High-risk Early Stage Research Articles

NeoTRACT: Phase II trial of neoadjuvant tumor infiltrating lymphocyte- and response-adapted chemoimmunotherapy for triple-negative breast cancer (TNBC).

TPS629 Background: Neoadjuvant chemoimmunotherapy is recommended for patients with high risk early stage TNBC. The 5 drug KEYNOTE-522 neoadjuvant chemoimmunotherapy regimen involves 5-6 months of treatment and is associated with suboptimal treatment completion due to toxicity. Approaches to deescalate chemoimmunotherapy without compromising outcomes for patients with highly chemosensitive disease are needed. Stromal tumor infiltrating lymphocyte (sTIL) enrichment is positively associated with pathologic complete response (pCR) in TNBC and may be useful to identify patients for whom de-escalation of neoadjuvant chemoimmunotherapy might be acceptable. NeoTRACT trial investigates deescalating neoadjuvant chemoimmunotherapy based on degree of pretreatment sTIL enrichment. We hypothesize that baseline immune upregulation assessed by sTILs can guide neoadjuvant treatment optimization in TNBC patients. Specifically, in patients with immune enriched TNBC (sTILs ≥30%), short anthracycline free taxane–platinum chemoimmunotherapy will yield high pCR rate. Methods: NeoTRACT is an ongoing open label phase II trial for patients with previously untreated TNM stage I (T>1cm)–III TNBC. TNBC is defined as estrogen and progesterone receptor ≤10% and HER2 negative per ASCO/CAP criteria. Patients with T4 or N3 breast cancer are excluded. Patients must have adequate organ function and no contraindication to pembrolizumab. All participants initiate carboplatin (AUC 6) + docetaxel (75mg/m2) + pembrolizumab (200mg) (CbD+P) every 21 days. After registration, sTILs are evaluated centrally on pretreatment H&E core needle biopsy slide using standard criteria. Participants are assigned to three neoadjuvant treatment regimens (A, B, or C) based on sTIL enrichment. Regimen A (sTILs ≥30%) includes four cycles CbD+P. All participants assigned to regimen A undergo breast MRI after four cycles: those with complete MRI response proceed to breast surgery; those with less than complete MRI response receive two additional cycles of CbD+P. Regimen B (sTILs 5-29%) includes six cycles of CbD+P. Regimen C (sTILs <5%) includes four cycles of CbD+P followed by four cycles of doxorubicin (60mg/m2) + cyclophosphamide (600mg/m2) + P (200mg) (AC+P). All patients undergo surgery after completing the assigned neoadjuvant regimen. Breast/axillary surgery, adjuvant systemic therapy, and radiotherapy are recommended per standard of care. pCR is defined as absence of residual invasive disease in breast and axilla. Primary endpoint is pCR rate among participants with ≥30% sTILs. Secondary endpoints include residual cancer burden (RCB) rates in patients with ≥30% sTILs, pCR and RCB rates in patients with 5-29% and <5% sTILs, and event free and overall survival for all patients. As of January 2024, 45 of 139 participants have been enrolled. Clinical trial information: NCT05645380 .

Abstract PO1-27-09: TRIPTORELIN (11.25MG) vs TRIPTORELIN (3.75MG) IN PREMENOPAUSAL WOMEN WITH HIGH-RISK EARLY STAGE BREAST CANCER RH(+) and HER2(-) REAL WORLD EXPERIENCE. TRIPTO3 RESULTS

Abstract Background. Premenopausal women with high risk early stage BC HR+/Her2- present as a complex disease and generally have worse survival outcomes compared to postmenopausal women with the same disease. There are pathological clinical factors and genomic platforms that help us in therapeutic decisions. The use of triptorelin 3.75mg associated with AI promotes favorable results in terms of survival for premenopausal women with high-risk Early stage BC. TEXT/SOFT trial. TRIPTO3 study evaluates the use of Triptorelin 11.25mg vs. Triptorelin 3.75mg in this specific patient population. Methods: We reviewed medical records of premenopausal female patients with high-risk early stage breast cancer who have been treated and received triptorelin 3.75mg and triptorelin 11.25mg as part of their treatment. All patients were treated at a private Oncology Center between 2013 and 2020. The primary objective was disease-free survival. Results: 52 patients were found who met the inclusion criteria. 28(53.8%) patients received triptorelin 11.25mg and 24(46.2%) patients received triptorelin 3.75mg respectively. The median follow-up was 63 months and the disease-free survival for the Triptorelin 11.25mg group was 91.2% and for the Triptorelin 3.75mg group was 86.8% respectively (Hazard Ratio of disease-free survival was 1.2; 95% IC (0.2-7.2). Disease-free survival for both groups regardless of triptorelin dose was 89% at 5 years. The median disease-free survival was not reached in both groups. Conclusions: Our findings show that triptorelin 11.25 mg is similar to the use of triptorelin 3.75 mg in terms of disease-free survival for premenopausal women with high-risk early stage breast cancer. Citation Format: Ronald Limon, Mariano Lopez-Pereyra, Mario Gianella, Neysa Espinoza, Denize Ramirez, Carlos Antelo, Claudia Sitic, Wara Cortez, Oscar Niño De Guzman, Silvia Neciosup, Natalia Valdivieso. TRIPTORELIN (11.25MG) vs TRIPTORELIN (3.75MG) IN PREMENOPAUSAL WOMEN WITH HIGH-RISK EARLY STAGE BREAST CANCER RH(+) and HER2(-) REAL WORLD EXPERIENCE. TRIPTO3 RESULTS [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-27-09.

