% CI, 31%-78%) probability of excellent pathologic response and DRFS of 92% (95% CI, 85%-100%), with an ARR of 18% (95% CI, 6%-28%). Survival was predicted in ER-positive (30% predicted sensitive; DRFS, 97% [95% CI, 91%-100%]; ARR, 11% [95% CI, 0.1%-21%]) and ER-negative (26% predicted sensitive; DRFS, 83% [95% CI, 68%-100%]; ARR, 26% [95% CI, 4%-48%]) subsets and was significant in multivariate analysis. Other genomic predictors showed paradoxically worse survival for patients predicted to be responsive to chemotherapy. A genomic predictor combining ER status, predicted chemoresistance, predicted chemosensitivity, and predicted endocrine sensitivity identified patients with high probability of survival following taxane and anthracycline chemotherapy.