High Rates Of Distant Recurrence Research Articles

Abstract 6416: Early stage endometrioid endometrial cancer recurrence risk stratification using a machine learning RNA-seq gene expression signature

Abstract Endometrioid endometrial cancer (EEC) adjuvant therapy decisions rely on risk stratification using histology, grade, stage, and lymphovascular space invasion (LVSI). Recently, molecular classification systems originating from TCGA, evaluated in GOG-210 and PORTEC-3 defined four prognostic subtypes based on POLE, MSI-H/MMR-D, and p53 alterations. Although valuable, this molecular approach still has significant limitations such as applicability to the majority of EEC patients categorized as no-specific molecular profile (NSMP) and the potential need to resolve pathogenic and prognostic heterogeneity within MMR-D, and TP53 subtypes. These unmet needs were key motivators for Tempus to develop a molecular classifier predicting distant recurrence risk in early-stage EEC with a focus on high intermediate-risk (HIR) patients. The RNA-seq-based gene expression profiler (GEP) was trained using a machine-learning pipeline with TCGA data which resulted in a 24 gene signature that classifies EEC patients as molecular risk (MR) high or low (MR-high, MR-low). The GEP MR test was then evaluated on a de-identified cohort of EEC patients (N=1037) from Tempus to test associations with known pathologic or molecular prognostic features. The GEP-MR risk predictor showed significant enrichment of MR high-risk in G3 versus G1/2 histology (p-value < 5e-8). A high correlation was found between the MR score and copy number alteration score (t-test p-value < 1e-5). Next, a clinical evaluation was performed in an early-stage EEC case-control cohort of patients with documented recurrence or no recurrence event at four years (N=109), from Stanford. In the entire cohort, the MR-high group had a significantly higher rate of distant recurrence in comparison to the MR-low group (HR=4.8, N=109). Next, we performed a subgroup analysis in the clinically important HIR patients. In this subgroup, the MR-high group had a significantly higher rate of distant recurrence in comparison to the MR-low group (HR=8.0, N=56). Lastly, given the significance of genomic biomarkers in the evolution of EEC FIGO staging, we stratified outcomes by the established TCGA subtypes as a reference standard and performed a subgroup analysis in patients classified as having no specific molecular profile (NSMP). Among patients who were NSMP, the MR-high group showed a significantly higher rate of distant recurrence in comparison to the MR-low group (HR=7.92, N=67). These evaluation studies demonstrate the performance of the GEP MR test in early-stage EEC distant recurrence risk stratification, specifically HIR patients, necessitating further studies to validate the test for clinical use in informing adjuvant clinical management. Citation Format: Rafi Pelossof, Talal Ahmed, Seung Won Hyun, Chithra Sangali, Ben Terdich, Calvin Chao, Michael Toboni, Casey Cosgrove, Elizabeth Kidd, Brook Howitt, Timothy Taxter. Early stage endometrioid endometrial cancer recurrence risk stratification using a machine learning RNA-seq gene expression signature [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6416.

Primary leiomyosarcoma of the inferior vena cava in a pediatric case: a case report and literature review

BackgroundLeiomyosarcoma is classified as a soft tissue sarcoma. In adults, leiomyosarcoma is the most common malignancy affecting the vascular system; however, vascular leiomyosarcoma in children is extremely rare as most pediatric soft tissue tumors are rhabdomyosarcomas. The survival rate is very low, and incomplete resection is a poor prognostic factor. There is also a high rate of distant recurrence, with the lungs and liver being the most common sites of metastasis. There is no established effective chemotherapy, and complete surgical resection is the only potentially curative treatment for leiomyosarcoma.Case presentationA 15-year-old female patient with no significant medical history presented with severe upper abdominal pain and was admitted. Abdominal contrast-enhanced computed tomography and magnetic resonance imaging showed a large retroperitoneal tumor protruding into the lumen of the inferior vena cava behind the liver and multiple small nodules, and metastasis to the liver was suspected. The tumor was 6 × 4 × 5 cm in diameter, located just behind the hepatic hilar structures, and was suspected to infiltrate into the right portal vein. The tumor was diagnosed as a leiomyosarcoma through an open tumor biopsy. As the multiple liver metastases were located only in the right lobe of the liver on imaging, we performed tumor resection with right hepatectomy and replacement of the inferior vena cava (IVC). The postoperative course was uneventful; however, on postoperative day 51, distant metastatic recurrences were found in the remaining liver and right lung. The patient was immediately started on chemotherapy and trabectedin proved to be the most effective drug in the treatment regimen; however, severe side effects, such as hepatotoxicity, prevented timely administration, and the patient passed away 19 months after surgery.ConclusionsIVC resection and reconstruction combined with right hepatectomy were able to be safely performed even in a pediatric case. To improve the prognosis of leiomyosarcoma with multiple metastases, an effective treatment strategy combining surgical treatment and chemotherapy, including molecularly targeted drugs, should be established as early as possible.