Immunotherapy for Early-Stage Triple Negative Breast Cancer: Is Earlier Better?

In this narrative review, we discuss the optimal timing ofimmune checkpoint inhibitors (ICI) in early triple negative breast cancer (TNBC), the landscape of predictive biomarkers for the use ofimmunotherapy, and the mounting literature suggesting a benefit for an early use of ICI. TNBC is associated with a poor prognosis relative to other breast cancer subtypes, and until recently, the treatment of TNBC was limited to cytotoxic chemotherapy. In 2021, the immune-checkpoint inhibitor, pembrolizumab, was approved in combination with neoadjuvant chemotherapy for patients with high-risk early stage TNBC. This approval changed the treatment paradigm of early TNBC concomitantly raised several challenges in clinical practice, pertaining to patient selection, toxicity management, and post-neoadjuvant treatment, among others. The introduction of neoadjuvant chemoimmunotherapy has transformed the treatment landscape for early TNBC. However, several challenges, including patient selection, toxicity management, and the identification of predictive biomarkers, need to be addressed. Future research should focus on refining the timing and duration of immunotherapy, optimizing the chemotherapy partner, and exploring novel predictive biomarkers of response or toxicity.

Practice patterns of adjuvant radiotherapy in women with stage I to II endometrial carcinoma: a real-world multi-institutional analysis in China

BackgroundThis study aimed to report clinical practice patterns of postoperative radiotherapy for stage I to II endometrial carcinoma (EC) patients treated in 13 Chinese medical centers.MethodsWe included early stage EC patients treated by hysterectomy and adjuvant RT between 2003 and 2017 from 13 institutions. Patients were classified into 4 risk groups based on ESMO-ESGO-ESTRO recommendations (2014).ResultsA total of 1,227 cases were analyzed. Along the 15 years of the study, an increasing tendency was found towards administration for vaginal brachytherapy (VBT) alone, while the proportion of external beam pelvic radiotherapy (EBRT) alone remained stable in the corresponding period. When radiation modalities were stratified by risk groups, proportion of VBT alone significantly increased in all risk groups. The higher the risk, the later VBT became the main adjuvant treatment modality. However, EBRT alone or with VBT remained the main adjuvant method for high-risk patients.There were 13 dose-fractionation schemes for VBT alone with the scheme of 30 Gy in 6 fractions prescribed at 0.5cm under the vaginal mucosa accounting for most. There were 17 schemes for VBT boost and the most common schedule was 10 Gy in 2 fractions. The upper 3–5cm part of vagina was the most frequent target. 89.6% of the practitioners performed two-dimensional VBT technique. The median dose for EBRT was 50 Gy. From 2003 to 2017, conventional radiotherapy was gradually replaced by three-dimensional conformal radiotherapy modality and intensity modulated radiotherapy.ConclusionWe report a significant shift from EBRT to VBT alone for high-intermediate-risk, intermediate-risk and low-risk EC patients from 2003 to 2017 while EBRT remained the main radiation modality for high-risk early stage patients. There has been remarkable heterogeneity among VBT dose fractionation schedules across China.Trial registrationThe clinical trial ID was ChiCTR-PRC-17010712. It was authorized by the Institutional Review Board of Peking Union Medical College Hospital (N0. S-K139).

61 Do the Peters criteria hold up for adenocarcinoma? A retrospective database study evaluating the effect of histology on outcomes in surgically-treated high-risk early stage cervical cancer

61 Do the Peters criteria hold up for adenocarcinoma? A retrospective database study evaluating the effect of histology on outcomes in surgically-treated high-risk early stage cervical cancer

118P Real-world treatment patterns and clinical outcomes among high risk, early stage HER2-negative breast cancer (BC) patients in Alberta, Canada

Data are needed to improve the current understanding of the epidemiology and clinical management of high-risk early stage HER2- BC patients. This study was a retrospective longitudinal cohort study using real-world, population-level data from Alberta, Canada. All individuals newly diagnosed with high-risk, stage II/III HER2- BC in Alberta, Canada between 2013-2019 were included. Data on treatment, laboratory results and pathology findings were collected through electronic health records and administrative databases. High-risk BC was defined as receipt of adjuvant systemic therapy within 120 days of surgery as well as the presence of the following characteristics: 1) For triple-negative BC (TNBC): tumor 2+ cm (AJCC T2 or greater) or axillary lymph node (LN) involvement; 2) For hormone-receptor positive (HR+/HER2-): four or more positive LNs. Treatment eras were separated into pre/post 2016. Overall survival (OS) was defined as the date of diagnosis to death from any cause or last known contact. The annual cumulative incidence of early-stage, high-risk, HER2- BC ranged from 6% to 9%. Individuals with TNBC were more likely to be younger, have grade 3 histology, stage II BC, and receive systemic therapy at a community centre (p < 0.05) when compared with HR+/HER2- BC. Germline BRCA testing was not widely conducted in this patient population, with an estimated 14% of patients diagnosed in 2010-2017 being tested at some point post-diagnosis. Neoadjuvant systemic therapy was given to 37% of patients with high-risk BC. The 5-year OS from initiation of adjuvant systemic therapy (for patients who received adjuvant systemic therapy) or date of surgery (for patients who did not receive adjuvant systemic therapy) was 77% (95% CI: 75 to 79). OS was significantly worse among patients who were older, had grade 3 histology, stage III BC, or had LN involvement (p < 0.05). OS among patients with TNBC between 2016-2019 who initiated adjuvant capecitabine was markedly worse than that of the overall cohort (2-year OS: 70% vs. 89%). Outcomes analyses in this population suggest a continued unmet clinical need. Additional analyses into the indications for use of systemic therapies are underway.

