Completion Of Neoadjuvant Therapy Research Articles

Abstract P6-10-05: TBCRC 040: Pathologic response evaluation and detection in circulating tumor DNA (PREDICT DNA): Initial results piloting a tissue-biopsy independent method of identifying and monitoring tumor-specific mutations in early stage breast cancer

Abstract Introduction: The PREDICT DNA trial is the first prospective, multi-center study aimed at validating cell-free plasma derived circulating tumor DNA (ctDNA) as a biomarker for treatment response and recurrence in early stage, triple-negative or HER2-positive (any hormone receptor status) breast cancer. Its primary aim is to determine the negative predictive value (NPV) of the absence of ctDNA after neoadjuvant therapy (NAT) for the achievement of pathologic complete response (pCR). This study has met its accrual goals and results of the overall trial are anticipated within the next year. The initial PREDICT DNA study design stipulated that tumor specific mutations (TSMs) to be tracked in blood would be identified by next gen sequencing (NGS) of tumor biopsy tissue. A disadvantage of this design is the dependence on adequate biopsy tissue. Recently, the advent of Safe-SeqS technology has enabled robust detection of rare variants using NGS with a sensitivity of approximately 0.05% mutant allele fraction. We employed these new NGS methods to pilot a novel tissue-independent approach to ctDNA detection and monitoring. Objective: The primary objective of this pilot study was to determine whether ultrasensitive NGS using a targeted cancer mutation panel can identify TSMs in ctDNA of early-stage breast cancer patients without the use of biopsy tissue. Methods: The PREDICT DNA trial enrolled 228 women from 22 sites with stage II/III breast cancer for whom standard neoadjuvant therapy was planned. Of these, 58 patients had matched pre-and post-NAT samples available for analysis at the time of this pilot. All pre-NAT samples were analyzed for the presence of TSMs using Sysmex Inostics’ SafeSEQ. Patients with detectable ctDNA before NAT were also evaluated for residual ctDNA after completion of NAT but prior to surgery. Five samples were also tested by digital PCR (BEAMing) for cross-platform comparison. Results: TSMs in ctDNA were identified in 29 of 58 patients (50%) prior to NAT. Of pre-NAT ctDNA(+) patients, TSMs were detected in TP53 (90%) and PIK3CA (10%); three patients (10%) were found to have 2 TSMs. Concordance between SafeSEQ and BEAMing was 100% in five samples tested [3 ctDNA(+), 2 ctDNA(-)]. Of 29 ctDNA(+) patients, 24 (83%) demonstrated reduction or elimination of detectable ctDNA following neoadjuvant therapy, with 16 (55%) converting to ctDNA(-). Conclusion: Identification of TSMs in the plasma of early-stage breast cancer patients without the need for biopsy tissue is feasible using a SafeSEQ cancer mutation panel. Further measures to improve the sensitivity of pre-treatment TSM analysis, such as increased plasma volume input and comprehensive TP53 mutational analysis are currently under investigation. Correlations between clinicopathologic factors with ctDNA detection and burden, as well as the NPV of post-NAT ctDNA for pCR and residual cancer burden, will be reported at the time of abstract presentation. NH and HP contributed equally to this work. Citation Format: Natasha Hunter, Heather Parsons, Alexander Sherry, Daniel Shinn, Dong Ho Shin, Alex Cole, Giovanni Cragnotti, Taylor Groginski, Margaret Leathers, Andrea L Richardson, Pedram Argani, Antonio Wolff, Leslie Cope, Dan Edelstein, Frank Holtrup, Hilary Sloane, Bapsi Chakravarthy, Vered Stearns, Ben H Park. TBCRC 040: Pathologic response evaluation and detection in circulating tumor DNA (PREDICT DNA): Initial results piloting a tissue-biopsy independent method of identifying and monitoring tumor-specific mutations in early stage breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-10-05.

Abstract PD9-06: Additive benefit of MRI background parenchymal enhancement (BPE) to an MRI tumor volume model for predicting pathologic complete response (pCR) to neoadjuvant treatment in ISPY2