Breast Cancer Presenting with Intravascular Tumor Emboli in Axillary Soft Tissue: Recurrence Risk and Radiotherapy Outcomes

<h3>Purpose/Objective(s)</h3> Intravascular tumor emboli in axillary soft tissue (ITE) is a rare pathologic finding in breast cancer and is associated with higher axillary nodal disease burden. The independent prognostic and predictive value of this biomarker is unknown, as is the role of radiotherapy for ITE. <h3>Materials/Methods</h3> We analyzed breast cancer patients treated at our institution from 1992-2020, excluding those over 90 years of age at diagnosis, primary tumors >5cm in size, receipt of neoadjuvant chemotherapy, or those with synchronous bilateral breast cancers. A 1:3 propensity score match was performed between patients with ITE and those without. Matching was based on age, pathologic T stage, number of positive nodes removed, receipt of radiotherapy or chemotherapy, and biologic subtype. Disease free survival (DFS) was evaluated using a Cox regression analysis. Locoregional recurrence (LRR) and distant recurrence were evaluated using competing risks methods. These endpoints were compared between patients with versus without ITE. Among those with ITE, we evaluated whether radiotherapy (RT) improved outcomes using the same methods with a six-month landmark. <h3>Results</h3> We identified 127 patients with ITE, of whom, 103 (81%) were propensity score matched to 309 without ITE. Median follow up from surgery was 6.9 years (IQR 2.5, 10). 5-year DFS for those with ITE was 68% (95% CI 57%-82%) versus 78% (95% CI 73%-84%) for those without ITE (HR 1.37, 95% CI 0.82-2.30, p = 0.2). ITE was associated with increased likelihood of distant recurrence (p=0.02; 5-year cumulative incidence 26%, 95% CI 16%-38% and 14%, 95% CI 10%, 19%, respectively), but was not associated with LRR (p=0.97; 5-year cumulative incidence 5.4%, 95% CI 1.3%-14% and 8.7%, 95% CI 5.6%-12%, respectively). Among those with ITE, 5-year DFS was 74% (95% CI 63%-87%) for those receiving RT versus 32% (95% CI 10%-98%) among those not receiving RT (HR 0.33, 95% CI 0.12-0.91, p=0.03). <h3>Conclusion</h3> Patients with intravascular tumor emboli in axillary soft tissue exhibited higher rates of distant recurrence compared to a propensity score matched control group. Among patients with ITE, those who received RT demonstrated improved DFS.

KRAS mutation allele frequency threshold alters prognosis in right-sided resected pancreatic cancer.

Next-generation sequencing (NGS) provides information on genetic mutations and mutant allele frequency in tumor specimens. We investigated the prognostic significance of KRAS mutant allele frequency in patients with right-sided pancreatic ductal adenocarcinoma (PDAC) treated with surgical resection. A retrospective study reviewed patients who underwent surgical resection for PDAC and analyzed tumors with an in-house mutational panel. Microdissected samples were studied using an NGS-based assay to detect over 200 hotspot mutations in 42 genes (Pan42) commonly involved in PDAC. A total of 144 PDAC right-sided surgical patients with a Pan42 panel were evaluated between 2015 and 2020; 121 patients (84%) harbored a KRAS mutation. Detected mutant allele frequencies were categorized as less than 20% (low mKRAS, n = 92) or greater than or equal to 20% (high mKRAS, n = 29). High mKRAS (KRAS ≥ 20%) patients were noted to have shorter disease-free survival after surgery (11.5 ± 2.1 vs. 19.5 ± 3.5 months, p = 0.03), more advanced tumor stage (p = 0.02), larger tumors (3.6 vs. 2.7 cm, p = 0.001), greater tumor cellularity (26% vs. 18%, p = 0.001), and higher rate of distant recurrence (p = 0.03) than low mKRAS patients. This study demonstrates the importance of KRAS mutant allele frequency on pathological characteristics and prognosis in right-sided PDAC treated with surgery.