57P Clinicopathologic landscape of high-risk early stage HER2-low breast cancer

57P Clinicopathologic landscape of high-risk early stage HER2-low breast cancer

Outcomes and clinicopathologic characteristics associated with disseminated tumor cells in bone marrow after neoadjuvant chemotherapy in high-risk early stage breast cancer: the I-SPY SURMOUNT study.

Disseminated tumor cells (DTCs) expressing epithelial markers in the bone marrow are associated with recurrence and death, but little is known about risk factors predicting their occurrence. We detected EPCAM+/CD45- cells in bone marrow from early stage breast cancer patients after neoadjuvant chemotherapy (NAC) in the I-SPY 2 Trial and examined clinicopathologic factors and outcomes. Patients who signed consent for SURMOUNT, a sub-study of the I-SPY 2 Trial (NCT01042379), had bone marrow collected after NAC at the time of surgery. EPCAM+CD45- cells in 4mLs of bone marrow aspirate were enumerated using immunomagnetic enrichment/flow cytometry (IE/FC). Patients with > 4.16 EPCAM+CD45- cells per mL of bone marrow were classified as DTC-positive. Tumor response was assessed using the residual cancer burden (RCB), a standardized approach to quantitate the extent of residual invasive cancer present in the breast and the axillary lymph nodes after NAC. Association of DTC-positivity with clinicopathologic variables and survival was examined. A total of 73 patients were enrolled, 51 of whom had successful EPCAM+CD45- cell enumeration. Twenty-four of 51 (47.1%) were DTC-positive. The DTC-positivity rate was similar across receptor subtypes, but DTC-positive patients were significantly younger (p = 0.0239) and had larger pretreatment tumors compared to DTC-negative patients (p = 0.0319). Twenty of 51 (39.2%) achieved a pathologic complete response (pCR). While DTC-positivity was not associated with achieving pCR, it was significantly associated with higher RCB class (RCB-II/III, 62.5% vs. RCB-0/I; 33.3%; Chi-squared p = 0.0373). No significant correlation was observed between DTC-positivity and distant recurrence-free survival (p = 0.38, median follow-up = 3.2years). DTC-positivity at surgery after NAC was higher in younger patients, those with larger tumors, and those with residual disease at surgery.

Role of systematic lymphadenectomy in patients with intermediate to high-risk early stage endometrial cancer.

To determine the clinical significance of systematic lymph node dissection (LND) and to better define the relevant extent of LND in intermediate- to high-risk early stage endometrial cancer (EC). Patients who received surgery as a primary treatment of histologically confirmed EC and preoperatively considered as uterus-confined early stage disease were included in the study population. The rates of lymph node metastasis (LNM) according to the risk groups and anatomic sites were assessed. Univariate and multivariate analyses were performed to evaluate risk factors for recurrence. A total of 804 patients were included in the study analysis. The rates of LNM were significantly different according to the risk group; 1.2% in low-risk, 20.1% in intermediate-risk, and 30.0% in high-risk group. When assessing the rates of LNM in individual anatomic sites, positive LNs were evenly distributed throughout the pelvic and para-aortic regions. In the intermediate to high-risk EC cases, the rates of para-aortic LNM below and above inferior mesenteric artery (IMA) were 11.1% and 12.5%, respectively. On multivariate analysis, LNM was the only independent risk factor for recurrence in the intermediate to high-risk EC (hazard ratio=2.63, 95% confidence interval=1.01-6.82, p=0.047). LNM was frequently observed in intermediate- and high-risk early stage EC and it served as an independent risk factor for recurrence. When considering the similar rates of LNM between below and above IMA, nodal assessment needs to be performed up to the infra-renal level, especially for the staging purpose in high-risk EC.

The clinical and prognostic significance of pre-chemotherapy serum CA-125 in high-risk early stage ovarian cancer: An NRG/GOG ancillary study

ObjectivesTo determine the clinical and prognostic significance of CA-125 trends prior to, during, and after chemotherapy in high-risk early-stage epithelial ovarian cancer patients. MethodsAll patients were enrolled in a phase III randomized trial (GOG 157) following upfront surgery for grade 3 stage IA/IB, stage IC, or stage II disease, and had been treated with either three or six cycles of carboplatin/paclitaxel. Kaplan-Meier method and Cox proportional hazards model were used to evaluate recurrence-free survival (RFS) and overall survival (OS). ResultsOf 350 patients, the median pre-chemotherapy CA-125 was 65 (IQR: 31–129). 71% of Whites had an elevated CA-125 compared to 47% of non-Whites (p = 0.006). Following the first cycle of chemotherapy, 74% of those with elevated CA-125 had normalization. Those who had normalization of CA-125 after 1 cycle had significantly better 5-year RFS (81% vs. 65%, p = 0.003) and OS (87% vs. 75%, p = 0.009) compared to those who did not normalize (defined as ≤35 U/mL). The pattern of CA-125 change following chemotherapy cycle 1, from normal to normal vs. elevated to normal vs. elevated to elevated had corresponding RFS of 87% vs. 80% vs. 68% (p = 0.013), and OS of 92% vs. 88% vs. 77% (p = 0.009). However, the percent decline (p = 0.993) and absolute nadir normal value of CA-125 (0–10 vs. 11–35 U/mL) were not predictive of outcome (p = 0.4). ConclusionsNormal baseline CA125 and normalization of this biomarker after the first cycle of chemotherapy were associated with better survival in high-risk early-stage epithelial ovarian cancer patients.