Abstract BACKGROUND: Background parenchymal enhancement (BPE) describes the natural phenomenon observed on breast MRI in which normal breast tissue demonstrates signal enhancement from uptake of intravenous contrast. BPE may provide independent and additive value for prediction of pathologic complete response (pCR) using MRI measured functional tumor volume (FTV), which has only moderate discrimination (FTV AUC ~ 0.7). We evaluated the additive value of quantitative whole breast BPE to a FTV model for prediction of pCR to neoadjuvant chemotherapy in the ISPY-2 trial. METHODS: In this HIPAA-compliant/IRB-approved study, women 18 years of age and older diagnosed with stage II or III breast cancer and with tumor size measured ≥ 2.5 cm were eligible to enroll in the I-SPY 2 TRIAL. Participants received a weekly dose of paclitaxel alone (control) or in combination with Veliparib and Carboplatin for 12 weekly cycles followed by four (every 2-3 weeks) cycles of anthracycline-cyclophosphamide prior to surgery. All breast cancers in these drug arms were Her2 negative. MRI was performed before the initiation of neoadjuvant therapy or “baseline” (T0), after three weeks of therapy or “early treatment” (T1), after twelve weeks between drug regimens or “inter-regimen” (T2), and after neoadjuvant therapy completion and prior to surgery or “pre-surgery” (T3). MRI segmentation was manually performed of the whole unaffected contralateral breast, and tissue classification was performed using fuzzy c-means clustering. BPE was calculated as the average enhancement of all tissue voxels at the first postcontrast acquisition. Predictor variables were parameterized as absolute values of BPE/FTV for each treatment time point or relative change values for each treatment time period. Logistic regression, stratified by hormone receptor (HR) subtype, was performed using 1) univariate models of FTV/BPE predictors alone and 2) multivariate models using all possible combinations of FTV/BPE predictors and HR status. Additive benefit for multivariate models was evaluated by estimating change in the area under the curve (AUC) for overall diagnostic performance with 10-repeat 5-fold cross validation. The 95% confidence interval (CI) of cross-validated AUC was estimated using 1,000 bootstrap resamples. RESULTS: A total of 88 patients (29 pCR, 59 non-pCR) were evaluated with serial breast MRIs to assess neoadjuvant response. Among univariate models, women with HR+ cancers who had PCR demonstrated a significantly greater decrease in BPE from baseline to pre-surgery compared to non-PCR (OR = 0.64, 95% CI = 0.39-0.92, p-value = 0.04). The associated AUC was 0.77 (95% CI 0.56-0.98), comparable to the range of univariate FTV AUC values (0.57-0.87). Among optimized multivariate models, the highest cross-validated AUC for FTV and HR predictors was 0.81 (95% CI 0.73-0.90), while adding BPE slightly increased AUC to 0.82 (95% CI 0.74-0.92). CONCLUSION: Changes in BPE in response to neoadjuvant therapy, which represents normal breast tissue changes measurable on any breast MRI, demonstrated significant association with pCR in women with HR+ breast cancer. Moreover, it had a similar diagnostic performance to univariate prediction with tumor volume. However, additive prediction of BPE to multivariate FTV models was only marginal. Citation Format: Vignesh A. Arasu, Paul Kim, Wen Li, Fredrik Strand, Cody McHargue, Ella Jones, David Newitt, John Kornak, Laura Esserman, Nola Hylton, ACRIN 6657 Trial TeamI-SPY Investigators Network. Additive benefit of MRI background parenchymal enhancement (BPE) to an MRI tumor volume model for predicting pathologic complete response (pCR) to neoadjuvant treatment in ISPY2 [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD9-06.

Abstract P4-03-01: Vacuum assisted core-needle biopsy after neoadjuvant therapy in breast cancer to predict the status of pathologic response

Abstract Introduction: Neoadjuvant breast cancer therapy trials have documented impressive rates of pathologic complete response (pCR) of up to 70% and above, depending on grade, hormone receptor and HER2 receptor status and type of therapy. The purpose of our prospective single institution trial is to examine the predictive value of a standardized vacuum assisted core-needle biopsy (VAB) of the tumor site after neoadjuvant therapy with respect to pathologic response status. Methods: From 2011-2017, all patients who had completed neoadjuvant breast cancer therapy at our institution were informed about this trial regardless of their clinical response status. In case of consent, a VAB of the clip-marked tumor site was performed directly before the operation. At least 3, in most cases 6 biopsy cylinders were obtained. Results: A total of 113 patients completing neoadjuvant therapy consented to the trial. Four patients presented with bilateral breast cancer, resulting in 117 cases of breast cancer. The pCR rate (ypT0ypN0) was 36% (n=42). In 14 cases, the biopsy did not show any sign of residual disease, although residual disease was detected upon operation, resulting in an accuracy of 88% for correct prediction of pathologic response. Pre-operative VAB correctly predicted residual tumor in 81%. The negative predictive value was 75%. Conclusions: Although the results of this trial are encouraging, a false negative rate of 19% is entirely insufficient. The method may be useful in guiding decisions regarding the modification of neoadjuvant therapy based on pathological response. Whether or not correct prediction of pathologic response may be improved by further standardizing the tumor marking procedure as well as better defining and increasing the volume of tissue removal by VAB should be examined in a further prospective trial. The omission of operative therapy in case of pCR in a preoperative biopsy after completion of NACT cannot be recommended. Citation Format: Regina Große, Antonia Lebioda, Jana Saegenschnitter, Tin Dao Nguyen, Holger Zentgraf, Joerg Buchmann, Christine Fathke, Susanne Steer, Christoph Thomssen. Vacuum assisted core-needle biopsy after neoadjuvant therapy in breast cancer to predict the status of pathologic response [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-03-01.

Complete neoadjuvant treatment for rectal cancer: A single institution experience.

148 Background: Full dose adjuvant chemotherapy following preoperative chemoradiation and surgery is poorly tolerated in stage II and III rectal cancer. We reviewed our institution’s experience with complete neoadjuvant treatment for rectal cancer since publication of the BrUOG R-224 trial results. Methods: After obtaining IRB approval, Data on patients with stage II and III rectal cancer who underwent complete neoadjuvant therapy were collected.. Patients who were planned to receive 8 cycles of modified FOLFOX6, chemoradiation with capecitabine 825 mg/m2 twice daily and 50.4 Gy intensity-modulated radiation therapy, then surgery were included. Results: Thirty-five patients were treated with complete neoadjuvant therapy between January 2014 and December 2017. Median age was 58 years (27 to 75 y); 1 patient (3%) was clinical stage II and 34 (97%) stage III. Twenty-seven patients (77%) received all 8 cycles of mFOLFOX6, of whom 24 completed subsequent chemoradiation. Therefore 69% of patients completed therapy according to the BrUOG R-224 protocol. Pathologic complete response (ypT0N0) was observed in 9 patients (26%). Treatment related toxicities resulted in dose reductions or treatment interruption in 57% and 29% of patients receiving chemotherapy and chemoradiation respectively. Conclusions: Complete neoadjuvant therapy for clinical stage II to III rectal cancer is well-tolerated in routine practice and offers an alternative to preoperative chemoradiation, surgery, then adjuvant full dose chemotherapy.

Comparison of survival results of patients with T0 and T1-2-3 in pathological T staging in patients with non-small cell lung cancer who underwent surgery after neoadjuvant treatment.