Abstract 35: Racial disparity in localized breast cancer: Pooled analysis of NSABP trials

Abstract Background: The purpose of this study was to evaluate whether there are differences in distant recurrence rates between Black and White women with localized breast cancer who participated in NCI-sponsored clinical trials, and thus had access to state of the art oncologic care and lacked major comorbidities. Methods: We analyzed pooled data from 10 NSABP trials including 10,364 patients with localized breast cancer treated with adjuvant chemotherapy (AC, n=8147) or neoadjuvant chemotherapy (NAC, n=2217), limited to those with self-reported race that was either Black (n=1006, 10.3%) or White (n=9358, 89.7%). AC/NAC included doxorubicin and cyclophosphamide, with or without a taxane. The association between race (Black vs. White) and distant relapse-free survival (DRFS) was analyzed in the overall population and stratified by AC or NAC use. Log rank tests were used to test for differences in DRFS. Multivariate Cox regression was performed to estimate risk of distant recurrence adjusted for other prognostic covariates including age (continuous), tumor size (&amp;gt; 2 cm vs. &amp;lt; 2 cm), ER expression (positive vs. negative), and nodal status (pathologically positive for AC cohort or clinically positive for NAC cohort vs. negative). Results: In the AC cohort, 7,419 (91%) patients were White and 728 (9%) Black. In the NAC cohort, 1,939 (88%) were White and 278 (12%) Black. Black race was associated with an inferior DRFS in the combined AC/NAC cohort (Logrank p&amp;lt;.0001), and in both the AC and NAC cohorts (Logrank p=0.0008 and p=0.01, respectively). After adjustment for other covariates in multivariate analysis, Black race remained significantly associated with an inferior DRFS in the combined AC/NAC cohort (HR 1.17, [95% CI 1.05-1.31], p=0.004), with similar trends noted in the AC (HR 1.17 [95% CI 1.02-1.33], p=0.03) and NAC cohort (HR 1.21 [95% CI 0.98-1.45], p=0.08). When the AC cohort was analyzed by ER status, Black race was associated with worse DRFS in ER-positive disease (HR 1.32 [95% CI 1.06-1.63], p=0.02), but not ER-negative disease (HR 1.06, [95% CI 0.87-1.30], p=0.57), although there was no statistically significant interaction with ER status (p=0.15). In the NAC cohort, Black women had a higher pathologic complete response (pCR) rate (22% vs 17%, Chi-squared test p=0.03). Black race was associated with a significantly worse DRFS in patients who did not achieve pCR (HR 1.34 [95% CI 1.06-1.63], p=0.01), but not in those who had a pCR (HR 0.89 [95% CI 0.49, 1.61], p=0.71). Conclusion: We observed that Black women with localized breast cancer had higher distant recurrence rates than White women. This and other reports suggest that factors other than social determinants of health may be contributing to racial disparities in breast cancer outcome/progression, most notably in ER-positive disease and patients with residual disease after NAC. Future research is needed to help delineate the biological differences that contribute to these observations. Citation Format: Gina Kim, Jessica M. Pastoriza, Jiyue Qin, Juan Lin, George S. Karagiannis, John S. Condeelis, Greg Yothers, Thomas B. Julian, Stewart J. Anderson, David Entenberg, Thomas E. Rohan, Joseph A. Sparano, Xiaonan Xue, Maja H. Oktay. Racial disparity in localized breast cancer: Pooled analysis of NSABP trials [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 35.

Association of pathological complete response rates and TILs in triple-negative breast cancer patients.