1423TiP CYCLONE 3: A phase III, randomized, double-blind, placebo-controlled study of abemaciclib in combination with abiraterone plus prednisone in men with high-risk metastatic hormone-sensitive prostate cancer (mHSPC)

Landmark trials led to the integration of docetaxel (D) or novel hormonal agents (NHA) added to androgen deprivation therapy (ADT) into the treatment paradigm for mHSPC. Recent data showed survival benefit for treatment intensification with ADT+D+NHA triplet therapy vs ADT+D in selected patients (pts). Yet, there is a significant medical need to expand therapeutic options especially for pts with poor prognoses, including those not candidates for chemotherapy. Abemaciclib is an oral selective inhibitor of cyclin-dependent kinase 4 and 6 (CDK4 & 6) dosed on a continuous schedule, approved for the treatment of advanced or metastatic and certain types of high-risk early stage HR+, HER2- breast cancer.

The PRECEDE consortium: A longitudinal international cohort study of individuals with genetic risk or familial pancreatic cancer.

e16239 Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with lack of effective early detection strategies. There is an incomplete understanding of who is at risk for PDAC development and the contribution of heritability to that risk. Further, efforts at biomarker development for detection of early stage disease have been hampered by small sample sizes, lack of coordination, and inadequate access to high quality clinical data and biospecimens in relevant clinical populations. The PRECEDE Consortium was established to serve as a collaborative international network of PDAC clinical and research centers to accelerate early detection advances by standardizing collection of clinical data and biospecimens from patients at increased risk for PDAC. The consortium goal is to increase the overall survival rate for PDAC to 50% in 10 years by enabling transformative biomarker-driven discoveries in early detection of high-risk premalignant lesions and early stage cancers. Methods: The PRECEDE Consortium (NCT04970056; precedestudy.org) launched in 2019 and began enrollment in May, 2020. Data and biospecimen sharing are required for centers to join the consortium, which is facilitated through use of standardized data and biospecimen collection, and a centralized database (PRECEDELink) managed by a data coordinating center (Arbor Research). Imaging and clinical sequencing data will be stored and analyzed via a PRECEDE solution in the Amazon Web Services cloud. Participants age 18-90 are enrolled into one of seven cohorts based on personal and/or family history of PDAC and carrier status of pathogenic germline variants (PGV) in cancer predisposition genes (CPG). Three-generation pedigrees are collected at enrolment from participants, and standardized clinical germline testing is offered. Blood sample collection for DNA, plasma, and serum is completed at enrollment, and repeated annually for individuals meeting guidelines for annual surveillance. Results: To date, 24 clinical sites have enrolled 2187 participants, with a target of 10,000 participants enrolled from100 sites over the next 5 years. Among enrolled patients, 55% meet criteria for annual surveillance by MRI or endoscopic ultrasound. Demographics of the cohort to date: 56% female; 73% white; 35% CPG PGV carriers; 32% meet criteria for familial pancreatic cancer. Conclusions: The PRECEDE Consortium study is a large international, longitudinal, prospective cohort study designed to accelerate the pace and scale of early diagnosis. Planned projects will address modifiers of risk, penetrance of disease, creating comprehensive risk models for clinical decision-making, and development and validation of biomarker assays. The PRECEDE Consortium provides a unique, innovative platform to bring together key stakeholders (academia, patients, public and private sector) to effect progress.

Local recurrence at the site of the Lone Star device through implantation of exfoliated cells during local excision for early rectal cancer: A case report.

IntroductionInvasive procedures for colorectal cancer can cause iatrogenic tumor cell seeding. Implantation of these exfoliated cells in the surrounding tissue can result in locoregional cancer recurrence. This has been described in endoscopic procedures and major surgical resections, however recurrence in iatrogenic lesions of the anal canal during minimal invasive rectal surgery has not been shown in literature yet. This is the first reported case of recurrent rectal cancer that developed into an anal metastasis at the site where hooks of the Lone Star Retractor disrupted the epithelial lining of the anal canal during a local excision of early rectal cancer using TAMIS.Presentation of caseA 57 year old male was diagnosed with a high risk early stage rectal adenocarcinoma. He was treated with transanal minimally invasive surgery (TAMIS) with the use of a Lone Star retractor and he received subsequent chemo-radiotherapy. 23 months later the patient developed a bleeding mass bulging out of the anus. A true cut and incision biopsy was performed and the pathology report revealed localization of adenocarcinoma at the anal canal which was similar to the earlier diagnosed rectal carcinoma. The patient underwent an abdominal perineal resection and left-sided lymph node dissection.Discussion and conclusionThis shows that local recurrence through implantation of exfoliated tumor cells can occur in iatrogenic lesions of the anal canal not only in major but also in minimal invasive rectal surgery. Careful tissue handling and rectal washout may reduce the chance of this implantation metastasis.