AimIn this study, we aimed to compare the survival results of patients who underwent neoadjuvant treatment with NSCLC between March 1997 and August 2014 and were found to have T0N0 and T1-2-3/N0.Material and methodsA hundred ninety-five patients who had complete neoadjuvant therapy, complete lung resection and lymph node dissection, and pathologically diagnosed as T0 or T1-2-3/N0, M0 were included in the study.ResultsOf the 195 patients included in the study, 181 were male, 14 were female and the mean age of the patients was 57.9. The mean age of the groups was as follows: group 1: 58.1, group 2: 57.7, group 3: 59.7 and group 4: 56.8. In our series the most common complication was atelectasis (n = 19). Others were prolonged air leak (n = 16), pneumonia (n = 12), apical pleural space (n = 6), wound infection (n = 3), cardiac problems (n = 3), hematoma (n = 3), bronchopleural fistula (n = 3), empyema (n = 2), chylothorax (n = 1). The 5-year survival rate for patients in the T0N0 group was 76.3%. This rate was 71.8% in group 2, 63.6% in group 3 and 44.1% in group 4.ConclusionsSurvival was found to be better in patients who underwent surgery after neoadjuvant therapy and had a complete pathological response. We believe that we can provide better results with the increase in the number of cases detected as TxN0 after the neoadjuvant treatment and prolongation of the follow-up period.

Management of Acute Cholecystitis during Neoadjuvant Therapy in Patients with Pancreatic Adenocarcinoma.

Patients with localized pancreatic cancer (PC) can develop acute cholecystitis during neoadjuvant therapy; optimal management remains undefined. Consecutive patients with localized PC who had indwelling biliary stents and received neoadjuvant therapy were reviewed. Time from stent placement to the development of acute cholecystitis was calculated. Patients were categorized as having surgical versus nonoperative management of cholecystitis. Time to PC resection was defined as the time from the start of treatment to pancreatic resection. Of the 283 patients with indwelling biliary stents, acute cholecystitis occurred in 17 (6%) patients. The median time from the date of stent placement to the development of cholecystitis was 2.3months [interquartile range (IQR) 4.6months]. Acute cholecystitis was managed with cholecystostomy tube placement in 15 (88%) patients and cholecystectomy in 2 (12%). In total, 189 (67%) of the 283 patients completed all intended neoadjuvant therapy and surgery; 10 (59%) of the 17 patients with cholecystitis (10 of 15 managed with a cholecystostomy tube and 0 of 2 managed with cholecystectomy) and 179 (67%) of the 266 patients without cholecystitis (p = 0.47). The median time to PC resection was 3.2months for the 179 patients without cholecystitis and 3.6months for the 10 patients with cholecystitis (p = 1.00). Acute cholecystitis occurred in 6% of patients with indwelling biliary stents during neoadjuvant therapy. Management with a cholecystostomy tube did not delay the completion of neoadjuvant therapy and surgery and should be considered the optimal management of this complication.

2852 Stenting and Suturing for Esophageal Cancer in Neo-Adjuvant Setting: A Tertiary Community Cancer Center Experience

INTRODUCTION: The place of esophageal stents for dysphagia in the neoadjuvant setting for esophageal cancer has recently been debated with recent Radiation oncology literature calling into question its use. Given the paucity of data and lack of clear guidelines, we performed a review our high volume esophageal cancer practice and analyze the outcomes in patients undergoing esophageal stent placement for malignant dysphagia in the neoadjuvant setting. METHODS: The data was collected retrospectively on all patients who underwent esophageal stent placement for malignant dysphagia due to esophageal cancer in a neoadjuvant setting at the Parkview Cancer Institute from September 2015 to November 2018. RESULTS: This case series includes 32 patients, collectively underwent placement of a total of 33 stents (fully covered self-expandable metal stents (FCSEMS)) of which 25 were anchored using esophageal suturing. The stent migration was only 6% (n = 2) compared to 30 -50% reported in literature. One key factor contributing to the low incidence of stent migrations could be the high proportion of endoscopic suturing performed. Out of the 33 stents, 25 (75%) were anchored to the esophagus by endoscopic suturing. 13 patients had successful completion of neoadjuvant therapy and subsequent esophagectomy. Seven patients decided not to undergo surgery due to stent unrelated issues. All of the patients had significant improvement in dysphagia immediately following stent placement. Only three patients developed eventual complications that resulted in need for repeat intervention with removal or replacement of stent. Overall rate of compilations for patients who received stent placement in neoadjuvant setting was 5 out of 33 (15.15%) (Table 1). CONCLUSION: This is a single center experience with significantly low number of stent migration, which can be attributed to the fact that all the stents were placed by a single advanced interventional endoscopy trained physician who maintains currently a high volume of esophageal stent placement of at least 15 to 20 procedures annually. This allows for increased proficiency, both in stent selection and placement. We use only fully covered metals stents and are extremely selective in stent length and diameter and almost always when possible, these stents are secured by sutures. This meticulous approach in esophageal stenting, tailoring to each individual patient has significantly contributed to the decrease in patient discomfort, migration and radiation toxicity.