e12596 Background: Triple negative breast cancers (TNBC), characterized by the lack of expression of estrogen receptors and progesterone receptors as well as human epidermal growth factor receptor 2, are associated with high distant recurrence rate and death. As a result, the majority of patients with TNBC are treated with perioperative chemotherapy with the goal of eradicating micrometastases and preventing distrant relapse. The preoperative systemic therapy offers the advantages of permitting an assessment of chemo-sensitivity, increased rates of breast conserving surgery and the ability to adapt postoperative therapies depending on the response. Recently, neoadjuvant chemotherapy has been used at an increasing frequency. The response to neoadjuvant chemotherapy, as measured by the residual cancer burden index, for example, is correlated with the long-term prognosis of TNBC and HER2 expressing breast cancers. Previous studies suggest that tumor-infiltrating lymphocytes (TILs) may correlate with pathological complete response (pCR) rates in TNBC patients treated with neoadjuvant chemotherapy. The pathologic evaluation of TILs in TNBC has been recommended by the International TILs working group since 2014. In this study we sought to analyze the association of TILs with pCR in a cohort of TNBC patients treated with neoadjuvant chemotherapy. Methods: An IRB-approved single-institution retrospective analysis was performed on 127 patients diagnosed with TNBC who received neoadjuvant anthracycline and taxane based chemotherapy at the Ohio State University Comprehensive Cancer Center between January 1st, 2012 and November 31st, 2018. We analyzed TILs as a continuous variable as a part of a secondary analysis of this data. Whole tissue sections from archived H&amp;E stained glass slides were scanned using Philips UltraFast Scanner at ×40 magnification with a single-focus layer. TIL scoring was performed according to guideline recommendations from the International TILs Working Group (2014). Results: A total of 127 female patients with TNBC were identified. The median age at diagnosis was 52.0 years (range 32.0, 74.0) and patients were predominately white (103, 81%), post-menopausal (68, 53.5%) and presented with invasive ductal cancer (113, 89%), stage II (88, 69%), and high grade (108, 85%). Of those patients, 56 had TILs measurement available. pCR was associated with statistically higher level of TILs in core biopsies taken prior to chemotherapy had (Wilcoxon rank-sum test, p = 0.04). Conclusions: The long-term prognosis of patients with TNBC is predicted by the response to neoadjuvant chemotherapy. Consistent with other studies, our study revealed that TILs are associated with a higher probability of pCR. Our future goals are to identify which TIL subsets correlate best with pCR and to identify the mechanism for the increased chemotherapy responsiveness of lymphocyte-infiltrated tumors.

Race, Ethnicity, and Clinical Outcomes in Hormone Receptor-Positive, HER2-Negative, Node-Negative Breast Cancer in the Randomized TAILORx Trial.

Black race is associated with worse outcomes in early breast cancer. We evaluated clinicopathologic characteristics, the 21-gene recurrence score (RS), treatment delivered, and clinical outcomes by race and ethnicity among women who participated in the Trial Assigning Individualized Options for Treatment. The association between clinical outcomes and race (White, Black, Asian, other or unknown) and ethnicity (Hispanic vs non-Hispanic) was examined using proportional hazards models. All P values are 2-sided. Of 9719 eligible women with hormone receptor-positive, HER2-negative, node-negative breast cancer, there were 8189 (84.3%) Whites, 693 (7.1%) Blacks, 405 (4.2%) Asians, and 432 (4.4%) with other or unknown race. Regarding ethnicity, 889 (9.1%) were Hispanic. There were no substantial differences in RS or ESR1, PGR, or HER2 RNA expression by race or ethnicity. After adjustment for other covariates, compared with White race, Black race was associated with higher distant recurrence rates (hazard ratio [HR] = 1.60, 95% confidence intervals [CI] = 1.07 to 2.41) and worse overall survival in the RS 11-25 cohort (HR = 1.51, 95% CI = 1.06 to 2.15) and entire population (HR = 1.41, 95% CI = 1.05 to 1.90). Hispanic ethnicity and Asian race were associated with better outcomes. There was no evidence of chemotherapy benefit for any racial or ethnic group in those with a RS of 11-25. Black women had worse clinical outcomes despite similar 21-gene assay RS results and comparable systemic therapy in the Trial Assigning Individualized Options for Treatment. Similar to Whites, Black women did not benefit from adjuvant chemotherapy if the 21-gene RS was 11-25. Further research is required to elucidate the basis for this racial disparity in prognosis.

Molecular Classification and Future Therapeutic Challenges of Triple-negative Breast Cancer.

Triple-negative breast cancer (TNBC) is an extremely diverse group of breast tumors, with aggressive clinical behavior, higher rates of distant recurrence and worse overall survival compared to other types of breast cancers. The genetic, transcriptional histological and clinical heterogeneity of this disease has been an obstacle in the progression of targeted therapeutic approaches, as a ubiquitous TNBC marker has not yet been discerned. In terms of that, current studies focus on the classification of TNBC tumors in subgroups with similar characteristics in order to develop a treatment specialized for each group of patients. To date, a series of gene expression profiles analysis in order to identify the different molecular subtypes have been used. Complementary DNA microarrays, PAM50 assays, DNA and RNA sequencing as well as immunohistochemical analysis are some of the methods utilized to classify TNBC tumors. In 2012, the Cancer Genome Atlas (TCGA) Research Network conducted a major analysis of breast cancers using six different platforms, the genomic DNA copy number arrays, DNA methylation, exome sequencing, messenger RNA arrays, microRNA sequencing and reverse-phase protein arrays, in order to assort the tumors in homogenous subgroups. Since then, an increasing number of breast cancer data sets are being examined in an attempt to distinguish the classification with biological interpretation and clinical implementation. In this review, the progress in molecular subtyping of TNBC is discussed, providing a brief insight in novel TNBC biomarkers and therapeutic strategies.