Abstract PD10-07: Chemokine12 (CK12) tertiary lymphoid gene expression signature as a predictor of response in 3 immunotherapy arms of the neoadjuvant ISPY 2 TRIAL - pembrolizumab with and without SD101, and durvalumab combined with olaparib - and in 9 other arms of the trial including platinum-based and dual-anti-HER2 therapies

Abstract Background: The CK12 expression signature consists of genes CCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL9, CXCL10, CXCL11, CXCL13 and was previously shown to associate with the presence of T and B cell rich tertiary lymphoid structures in melanoma and other cancers, and with better patient survival independent of tumor staging and treatment. I-SPY 2 is a biomarker-rich, phase II neoadjuvant platform trial for high risk early stage breast cancer. Here we leverage the I-SPY 2 biomarker program to test the hypothesis that this signature associates with sensitivity to neoadjuvant immunotherapies and potentially other classes cancer therapeutics in breast cancer. Methods: Data from 1130 patients across 12 arms of I-SPY2 (control (ctr): 210; veliparib/carboplatin (VC): 71; neratinib (N): 114; MK2206: 93; ganitumab: 106; ganetespib: 93; AMG386: 134; TDM1/pertuzumab(P): 52; H/P: 44; pembrolizumab (pembro): 69; durvalumab/olaparib (durva/olap): 71; pembro/SD101: 72) were available for analysis. Pre-treatment FF (n=987) or FFPE (n=143) biopsies were assayed using Agilent gene expression arrays. Signature scores were calculated as the average expression level across the 12 genes, after z-score normalization. We used logistic modeling to assess association with pCR in each arm in a model adjusting for HR and HER2 (likelihood ratio test, p&amp;lt;0.05). This analysis was also performed within HR/HER2 receptor subsets, numbers permitting. We also assessed differences in levels across HR/HER2 subsets using ANOVA and Tukey post-hoc testing. Our statistics are descriptive rather than inferential and do not adjust for multiplicities of other biomarkers outside this study. Results: CK12 levels associate with HR/HER2 status (ANOVA p=1.07E-14), with higher levels in TN and HR-HER2+ subsets and lower levels in HR+ groups. Overall, patients with higher levels of CK12 were significantly more likely to achieve pCR in all 3 IO arms: pembro (OR=3.4/1SD), pembro/SD101 (OR=4/1SD), and durva/olaparib (OR=2.5/1SD) (LR p&amp;lt;0.05), in a model adjusting for HR status. The CK12 performed favorably in predicting response to pembro/SD101 compared to several other genomic signatures measuring intratumoral immune response. Higher CK12 also associates with response to the ANG1/2 inhibitor AMG386, an agent known to have immune modulatory activity. Higher CK12 was moderately associated with pCR in the control (OR=2.0/1SD), neratinib (OR=1.7/1SD), veliparib/carboplatin (OR=2.0/1SD), ganitumab (OR= 1.7/1SD) and TDM1/P arms (OR=2.1/1SD). Within the HR+HER2- subset, CK12 associated with pCR in all three IO arms, and in the control, AMG386, ganitumab, and ganetespib arms. Within the smaller TN subset, it associated with response in pembro and pembro/SD101 arms but not in durva/olaparib, and in the neratinib and AMG386 arms. Chemokine12 mostly did not associate with pCR in HER2+ subsets, except for HR+HER2+ patients treated with neratinib, and HR-HER2+ patients in the original control arm (trastuzumab). Conclusion: The CK12 signature is highly predictive of complete pathologic response to immuno-oncology agents and other therapeutics supporting the role of the crosstalk within the tumor immune microenvironment in predicting response across subtypes. This gene expression signature can be readily obtained from microarrays and warrants further investigation in future arms of ISPY2 as a predictive biomarker. Citation Format: Hatem Soliman, Denise Wolf, Jo Chien, Christina Yau, Michael Campbell, Mark Magbanua, Ruixiao Lu, Nicholas O'Grady, Lamorna Brown-Swigart, Gillian Hirst, Beverly Parker, Laura Sit, Smita Asare, Doug Yee, Angie DeMichele, Rita Nanda, Lajos Pusztai, Don Berry, Laura Esserman, Laura Van't Veer. Chemokine12 (CK12) tertiary lymphoid gene expression signature as a predictor of response in 3 immunotherapy arms of the neoadjuvant ISPY 2 TRIAL - pembrolizumab with and without SD101, and durvalumab combined with olaparib - and in 9 other arms of the trial including platinum-based and dual-anti-HER2 therapies [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD10-07.

Abstract GS3-06: Primary results of the cTRAK TN trial: A clinical trial utilising ctDNA mutation tracking to detect minimal residual disease and trigger intervention in patients with moderate and high risk early stage triple negative breast cancer