A Comparison of the Tumor Response in Esophageal Cancer Patients Treated with Tri-modality Approach Using Either Cisplatin/5-FU or Carboplatin/Paclitaxel and Concomitant Radiation Therapy

We know that a major pathologic tumor response following neoadjuvant therapy is associated with an increased overall survival. In recent years standard of care chemotherapy regimen in neoadjuvant management of esophageal cancer has changed from cisplatin/5-FU (CIF) to carboplatin/paclitaxel (CAP). We compared treatment responses (using College of American Pathologist’s protocol) among patients who received neoadjuvant therapy using either CIF or CAP with concomitant radiation therapy (RT). Retrospective chart review of all patients who received neoadjuvant therapy followed by surgery for esophageal cancer diagnosed between 2008- 2018 at a single academic center was completed. Descriptive statistics and bivariate analyses (Chi-square, t-tests) were utilized to analyze the data. Of the 80 eligible patients, 84% were male with a median age was 62.5 years, most (85%) had lower esophageal lesions and the most common histology was adenocarcinoma (86.3%), followed by squamous cell carcinoma (12.5%). Most patients received 50Gy radiation dose (92.5%) with fewer receiving 41.4Gy (7.5%). All recent patients (57.5%) received CAP in comparison with historical controls (42.5%), who received CIF. Median time between completion of neoadjuvant therapy and surgery was 65.5 days. Following neoadjuvant therapy, 63.2% had a tumor regression grade (TRG) of 0 or 1. There was no significant difference in tumor regression grade of (0 and 1) or (2 and 3) between groups receiving CAP or CIF (p=0.686), or in tumor down staging (ypT) (p=1.0). There was no change in TRG after excluding patients receiving 41.4 Gy. Most resection specimens (74%) were negative for lymph node metastasis (ypN0). Pathologic ypT stages (AJCC 8e.) were 0 (37.5%), 1A (3.8%), 1B (8.8%), 2 (12.5%) and 3(37.5%). Five patients (6.3%) had positive resection margins; of these, 3 died of metastatic disease and 2 are well with no evidence of local recurrence or metastatic disease. Most esophageal cancer patients had a major pathologic response (TRG score 0 or 1) to neoadjuvant chemo-radiation therapy and were ypN0. There was no significant difference in tumor regression grade or tumor down-staging between the two chemotherapy regimens.

Personalized circulating tumor DNA analysis to detect residual disease after neoadjuvant therapy in breast cancer.

Longitudinal analysis of circulating tumor DNA (ctDNA) has shown promise for monitoring treatment response. However, most current methods lack adequate sensitivity for residual disease detection during or after completion of treatment in patients with nonmetastatic cancer. To address this gap and to improve sensitivity for minute quantities of residual tumor DNA in plasma, we have developed targeted digital sequencing (TARDIS) for multiplexed analysis of patient-specific cancer mutations. In reference samples, by simultaneously analyzing 8 to 16 known mutations, TARDIS achieved 91 and 53% sensitivity at mutant allele fractions (AFs) of 3 in 104 and 3 in 105, respectively, with 96% specificity, using input DNA equivalent to a single tube of blood. We successfully analyzed up to 115 mutations per patient in 80 plasma samples from 33 women with stage I to III breast cancer. Before treatment, TARDIS detected ctDNA in all patients with 0.11% median AF. After completion of neoadjuvant therapy, ctDNA concentrations were lower in patients who achieved pathological complete response (pathCR) compared to patients with residual disease (median AFs, 0.003 and 0.017%, respectively, P = 0.0057, AUC = 0.83). In addition, patients with pathCR showed a larger decrease in ctDNA concentrations during neoadjuvant therapy. These results demonstrate high accuracy for assessment of molecular response and residual disease during neoadjuvant therapy using ctDNA analysis. TARDIS has achieved up to 100-fold improvement beyond the current limit of ctDNA detection using clinically relevant blood volumes, demonstrating that personalized ctDNA tracking could enable individualized clinical management of patients with cancer treated with curative intent.

RS18. Influence of Malignant Disease and Chemoradiation on Aortic Aneurysmal Progression: A 12-Year, Single-Center Series

Aortic aneurysms occur concomitantly with malignant neoplasms in approximately 4% to 14% of patients. However, there is little information about the effects of malignant neoplasms, chemotherapeutics, and radiation treatment on the natural progression of abdominal aortic aneurysms (AAAs), thoracic aortic aneurysms, and thoracoabdominal aortic aneurysms. The aims of this study were to determine the effects that malignant neoplasms and their associated chemoradiation therapies impart on the progression and outcomes of aortic aneurysms. Patients diagnosed with malignant disease with concomitant AAAs or thoracic aortic aneurysms from 2005 to 2017 were reviewed. Inclusion criteria included complete neoadjuvant or adjuvant therapy documentation with multiplanar axial and coronal imaging or ultrasound before, during, and after therapy. Patients with repairs before malignant diagnosis and therapies were excluded. Multivariate risk factor and survival analysis were performed. Of 340 included aneurysms from 288 patients, 193 aortic aneurysms coexisted with malignant neoplasms necessitating chemoradiation (MAA), and 147 were aneurysms alone (AA). Average demographics were as follows: 75.4 ± 8.2 years old, white (60.8%), male (57.6%), hypertension (81.5%), history of smoking (77.9%), coronary atherosclerotic disease (62.6%), and AAA (73.8%). The most common malignant neoplasm was lung cancer (47.9%), with an initial chemotherapy regimen including a platinum-based alkylating agent and concurrent antimetabolite (67.5%). The overall median follow-up time and MAA group chemotherapy durations were 20.9 and 7.5 months, respectively. The AA group had a significantly older mean age of aneurysm discovery (78.0 vs 73.3 years; P < .001) and demonstrated overall increased comorbid states (hypertension, coronary artery disease, chronic kidney disease; P < .020), but with significantly decreased smoking and chronic obstructive pulmonary disease incidence (both P < .001) compared with the MAA group. Overall, the MAA group presented with smaller aneurysms (Fig 1; P = .044) and a slower median growth in the anteroposterior axis compared with the AA group (0.11 vs 0.17 cm/y; P = .070), which approached significance. Multivariate analysis demonstrated aneurysm size ≥4.0 cm on presentation as an independent predictor for requiring repair for any reason (odds ratio, 3.861; confidence interval, 2.261-6.591; P < .001; Fig 2). There were no associations with chemotherapy, radiation, duration of chemotherapeutic treatment, and growth rates or need for repair on analysis. There were no differences in complications between groups. Aortic aneurysms with concomitant malignant neoplasms necessitating chemotherapeutics are discovered earlier and at smaller sizes, and they exhibit decreased rates of growth compared with aortic aneurysms alone. Patients with coexisting malignant neoplasms do not appear to be at increased risk of aneurysm-associated adverse events compared with patients without malignant disease and should subscribe to standard institutional surveillance protocols.Fig 2Proportion of aneurysms not meeting repair criteria. AA, Aneurysm alone; MAA, aortic aneurysm with malignant neoplasm necessitating chemoradiation.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Association between tumor biology and occult lymph node metastases before and after primary neoadjuvant therapy (NAT) for patients with early breast cancer.