Total neoadjuvant treatment of locally advanced rectal cancer with high risk factors in Slovenia.

BackgroundIn the light of a high rate of distant recurrence and poor compliance of adjuvant chemotherapy in high risk rectal cancer patients the total neoadjuvant treatment was logical approach to gaining acceptance. We aimed to evaluate toxicity and efficiency of this treatment in patients with rectal cancer and high risk factors for local or distant recurrence.Patients and methodsPatients with rectal cancer stage II and III and with at least one high risk factor: T4, presence of extramural vein invasion (EMVI), positive extramesorectal lymph nodes or mesorectal fascia (MRF) involvement were treated with four cycles of induction CAPOX/FOLFOX, followed by capecitabine-based radiochemotherapy (CRT) and two consolidation cycles of CAPOX/FOLFOX before the operation. Surgery was scheduled 8–10 weeks after completition of CRT.ResultsFrom November 2016 to July 2018 66 patients were evaluable. All patients had stage III disease, 24 (36.4%) had T4 tumors, in 46 (69.7%) EMVI was present and in 47 (71.2%) MRF was involved. After induction chemotherapy, which was completed by 61 (92.4%) of patients, radiologic downstaging of T, N, stage, absence of EMVI or MRF involvement was observed in 42.4%, 62.1%, 36.4%, 69.7% and 68.2%, respectively. All patients completed radiation and 54 (81.8%) patients received both cycles of consolidation chemotherapy. Grade 3 adverse events of neoadjuvant treatment was observed in 4 (6%) patients. Five patients rejected surgery, 3 of them with radiologic complete clinical remissions. One patient did not have definitive surgery of primary tumor due to unexpected cardiac arrest few days after sigmoid colostomy formation. Among 60 operated patients pathological complete response rate was 23.3%, the rate of near complete response was 20% and in 96.7% radical resection was achieved. Pathological T, N and stage downstaging was 65%, 96.7% and 83.4%, respectively. Grade ≥ 3 perioperative complications were anastomotic leakage in 3, pelvic abscess in 1 and paralytic ileus in 2 patients. The rate of pathologic complete response (pCR) in patients irradiated with 3D conformal technique was 12.1% while with IMRT and VMAT it was 37% (p < 0.05). Hypofractionation with larger dose per fraction and simultaneous integrated boost used in the latest two was the only factor associated with pCR.ConclusionsTotal neoadjuvant treatment of high risk rectal cancer is well tolerated and highly effective with excellent tumor and node regression rate and with low toxicity rate. Longer follow up will show if this strategy will improve distant disease control and survival.

298P - Targeting CDCA3 to improve chemotherapy response in triple negative breast cancer patients

BackgroundBreast cancer is the second most diagnosed cancer globally accounting for over 2 million new worldwide cases of the disease in 2017. Chemotherapy (including cyclophosphamide and anthracyclines) is the mainstay for triple-negative breast cancer (TNBC) treatment. Despite high rates of responses to neoadjuvant chemotherapy, TNBC patients experience high rates of distant recurrence and less than 30% of patients with metastatic disease treated with chemotherapy will survive 5 years. These poor cancer patient outcomes highlight the need for novel companion diagnostics and therapies to identify the patients who will derive benefit and improve the response to therapy. Herein, we have identified ‘cell division cycle associated protein 3’ (CDCA3) as a novel protein that may prove useful to enhance chemotherapy response in TNBC. MethodsBioinformatics, Western blot, immunohistochemistry, siRNA depletion of CDCA3, CRISPR-Cas9 knockout, dose response, cell viability. ResultsCDCA3 transcripts are elevated across increasing grades of breast cancer, TNBC versus non-TNBC and in basal-like (BLIA and BLIS) versus luminal-AR and mesenchymal TNBC subtypes (METABRIC datasets). Elevated CDCA3 levels were strongly prognostic for patient outcome in high grade breast cancer and TNBC. Tissue microarray (TMA) immunohistochemistry analysis of over 300 breast cancers indicated heterogeneous CDCA3 staining is strongly prognostic in Ki67+ and TNBC cases of disease. CDCA3 staining correlated with markers of poor prognosis (nuclear grade, mitotic score, nuclear pleomorphism) and was associated with a poor prognosis. In vitro, we identified that, consistent with clinical data, CDCA3 levels were elevated in TNBC versus non-TNBC cell lines. In 10 TNBC cell lines, endogenous CDCA3 expression correlated with sensitivity to both cisplatin and doxorubicin, with CDCA3high levels having higher IC50 values and thereby being associated with a poor prognosis. Consistently, depleting these cells of CDCA3 markedly enhanced sensitivity to both cisplatin and doxorubicin. ConclusionsOur data highlight CDCA3 as a novel prognostic factor in TNBC that modulates sensitivity to chemotherapy. These findings point to the therapeutic potential of targeting CDCA3 in TNBC. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Clinical Outcomes in Early Breast Cancer With a High 21-Gene Recurrence Score of 26 to 100 Assigned to Adjuvant Chemotherapy Plus Endocrine Therapy