Abstract Background Detection of circulating tumour DNA (ctDNA) in patients (pts) who have completed treatment for early-stage triple negative breast cancer (TNBC) is associated with a very high risk of future relapse. Identifiying those at high risk of subsequent relapse may allow tailoring of further therapy to delay or prevent recurrence. The c-TRAK TN trial assessed the utility of prospective ctDNA surveillance in pts treated for TNBC and the activity of pembrolizumab (P) in pts with ctDNA detected.. Methods c-TRAK TN, a multi-centre phase II trial with integrated prospective screening component, enrolled pts with early-stage TNBC and either residual disease following neoadjuvant chemotherapy, or tumour size &amp;gt;20mm and/or axillary lymph node involvement if adjuvant chemotherapy was given. Tumour tissue was sequenced to identify somatic mutations suitable for tracking using personalised digital PCR ctDNA assays (BioRad QX200). Pts had “active” ctDNA surveillance via blood sample testing every 3 months to 12 months (potential up to 18 months if samples missed due to COVID) during which time if ctDNA was detected (ctDNA+) pts could be randomised 2:1 to P (200mg i.v. q 3 weeks for 1 year) or observation (Obs). Pts and clinicians were blinded to ctDNA+ results unless they were allocated P, when staging scans were done and those free of clinical recurrence started treatment. Following advice from the Independent Data Monitoring Committee, the Obs arm closed on 16/06/2020 with all subsequent ctDNA+ pts allocated P. Following the completion of active ctDNA surveillance, 3-monthly visits continued to 24 months to be analysed retrospectively. The aim was to recruit 150 pts to ctDNA surveillance, assuming 30% would be ctDNA+ within 12 months, allowing ctDNA+ rate to be estimated with a 2-sided 95%CI of +/- 7.3%. Co-primary endpoints are i) rates of ctDNA detection by 12 and 24 months from start of ctDNA surveillance; ii) rates of sustained ctDNA clearance on P defined as absence of detectable ctDNA, or disease recurrence 6 months after starting P.. Results 208 pts were registered between 30/01/18 and 06/12/19, 185 had tumour sequenced, 171 (92.4%) had trackable mutations, and 161 entered ctDNA surveillance. The rate of ctDNA detection by 12 months after start of surveillance was 27.3% (44/161, 95% CI 20.6-34.9). ctDNA+ rates from baseline, 3, 6, 9 and 12 month ctDNA samples were 23/161 (14.3%), 6/115 (5.2%), 6/99 (5.1%), 7/84 (8.3%), and 2/84 (2.4%) respectively. An additional 2 pts were ctDNA+ on COVID extended active surveillance at 15 (1/51, 2%) or 18 months (1/11, 9%). 7 pts relapsed without prior ctDNA detection. 45 pts entered the therapeutic component of the trial (initially 31 to P and 14 to Obs). 1 Obs pt was re-allocated to P. Of pts allocated to P, 72% (23/32) had metastatic disease at time of ctDNA detection on staging scans (75% (12/16) who were ctDNA+ at baseline and 69% (11/16) at other timepoints). 4 pts declined to start P, largely due to COVID concerns. Of the 5 pts who commenced P, at the time of analysis none achieved sustained ctDNA clearance and 4 had recurred. In pts allocated to Obs, median time to recurrence was 4.1 months (95% CI: 3.2-not-defined).. Conclusion The c-TRAK TN trial is to our knowledge the first study to assess the proof-of-principle of whether ctDNA assays have clinical utility in guiding further therapy in TNBC. Relatively few pts commenced P treatment precluding assessment of potential activity. At enrollment, patients had a relatively high of rate of undiagnosed metastatic disease when imaged. Our findings have implications for future trial design, emphasizing the importance of early start of ctDNA testing, and more sensitive and/or more frequent ctDNA testing regimes. Citation Format: Nicholas Turner, Claire Swift, Ben Jenkins, Lucy Kilburn, Maria Coakley, Matthew Beaney, Lisa Fox, Katie Goddard, Isaac Garcia-Murillas, Peter Hall, Catherine Harper-Wynne, Tamas Hickish, Sarah Kernaghan, Iain Macpherson, Alicia Okines, Carlo Palmieri, Sophie Perry, Katrina Randle, Claire Snowdon, Hilary Stobart, Andrew Wardley, Duncan Wheatley, Simon Waters, Matthew Winter, Judith Bliss. Primary results of the cTRAK TN trial: A clinical trial utilising ctDNA mutation tracking to detect minimal residual disease and trigger intervention in patients with moderate and high risk early stage triple negative breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS3-06.

Abstract P2-14-07: Marrow-infiltrating lymphocytes as adoptive immunotherapy for breast cancer

Abstract Background: The bone marrow harbors tumor-antigen specific T cells in patients with breast cancer (1). Marrow-infiltrating lymphocytes (MILs®) are the product of activating and expanding bone-marrow T cells (2). In multiple myeloma, transfer of MILs as adoptive cell therapy has demonstrated anti-tumor activity (3). The use of adoptive transfer of autologous tumor-infiltrating lymphocytes (TILs) has been used successfully for hormone-receptor positive (HR+) metastatic breast cancer (4). Expansion of MILs was previously shown to be feasible in breast cancer, non-small cell lung cancer (NSCLC), prostate, head and neck, glioblastoma and multiple myeloma (5). Using an expanded cohort, we demonstrate that tumor-specific MILs can be expanded from bone marrow in patients with breast cancer. Methods: Bone marrow aspiration and blood samples were collected from 8 patients with metastatic and high-risk early-stage breast cancer, including 3 patients with HR+/HER2-, 2 patients with HER2+, and 3 patients with triple negative subtypes, at Providence Cancer Institute (Portland, OR). MILs and peripheral blood lymphocytes were activated and expanded from patient samples during a 10-day proprietary process. T cell lineage-specific markers CD3, CD4 and CD8 were characterized by flow cytometry pre- and post- expansion. Tumor-specific T cells were quantitated in expanded MILs and peripheral blood lymphocytes using a previously described cytokine-secretion assay (3). Briefly, they were defined as the IFNy-producing population by flow cytometry. Autologous antigen-presenting cells (APCs) were pulsed with lysates from allogeneic cancer cell lines and co-cultured with activated MILs or peripheral blood lymphocytes. APCs pulsed with irrelevant mis-matched cancer cell line lysates or media alone were used as negative controls. Results: In all harvested samples, MILs expansion successfully resulted in a selective increase in CD3+ T cells. Cytokine-producing CD4+ and CD8+ T cells were detected in all expanded MILs samples, but not in any of the matched activated and expanded peripheral blood lymphocytes. MILs were successfully expanded in HR+/HER2-, HER2+, and triple negative subtypes without apparent differences in activity as measured by cytokine production. Conclusion: MILs isolated from this expanded cohort of metastatic and high-risk early stage breast cancer patients demonstrated cytokine production in response to pulsed cancer cell line lysates, consistent with our experience with other solid (5) and hematological (3) malignancies. A phase II trial to evaluate MILs in combination with a checkpoint inhibitor is underway in patients with anti-PD1/PDL1-refractory NSCLC (NCT04069936). These preclinical data demonstrate that expanding MILs is feasible and could be evaluated therapeutically in breast cancer.