518 Background: Scientific efforts aim at a reduction of axillary morbidity through reduced axillary intervention among patients with early breast cancer. However, it is still unclear if this approach is feasible in all subtypes based on their risk of axillary involvement. We analyzed the association of tumor biology and occult axillary involvement with data from arms A and B of the SENTINA trial (Kühn T et al., Lancet Oncol 2013). Methods: Patients were included if they presented with a clinically negative axilla before NAT (arms A and B) and stratified according to tumor biology. All patients received SLNB before NAT, in cases of negative SLNB without further axillary surgery (Arm A) and in cases of positive SLNB (Arm B) with SLNB and axillary dissection after NAT. Logistic and linear regression analyses were carried out to evaluate the association between tumor biology and axillary involvement before and after NAT. Results: Of the 1022 patients in arms A and B of the SENTINA trial 926 were evaluable for this analysis. Of these, 27.9% had triple negative (TN), 16.3% hormone receptor (HR) and HER2 positive (triple positive = TP), 47.6% HR positive and HER2 negative (luminal) and 8.2% HR negative and HER2 positive (HER2) tumors. 39.7% of the luminal, 28.9% of the HER2, 19% of the TN and 47% of the TP tumors had involved SLN before NAT. Subgroup comparisons showed a significant difference between luminal and TN (p &lt; 0.0001), whereas the differences between luminal and TP (p = 0.115) and HER2 (p = 0.077) were not statistically significant. The 317 patients with involved SLN prior to NAT received SLNB and axillary dissection after completion of NAT. The analysis after NAT showed trends for lower rates of involved lymph nodes for the high-risk groups (TN 20% / TP 14.3% / HER2 8.7%) compared to luminal tumors (27.6%) without reaching statistical significance. Conclusions: Our analysis demonstrates that among patients enrolled in the SENTINA trial, patients with triple negative disease have the lowest risk for occult lymph node metastases at initial presentation. Our results do not justify more intense local intervention among patients with triple negative breast cancer.

Neoadjuvant chemo-immunotherapy for the treatment of stage IIIA resectable non-small-cell lung cancer (NSCLC): A phase II multicenter exploratory study—Final data of patients who underwent surgical assessment.

8509 Background: Patients with stage IIIA (N2 or T4N0) are potentially curable but median overall survival is only around 15 months and complete pathologic response with conventional chemotherapy (CT) is no more than 9%. Methods: A Phase II, single-arm, open-label multicenter study of resectable stage IIIA N2-NSCLC adult patients with CT plus IO as a neoadjuvant treatment: three cycles of Nivolumab (NV) 360mg IV Q3W + paclitaxel 200mg/m2 + carboplatin AUC 6 IV Q3W followed by adjuvant NV treatment for 1 year. After complete neoadjuvant therapy, tumor assessment is performed prior to surgery. Surgery is performed in the 3rd or 4th week after day 21 of the third cycle of neoadjuvant treatment. The study aims to recruit 46 pts. The primary endpoint is Progression-Free Survival (PFS) at 24 months. Efficacy is explored using objective pathologic response criteria. We present final data on all patients included in this study that underwent surgical assessment. Results: At the time of submission, 46 pts had been included and 41 had undergone surgery. CT-IO was well-tolerated and surgery was not delayed in any patient. None of the pts withdrew from the study preoperatively due to progression or toxicity. 41 surgeries had been performed and all tumors were deemed resectable, with R0 resection in all cases. 34 pts (83%) achieved major pathologic response (MPR) (CI 95% 71-95%), and 24 (71%) of them had a complete pathologic response (CPR) (CI 95% 54-87%). Downstaging was seen in 90% (CI 95% 81-100%) of cases. By RECIST, 29 pts (71%) (CI 95% 56-85%) had partial response and 3 (7%) (CI 95% 0-16%) complete response. Conclusions: This is the first multicentric study to CT-IO in the neoadjuvant setting in stage IIIA. Neoadjuvant CT-IO with nivolumab in resectable IIIA NSCLC yields a high complete pathologic response rate that has never been seen previously and unsuspected by RECIST criteria. Preliminary correlative analyses in blood samples are included in a separate abstract. EudraCT Number: 2016-003732-20. Clinical trial information: NCT 03081689.

Role of the Interval from Completion of Neoadjuvant Therapy to Surgery in Postoperative Morbidity in Patients with Locally Advanced Rectal Cancer.