A high 21-gene recurrence score (RS) by breast cancer assay is prognostic for distant recurrence of early breast cancer after local therapy and endocrine therapy alone, and for chemotherapy benefit. To describe clinical outcomes for women with a high RS who received adjuvant chemotherapy plus endocrine therapy in the TAILORx trial, a population expected to have a high distant recurrence rate with endocrine therapy alone. In this secondary analysis of data from a multicenter randomized clinical trial, 1389 women with hormone receptor-positive, ERBB2-negative, axillary node-negative breast cancer, and a high RS of 26 to 100 were prospectively assigned to receive adjuvant chemotherapy in addition to endocrine therapy. The analysis was conducted on May 12, 2019. The adjuvant chemotherapy regimen was selected by the treating physician. Freedom from recurrence of breast cancer at a distant site, and freedom from recurrence, second primary cancer, and death (also known as invasive disease-free survival [IDFS]). Among the 9719 eligible women, with a mean age of 56 years (range 23-75 years), 1389 (14%) had a recurrence score of 26 to 100, of whom 598 (42%) had an RS of 26 to 30 and 791 (58%) had an RS of 31 to 100. The most common chemotherapy regimens included docetaxel/cyclophosphamide in 589 (42%), an anthracycline without a taxane in 334 (24%), an anthracycline and taxane in 244 (18%), cyclophosphamide/methotrexate/5-fluorouracil in 52 (4%), other regimens in 81 (6%), and no chemotherapy in 89 (6%). At 5 years, the estimated rate of freedom from recurrence of breast cancer at a distant site was 93.0% (standard error [SE], 0.8%), freedom of recurrence of breast cancer at a distant and/or local regional site 91.0% (SE, 0.8%), IDFS 87.6% (SE, 1.0%), and overall survival 95.9% (SE, 0.6%). The estimated rate of freedom from recurrence of breast cancer at a distant site in women with an RS of 26 to 100 treated largely with taxane and/or anthracycline-containing adjuvant chemotherapy regimens plus endocrine therapy in the prospective TAILORx trial was 93% at 5 years, an outcome better than expected with endocrine therapy alone in this population. ClinicalTrials.gov identifier: NCT00310180.

Prognostic Determinants of Salvage Image-Guided Brachytherapy for Vaginal Recurrence of Endometrial Cancer