Patterns of Practice for Adjuvant Treatment of FIGO 1B Grade 3 Endometrial Adenocarcinoma Following Publication of ASTRO 2014 Guidelines for Postoperative Treatment in Women With Early Stage High Risk Endometrial Cancer

In 2014, the American Society for Radiation Oncology (ASTRO) published evidence-based guidelines for the role of postoperative radiation therapy in endometrial cancer. These guidelines were also endorsed by the Society of Gynecologic Oncology (SGO). They strongly recommended that women with grade 3 endometrioid endometrial cancer with deep myometrial invasion) receive pelvic radiation (EBRT) and not vaginal cuff brachytherapy (VCBT) given their increased risk of pelvic recurrence based on high quality evidence. We analyzed patterns of practice before and after this consensus guideline was published.We queried the National Cancer Database to identify all women with either FIGO 1C grade 3 disease from 2004-2009 and FIGO 1B grade 3 disease from 2009-2017 with endometrioid histology who were treated surgically. Patients were then stratified to treatment between 2004-2014 (prior to ASTRO guideline updates) and 2015-2017. Patients were excluded from final analysis if they were metastatic at diagnosis, received palliative-intent radiation, treatment parameters were unknown, or age < 18. Multivariable logistic regression was performed to evaluate for factors associated with receipt of VCBT using clinical and sociodemographic covariates.We identified 6,792 patients with grade 3 endometrioid endometrial carcinoma meeting current FIGO 1B disease classification, diagnosed between 2004 and 2017. Adjuvant radiation was not delivered to 38% of patients identified in the study period, and 26% received both EBRT and VCBT. From 2004-2014, of the patients that received single modality adjuvant radiation, 1168 patients received VCBT only (56%) and 908 received EBRT only (44%). The corresponding numbers for 2015 to 2017 for VCBT and EBRT were 347 (62%) and 217 (38%), respectively. The increase in VCBT utilization in 2015-2017 was statistically significant (P = 0.025). Patients who received VCBT were more likely to receive chemotherapy, be treated at a community cancer center or academic cancer center, or live within 50 miles of the treatment center (all P < 0.01). Racial and sociodemographic factors were not associated with likelihood of receipt of VCBT.Based on ASTRO 2014 guidelines, EBRT is strongly recommended in patients with FIGO 1B/ grade 3 endometrioid endometrial carcinoma. However, the rate of EBRT paradoxically declined in the period after the publication of the guideline. This may be in part due to conflicting data from ongoing trials during that time such as GOG 249 and PORTEC 3. Further investigation is warranted to investigate reasons for these variations in practice.C. Weil: None. F. Lew: None. D.K. Gaffney: Research Grant; NCI. Consultant; NCI. run meetings; NCI.G. Suneja: Research Grant; National Institutes of Health. Honoraria; National Comprehensive Cancer Network. Travel Expenses; National Comprehensive Cancer Network, Radiation Oncology Institute, American Board of Radiology; Radiation Oncology Institute, National Comprehensive Cancer Network, ASTRO.V.M. Williams: Involved in planning the mission and activities for the subcommittee; ARRO Equity and Inclusion Subcommittee.

800P Tailoring adjuvant treatments in high-risk early stage endometrial cancer: Clinical outcomes of sequential chemoradiation in a real-word scenario

Chemotherapy plus external beam radiotherapy (EBRT) is the current standard adjuvant therapy for patients (pts) with high-risk stage I-III endometrial cancer (EC). Despite this, the best combination schedule for chemoradiation (CR) has not been defined yet. We aimed at describing the clinical outcomes of pts with EC receiving platinum-based chemotherapy administered 2-3 cycles before and after radiotherapy as adjuvant treatment (‘sandwich’ chemoradiation, SCR).