Increasing the interval from completion of neoadjuvant therapy to surgery beyond 8weeks is associated with increased response of rectal cancer to neoadjuvant therapy. However, reports are conflicting on whether extending the time to surgery is associated with increased perioperative morbidity. Patients who presented with a tumor within 15cm of the anal verge in 2009-2015 were grouped according to the interval between completion of neoadjuvant therapy and surgery: < 8weeks, 8-12weeks, and 12-16weeks. Among 607 patients, the surgery was performed at < 8weeks in 317 patients, 8-12weeks in 229 patients, and 12-16weeks in 61 patients. Patients who underwent surgery at 8-12weeks and patients who underwent surgery at < 8weeks had comparable rates of complications (37% and 44%, respectively). Univariable analysis identified male sex, earlier date of diagnosis, tumor location within 5cm of the anal verge, open operative approach, abdominoperineal resection, and use of neoadjuvant chemoradiotherapy alone to be associated with higher rates of complications. In multivariable analysis, male sex, tumor location within 5cm of the anal verge, open operative approach, and neoadjuvant chemoradiotherapy administered alone were independently associated with the presence of a complication. The interval between neoadjuvant therapy and surgery was not an independent predictor of postoperative complications. Delaying surgery beyond 8weeks from completion of neoadjuvant therapy does not appear to increase surgical morbidity in rectal cancer patients.

Abstract GS1-10: Phase III study of trastuzumab emtansine (T-DM1) vs trastuzumab as adjuvant therapy in patients with HER2-positive early breast cancer with residual invasive disease after neoadjuvant chemotherapy and HER2-targeted therapy including trastuzumab: Primary results from KATHERINE

Abstract Background: Patients with HER2-positive early breast cancer who have residual invasive disease after neoadjuvant chemotherapy plus HER2-targeted therapy have a high risk of recurrence and death. The current standard of care is continuation of the same HER2-targeted therapy in the adjuvant setting for one year. T-DM1 has shown activity and a favorable benefit-risk profile in metastatic patients with disease progression after prior chemotherapy plus HER2-targeted therapy. Thus, T-DM1 may also be active in patients with residual invasive disease after neoadjuvant HER2-targeted therapy. Methods: KATHERINE (NCT01772472/BO27938/NSABP B-50-I/GBG 77) is a phase III, open-label, global study of patients with centrally confirmed HER2-positive (IHC3+ or ISH+) primary breast cancer (T1–4, N0–3, M0) who received neoadjuvant chemotherapy plus HER2-targeted therapy, which had to include a taxane and trastuzumab, followed by surgery, with pathologically documented residual invasive disease in the breast and/or axillary lymph nodes. Within 12 weeks of surgery, patients were randomized 1:1 to T-DM1 (3.6 mg/kg IV q3w) or trastuzumab (6 mg/kg IV q3w), for 14 cycles. Randomization was stratified by clinical stage at presentation, hormone receptor status, single versus dual neoadjuvant HER2-targeted therapy, and pathological nodal status after neoadjuvant therapy. Patients received radiotherapy and/or endocrine therapy per local standards. The primary endpoint is invasive disease-free survival (IDFS). A single interim analysis (IA) was planned after approximately 67% of the IDFS events required for the primary analysis had occurred, with an efficacy stopping boundary of HR?0.732 or p&amp;lt;0.0124. The statistical plan stipulated an IA of OS if the IDFS IA boundary was crossed. Secondary endpoints include IDFS including second primary non-breast cancer, disease-free survival, distant recurrence-free interval, overall survival, and safety. Results:After review of the pre-specified IA, the IDMC recommended full analysis and disclosure of the results. With 256 IDFS events reported, administration of T-DM1 significantly improved IDFS compared with trastuzumab (unstratified HR=0.50; 95% CI: 0.39 to 0.64; p&amp;lt;0.0001). IDFS events occurred in 91 patients (12.2%) in the T-DM1 arm compared with 165 patients (22.2%) in the trastuzumab arm. T-DM1 treatment increased estimated three-year IDFS rates (88.3% vs 77.0% with trastuzumab). A consistent benefit was shown across all stratification subgroups. With 98 deaths reported, the OS analysis is immature (HR=0.70; 95% CI: 0.47 to 1.05; p=0.085). The safety data were consistent with the known safety profile of T-DM1, with expected increases in AEs associated with T-DM1 compared to trastuzumab alone. One grade 5 AE (0.1%) occurred in each arm. Conclusions: Adjuvant T-DM1 substantially improved IDFS in patients with HER2-positive early breast cancer with residual disease after completion of neoadjuvant therapy. Citation Format: Geyer, Jr. CE, Huang C-S, Mano MS, Loibl S, Mamounas EP, Untch M, Wolmark N, Rastogi P, Fischer HH, Redondo A, Jackisch C, Jacot W, Conlin AK, Schneeweiss A, Wapnir IL, Fasching PA, DiGiovanna MP, Wuelfing P, Arce-Salinas C, Crown JP, Shao Z, Rota Caremoli E, Wu H, Lam LH, Tesarowski D, Smitt M, Douthwaite H, Singel SM, von Minckwitz G. Phase III study of trastuzumab emtansine (T-DM1) vs trastuzumab as adjuvant therapy in patients with HER2-positive early breast cancer with residual invasive disease after neoadjuvant chemotherapy and HER2-targeted therapy including trastuzumab: Primary results from KATHERINE [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 GS1-10.

Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer

BackgroundPatients who have residual invasive breast cancer after receiving neoadjuvant chemotherapy plus human epidermal growth factor receptor 2 (HER2)–targeted therapy have a worse prognosis than those who have no residual cancer. Trastuzumab emtansine (T-DM1), an antibody–drug conjugate of trastuzumab and the cytotoxic agent emtansine (DM1), a maytansine derivative and microtubule inhibitor, provides benefit in patients with metastatic breast cancer that was previously treated with chemotherapy plus HER2-targeted therapy.MethodsWe conducted a phase 3, open-label trial involving patients with HER2-positive early breast cancer who were found to have residual invasive disease in the breast or axilla at surgery after receiving neoadjuvant therapy containing a taxane (with or without anthracycline) and trastuzumab. Patients were randomly assigned to receive adjuvant T-DM1 or trastuzumab for 14 cycles. The primary end point was invasive disease–free survival (defined as freedom from ipsilateral invasive breast tumor recurrence, ipsilateral locoregional invasive breast cancer recurrence, contralateral invasive breast cancer, distant recurrence, or death from any cause).ResultsAt the interim analysis, among 1486 randomly assigned patients (743 in the T-DM1 group and 743 in the trastuzumab group), invasive disease or death had occurred in 91 patients in the T-DM1 group (12.2%) and 165 patients in the trastuzumab group (22.2%). The estimated percentage of patients who were free of invasive disease at 3 years was 88.3% in the T-DM1 group and 77.0% in the trastuzumab group. Invasive disease–free survival was significantly higher in the T-DM1 group than in the trastuzumab group (hazard ratio for invasive disease or death, 0.50; 95% confidence interval, 0.39 to 0.64; P<0.001). Distant recurrence as the first invasive-disease event occurred in 10.5% of patients in the T-DM1 group and 15.9% of those in the trastuzumab group. The safety data were consistent with the known safety profile of T-DM1, with more adverse events associated with T-DM1 than with trastuzumab alone.ConclusionsAmong patients with HER2-positive early breast cancer who had residual invasive disease after completion of neoadjuvant therapy, the risk of recurrence of invasive breast cancer or death was 50% lower with adjuvant T-DM1 than with trastuzumab alone. (Funded by F. Hoffmann–La Roche/Genentech; KATHERINE ClinicalTrials.gov number, NCT01772472.)

The association of 5FU-based chemotherapy with pathological response or survival compared to carbo/taxol with locally advanced resectable esophageal cancer.

165 Background: Neoadjuvant chemoradiation followed by esophagectomy is the standard of care in advanced EC. While 5FU based chemoradiation has been a common regimen in the past, its utilization has declined in recent years as the CROSS trial study regimen of carboplatin/paclitaxel has become widely adopted. A prospective evaluation of the CROSS regimen compared to the 5FU based regimen was never performed. The aim of this study is to report our institutional experience with these two chemotherapy regimens. To the best of our knowledge, this is the largest retrospective study comparing the two types of chemotherapy regimens. Methods: We performed an IRB-approved retrospective review of a prospectively maintained institutional cancer registry. EC patients who completed trimodality therapy with either carboplatin/paclitaxel or 5FU/platinum were identified and divided into groups based on their chemotherapy regimens. Multivariable logistic regression was used to analyze pathologic complete response (pCR) rates, while the Kaplan–Meier and Cox proportional hazards models were utilized to evaluate DFS and OS. Analytical models were adjusted for age, stage, radiation dose, histology sub-type, and time interval from completion of neoadjuvant therapy to surgery. Results: 224 patients treated between January of 2007 and July of 2017 were identified . Of this group, 139(62%) had received Carbo/Taxol, while 85 (37%) had received 5FU/platinum. There was no increase in the odds of pCR with 5FU based chemo compared to CROSS regimen (OR = 2.68, P = 0.671). Furthermore, the OS and DFS of 159 patients(80 5FU/platinum, 77 carbo/taxol) with median follow up of ~ 5 yrs were not statistically different with HR 1.08 (0.6-1.7) and P value 0.71. Conclusions: Neoadjuvant chemoradiation with 5FU/platinum in resectable EC is not associated with higher rates of pCR, DFS and OS compared to the CROSS regimen of carbo/taxol. Those findings will need to be validated in a larger cohort.

Outcomes of younger patients diagnosed with locally advanced rectal cancer.

500 Background: The incidence of rectal cancer is higher in the older population. In developed nations there has been a rise in incidence in young onset rectal cancer (yRC). We evaluated and compared the presentation and survival outcomes of treatments for locally advanced rectal cancer in yRC patients to that of older patients. Methods: All cases of rectal cancers referred to a large tertiary referral cancer centre in Western Sydney between 2009-2016 were examined. Patient demographics, presenting symptoms, treatment, clinico-pathological characteristics, progression free survival (PFS) and overall survival (OS) were obtained. Under 50 years old was used as the cut-off age for defining yRC. Results: One hundred sixty-two patients were identified, 33 in the yRC and 129 in the older patient group. The median age at diagnosis was 62 (24 – 92). Median follow-up was 40 months. There was no difference in presenting symptoms between the two groups, with per rectal bleeding being the most common symptom at presentation. 17.5% of yRC presented with stage IV disease, compared with 22.1% of older patients. yRC were more likely to complete neoadjuvant therapy (97% vs 81%; P=0.02). yRC were more likely to proceed to surgery (91% vs 72%, P=0.02). There were no significant differences in surgical outcomes, including complications and postoperative TNM staging. yRC were more likely to have microsatellite high tumours (18% vs 4%; P=0.01). No statistical differences were seen in survival outcomes (PFS 57.1 vs 62.9 months, P=0.26; OS 85.1 Vs 92.8 months, P=0.57) between older and yRC patients. Eight progressions (eight deaths) were observed in the yRC group and 40 progressions (36 deaths) were observed in the older patient group. Conclusions: 20% of rectal cancers were considered yRC. These patients were more likely to complete neoadjuvant therapy and proceed to surgery. In this cohort, median PFS and OS were longer compared to the older patient group, although this was not statistically significant. yRC were more likely to have MMR deficiency. Patients under 50 years with alarm symptoms including per rectal bleeding require vigilance in investigations to allow for earlier detection and appropriate management of rectal cancer.