In PORTEC-1, the 5-year survival after vaginal relapse from early stage endometrial cancer was 65% for patients in the observation arm. In this study, we evaluated clinical outcomes and toxicity in patients with vaginal relapse of endometrial cancer treated with salvage image-guided brachytherapy (BT). Retrospective review identified 62 patients with early stage endometrial cancer and biopsy-proven vaginal recurrence treated with external beam (EBRT) and image-guided BT with definitive intent between 10/04 and 05/17. All patients had prior hysterectomy without adjuvant radiotherapy (RT) and >3 months follow-up (FU). Rates of vaginal control (VC), recurrence-free survival (RFS) and overall survival (OS) were estimated by Kaplan-Meier method. Univariate analysis was performed by Cox proportional hazards or log-rank test. Late toxicity was graded by CTCAE. Median FU was 31.8 months (r: 3.2 – 160.5). Baseline characteristics are summarized in table 1. The median time to recurrence after hysterectomy was 18.2 months (range [r]: 1.6 – 158). Median tumor size was 2.3 cm (r: 0.3-7.5). Median prescribed dose and HR-CTV D90 in EQD2 were 75.4 Gy and 75.3 Gy, respectively. Twenty patients had disease relapse at a median of 14.2 months after completion of BT (6 with vaginal failure only, 2 vaginal and distant, and 12 distant only). The 3-year rates of VC, RFS, and OS were 86%, 70% and 80%. respectively. Tumor grade at hysterectomy was a strong determinant of outcome, with 3-year RFS rates of 80% for grade 1 tumors, 78% for grade 2, and 13% for grade 3 (p<0.01). Age, stage at diagnosis, nodal involvement and BT modality were not associated with RFS (all p>0.2). Median HR-CTV D90 was 75.7 Gy for patients with vaginal failure and 75.2 Gy for those without (p=0.9). Age, BT modality, tumor grade, tumor size and cumulative prescribed dose were not prognostic for VC (all p>0.5). Late grade 3 toxicity included 2 patients with proctitis and 1 with urinary incontinence; all received interstitial BT. One cylinder patient had grade 3 vaginal stenosis. Salvage RT with image-guided BT results in excellent clinical outcomes for patients with grade 1 or 2 tumors and vaginal relapse. Those with grade 3 tumors or non-endometrioid histologies have high rates of distant recurrence and poor survival. Adjuvant treatment should be considered for all high risk patients given the low rates of salvage.Abstract 2796; Table 1Baseline characteristics for 62 patientsn (%)FIGO 2009 stage at diagnosis • IA• 56 (90%) • IB• 5 (8%) • II• 1 (2%)Histology • Endometrioid• 55 (89%) • Serous• 5 (8%) • Carcinosarcoma• 2 (3%)Grade • 1• 40 (65%) • 2• 13 (21%) • 3• 9 (14%)Median age at recurrence67 years (r: 41-86)Site(s) of recurrence • Vaginal only• 55 (89%) • Vaginal + nodal• 7 (11%)Image-guided BT modality • Intracavitary (cylinder)• 26 (42%) • Interstitial• 36 (58%)Median central EBRT dose• 45Gy (r: 44 – 54)Median BT dose• 25Gy (r: 16 – 35)Median D2cc OAR • Bladder• 65.8 Gy (r: 50.7 – 87.2) • Rectum• 64.7 Gy (r: 52.1 – 86.9) • Sigmoid• 53.7 Gy (r: 44.7 – 75.5)Chemotherapy use11 (18%) Open table in a new tab

A randomized phase II study of pembrolizumab with or without radiation in patients with recurrent or metastatic adenoid cystic carcinoma.

6082 Background: Adenoid cystic carcinoma (ACC) is a salivary gland malignancy characterized by a high rate of distant recurrence. Systemic therapy has generally failed to produce durable benefit. Radiation (RT) is used for localized disease and as directed treatment for metastases. Here, we report the safety and efficacy of pembrolizumab (pembro) administered with or without hypofractionated RT in a phase II randomized study. Methods: Eligible patients (pts) had recurrent or metastatic ACC with evidence of progressive disease (PD) within the last 12 mos and &gt;=1 measurable non-CNS lesion, along with 1-5 additional lesions deemed appropriate for RT to 30 Gy in 5 fractions. Pts were randomized to pembro alone (200 mg IV q3 weeks) or in combination with RT given within 7 days of cycle 1, day 1. The primary endpoint was objective response rate (ORR) outside the RT field by RECIST 1.1. Using a parallel two-stage design, if &gt;=1 response out of 10 was observed in either arm, 10 more pts would be enrolled to that arm. If &gt;=3 responded, the null hypothesis (ORR=5%) would be rejected in favor of a 25% ORR. Predefined secondary endpoints included progression free survival (PFS) and toxicity. Analyses of tumor growth rate (TGR) excluding RT lesions and immune biomarkers were exploratory. Results: Ten pts per arm were randomized into the trial’s first stage with median age 65 (45-79). No objective responses were seen. Stable disease (SD) was observed in 13 pts; 6 had PD as best response, 1 was unevaluable. Median PFS was 7 mos 95% CI (3 - 13 mos), with 9 pts without progression at 6 mos. 3 pts remain on study treatment (range 8-11 mos). In pts with SD, TGR decreased by &gt;25% in 7 of 12 pts and by &gt;75% in 4 pts. There was no difference in likelihood of SD or PFS between arms. Treatment related AEs (TRAEs) occurred in 18 pts but there were no G3-5 TRAEs. Among 8 biopsies analyzed, PD-L1+ tumor/immune cells ranged from 12-52%. Conclusions: Pembro alone or with hypofractionated RT was well tolerated. We observed no objective responses, but 65% of pts with PD prior to study entry achieved SD, the majority with decreased TGR, and 15% had prolonged SD. Additional strategies are needed to further delay progression and effect response. Clinical trial information: NCT03087019.