A clinical calculator to personalize chemotherapy in early-stage high risk epithelial ovarian cancer

<h3>Objectives:</h3> To determine the utility of a clinical calculator to predict the benefits of chemotherapy and outcomes in women with early stage high risk ovarian cancer. <h3>Methods:</h3> Data from 2006-2015 was abstracted from the National Cancer Database. All patients had stage I, grade 3; stage IC, stage II, or clear cell carcinoma. Using a Cox regression model, based on demographic, surgico-pathologic, and laboratory characteristics, a clinical score was developed. Propensity score matching was used to reduce bias between patients who did and did not receive chemotherapy. The clinical calculator was validated by both bootstrapping and in an independent validation set. <h3>Results:</h3> Of 8,289 patients with early stage high risk ovarian cancer, 6,990 (84%) did and 1,299 (16%) did not receive chemotherapy. Patients who underwent chemotherapy had a 5-year overall survival (OS) of 85% vs 80% in those without treatment (p<0.001). On univariate analysis, significant prognostic factors included older age (HR 1.71), larger tumor size (HR 1.13), malignant ascites (HR 1.32), decreased number of lymph nodes examined (HR 1.38), higher stage (HR 1.70), carcinosarcoma (HR 3.35), high grade histology (HR 2.23), lymphovascular invasion (HR 1.44), and elevated CA-125 (HR 1.17). To better define those who may have an increased benefit from chemotherapy, we designed a clinical calculator capable of dividing patients into low (n=2,518), moderate (n=3,361), and high-risk (n=2,410) groups with associated 5-year overall survival of 92%, 86% and 73%. Using the calculator, chemotherapy was associated with an improved 5-year overall survival in the high (58% to 75%, p<0.001) and moderate risk groups (82% to 86%, p=0.001), but did not benefit the low risk patients (92% to 92%, p=0.13). There was an interaction between increasing score and improved patient outcomes with the administration of chemotherapy (p<0.001). <h3>Conclusions:</h3> Our results suggest a clinical calculator can help direct chemotherapy decision making for women with high risk early stage ovarian cancer.

A Phase 2 Trial of Early Intervention with Ibrutinib in Patients with Asymptomatic, High-Risk CLL

▪Introduction:The current IWCLL guidelines recommend initiation of therapy for progressive, symptomatic disease since studies have yet to demonstrate improved survival with early treatment with chemotherapy. However, available therapeutic options have recently increased significantly, including the development of Bruton's tyrosine kinase inhibitors such as ibrutinib (IB). IB is now approved for both previously untreated and relapsed patients requiring therapy. While IB achieves complete remissions in the minority of relapsed/refractory cases, the drug effects sustained responses, including >20% complete responses in frontline patients, hence providing a rationale for its use earlier in the disease course. Because CLL is associated with profound cellular, humoral and innate immune suppression that worsens with disease progression even in the absence of treatment, patients with CLL respond poorly to routine vaccinations. IB has been shown to reverse disease mediated immune dysfunction partly through Th1 skewing. We sought two test two hypotheses in this study: 1) the safety and efficacy of a defined period of therapy (2 years) of ibrutinib in early stage high risk disease and 2) ability of ibrutinib to improve the efficacy of routine vaccines administered to patients undergoing IB therapy.Methods:This is a single-stage phase II study of IB in previously untreated asymptomatic, genetically high-risk patients with CLL, who did not meet IWCLL treatment criteria. High risk genomics were defined as del(11)(q22.3), del(17)(p13.1), unmutated IGHV, and/or complex karyotype (≥3 cytogenetic abnormalities). Patients were randomized to receive IB 420mg PO daily in 4-week cycles either with the pneumococcal, influenza and TdaP vaccines (Arm A, concurrent) or following vaccination (Arm B, sequential)(see Fig 1). The primary objective of the study is to determine the safety and 2-year progression-free survival of asymptomatic, high-risk CLL patients treated with IB. Secondary objectives include determination of safety and immune responses to vaccines in relation to IB administration along with response characteristics, resistance development and quality-of-life outcomes.Results:Forty-four patients (66% male) have been enrolled on the trial. All patients are high-risk; 91% with unmutated IGHV, 86% with del17p, 66% with del11q, and 76% with complex karyotype. Two patients who progressed on arm B prior to starting therapy with IB are not included in the primary endpoint analysis, and one discontinued because of lung cancer diagnosis 8 months after starting IB. Patients on arms A and B have completed a median of 17 and 15.5 cycles of treatment respectively. Vaccinations in patients with CLL were generally safe and well-tolerated with only 3 patients in Arm B experiencing 5 grade 1 AEs (injection site reactions). There have been no grade 4 toxicities related to IB, and 2 patients have experienced 4 occurrences of grade 3 atrial fibrillation related to IB. Two additional patients experienced 1 episode of grade 3 fever and grade 3 chest pain respectively, which were deemed to be unrelated to IB. No hematologic grade 3 or 4 adverse events were observed. All 41 remaining patients continue IB without evidence of progressive disease. Early treatment with IB was associated with reduction in cancer related stress (p<0.01), anxiety (p=0.004) and improvement in sleep (p=0.02). Patients in Arm A reported a higher decline in anxiety levels as compared to patients in the sequential treatment arm (p=0.04).Conclusion:Treatment of early stage, high risk CLL patients with ibrutinib demonstrates no unexpected safety signals and all patients remain progression free (at median 16 months of follow-up) providing support that this treatment approach is feasible. Earlier IB treatment also results in a decline in stress and anxiety and improvements in sleep compared to patients awaiting treatment. The study is ongoing and updated clinical and vaccine response data will be reported. [Display omitted] DisclosuresJones:Sunesis: Other: Institutional research funding; Abbvie, Pharmacyclics, Genentech, Gilead, Janssen, Merck, and Acerta: Other: Institutional research funding; Genentech, Abbvie, Pharmacyclics, Gilead, Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Byrd:Janssen: Research Funding; Genentech: Research Funding; The Ohio State University: Patents & Royalties: OSU-2S; Acerta Pharma: Research Funding; Pharmacyclics: Research Funding.