Assessment of a Watch-and-Wait Strategy for Rectal Cancer in Patients With a Complete Response After Neoadjuvant Therapy

The watch-and-wait (WW) strategy aims to spare patients with rectal cancer unnecessary resection. To analyze the outcomes of WW among patients with rectal cancer who had a clinical complete response to neoadjuvant therapy. This retrospective case series analysis conducted at a comprehensive cancer center in New York included patients who received a diagnosis of rectal adenocarcinoma between January 1, 2006, and January 31, 2015. The median follow-up was 43 months. Data analyses were conducted from June 1, 2016, to October 1, 2018. Patients had a clinical complete response after completing neoadjuvant therapy and agreed to a WW strategy of active surveillance and possible salvage surgery (n = 113), or patients underwent total mesorectal excision and were found to have a pathologic complete response (pCR) at resection (n = 136). Kaplan-Meier estimates were used for analyses of local regrowth and 5-year rates of overall survival, disease-free survival, and disease-specific survival. Compared with the 136 patients in the pCR group, the 113 patients in the WW group were older (median [range], 67.2 [32.1-90.9] vs 57.3 [25.0-87.9] years, P < .001) with cancers closer to the anal verge (median [range] height from anal verge, 5.5 [0.0-15.0] vs 7.0 [0.0-13.0] cm). All 22 local regrowths in the WW group were detected on routine surveillance and treated by salvage surgery (20 total mesorectal excisions plus 2 transanal excisions). Pelvic control after salvage surgery was maintained in 20 of 22 patients (91%). No pelvic recurrences occurred in the pCR group. Rectal preservation was achieved in 93 of 113 patients (82%) in the WW group (91 patients with no local regrowths plus 2 patients with local regrowths salvaged with transanal excision). At 5 years, overall survival was 73% (95% CI, 60%-89%) in the WW group and 94% (95% CI, 90%-99%) in the pCR group; disease-free survival was 75% (95% CI, 62%-90%) in the WW group and 92% (95% CI, 87%-98%) in the pCR group; and disease-specific survival was 90% (95% CI, 81%-99%) in the WW group and 98% (95% CI, 95%-100%) in the pCR group. A higher rate of distant metastasis was observed among patients in the WW group who had local regrowth vs those who did not have local regrowth (36% vs 1%, P < .001). A WW strategy for select rectal cancer patients who had a clinical complete response after neoadjuvant therapy resulted in excellent rectal preservation and pelvic tumor control; however, in the WW group, worse survival was noted along with a higher incidence of distant progression in patients with local regrowth vs those without local regrowth.

Inflammatory breast cancer: no longer an absolute contraindication for breast conservation surgery following good response to neoadjuvant therapy.

Inflammatory breast cancer (IBC) is a rare form of breast cancer characterised by an erythematous swollen breast with extensive oedema and has in the past been associated with a very poor prognosis. After diagnosis by core biopsy of the cancer and any involved nodes patients in the Edinburgh Breast Unit (EBU) are primarily managed with neoadjuvant systemic therapy-chemotherapy or endocrine therapy. If the cancer is localised to one or a few well defined lesions then each of these lesions together with the lowest involved node are clipped. Response during neoadjuvant treatment is monitored clinically and by ultrasound plus mammography +/- magnetic resonance imaging (MRI). Following completion of neoadjuvant therapy, imaging is reviewed at a multidisciplinary meeting and patients with a localised single or multiple areas of cancer where all signs of erythema and oedema have settled are considered as to their suitability for breast conserving surgery and whole breast radiotherapy [breast conserving treatment (BCT)]. Here we discuss the results and outcomes of a selected group of patients with IBC who after obtaining a very good response to neoadjuvant chemotherapy or endocrine therapy were treated by BCT and we compare these with other recent publications on this topic. Our data show that patients treated by BCT did not have worse outcomes than patients treated with mastectomy. Importantly other series published recently support our conclusions. Another important observation is that response in estrogen receptor (ER) rich IBC is seen with neoadjuvant endocrine treatment and so not everyone with IBC needs to have neoadjuvant chemotherapy. In conclusion, patients with one or more well defined and localised breast masses and IBC may be suitable for BCT after a major response to neoadjuvant therapy and for these patients BCT should now be considered a viable option.

PS01.170: IMPACT OF MUSCLE MASS, NUTRITIONAL STATUS AND MUSCLE STRENGTH ON OUTCOMES FOLLOWING SURGERY FOR ESOPHAGEAL CANCER

Abstract Background Muscle function loss and loss of skeletal muscle have been associated with worse outcomes following surgery for malignancies of gastrointestinal origin. The influence on post-operative outcomes and survival after esophageal surgery remains unclear. Primary objectives of this study were to evaluate the incidence of sarcopenia and malnutrition and to evaluate the influence of skeletal muscle surface area and muscle strength on postoperative outcomes and overall survival in esophageal cancer patients. Methods A retrospective cohort study from a prospective database was conducted in patients with resectable esophageal cancer who underwent curative-intent treatment between January 2011 and January 2016. Skeletal muscle surface area was calculated with CT scans at L3 level and corrected for height and weight before start of treatment and in the interval between neoadjuvant treatment and surgery. Muscle strength was evaluated with various tests on muscle functions and lung function tests. Nutritional status was evaluated using BMI. Results 273 Patients were included. There were 4 patients with sarcopenia before neoadjuvant therapy and only one patient with sarcopenia after completion of neoadjuvant therapy. Median skeletal muscle surface area was 78cm2/m2 for men and 61cm2/m2 for woman. Table 1 shows skeletal muscle surface area, muscle strength and BMI in relation to no, minor or major complications. Muscle strength and nutritional status did not have a significant influence on postoperative complications and overall survival. Conclusion Sarcopenia did not occur frequently in this cohort with potentially curable esophageal cancer patients. Muscle function, skeletal muscle index and BMI did not statistically influence post-operative complications or survival. Disclosure All authors have declared no conflicts of interest.