Abstract P4-08-29: Lymphatic invasion is an independent risk factor in patients with small node-negative luminal breast cancer

Abstract [Background] In patients with node-negative (N0), hormone receptor-positive, human epidermal growth factor receptor (HER2) -negative (luminal) breast cancer, the impact of lymphatic invasion (ly) on the prognosis remains to be clarified. [Methods] Among 3,158 patients with primary breast cancers who underwent surgery in our institute from January 2007 to December 2009, we analyzed 1027 N0 luminal invasive breast cancers without preoperative systemic therapy. The luminal breast cancer was defined as hormone receptor-positive (ER of ≥ 10% or PgR of ≥ 10%) and HER2-negative (immunohistochemistry: 0, 1+ or FISH: ratio &amp;lt; 2.0) cancer in the postoperative pathological specimen. ly was defined as positive when cancer cell nests were detected within the lymph duct in the whole specimen. N0 was confirmed pathologically by the sentinel lymph node biopsy in all the patients. The Fisher's exact test was used for comparison between different categories. The distant recurrence rate (DRR) was analyzed using the Kaplan-Meier method and the log-rank test. For multivariate analysis, Cox's regression analysis was performed. [Results] The median follow-up period was 103.8 months (range: 5.6-128.8). Recurrence with distant metastasis occurred in 26 patients (2.5%). There were 5 (0.7%) deaths related to breast cancer. ly was detected in 240 patients (23.4%). In the ly-positive group, the tumor size was larger (p = 0.007), and the nuclear grade (NG) was higher (p &amp;lt; 0.001) than in the ly-negative group. Postoperative endocrine therapy (p &amp;lt; 0.001) and postoperative chemotherapy (p &amp;lt; 0.001) were more frequently employed for patients with ly-positive tumor. The univariate analysis showed that ly positivity (p &amp;lt; 0.001), large tumor size (p &amp;lt; 0.001), high NG (p &amp;lt; 0.001), PgR negativity (p = 0.002) and the history of adjuvant chemotherapy (p &amp;lt; 0.001) were associated with high DRR. In the multivariate analysis, large tumor size (p = 0.007) and PgR negativity (p = 0.015) remained significant. Although positive ly had a risk ratio of 2.2, it was not an independent risk factor.When restricted to T1 tumor (n = 899), the aforementioned factors still showed prognostic value in the univariate analysis, among which ly positivity (p = 0.004)remained significant together with PgR negativity (p = 0.047)in themultivariate analysis.The 8-year DRR was very favorable (0.8%) in patients with ly-negative T1N0 tumor while it was modest (6.6%) in patients with ly-positive T1N0 tumor (p &amp;lt; 0.001). Only 1.3% of the patients had received adjuvant chemotherapy in the ly-negative group while 27% of the patients had in the ly-positive group. [Conclusion] Lymphatic invasion was associated with higher DRR although it was not independent in the multivariate analysis among patients with N0 luminal breast cancer. When restricted to patients with T1N0 luminal breast cancer, the presence of ly was independently associated with higher risk of distant recurrence. It suggests that the assessment of ly is clinically more relevant when considering treatment options for small luminal breast cancer. Citation Format: Abe T, Ito Y, Fukada I, Shibayama T, Ono M, Kobayashi T, Kobayashi K, Takahashi S, Horii R, Akiyama F, Iwase T, Ueno T, Ohno S. Lymphatic invasion is an independent risk factor in patients with small node-negative luminal breast cancer [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 P4-08-29.

Prognostic influence of korean public medical insurance system on breast cancer patients

Purpose To investigate the prognostic influence of Korean public medical insurance system on breast cancer patients. Methods Data of 1,068 patients with primary invasive breast cancer were analyzed. Korean public medical insurance status was classified into 2 groups: National Health Insurance and Medical Aid. Kaplan-Meier estimator and Cox proportional hazards model were used for survival analysis. Results The Medical Aid group showed worse prognoses compared to the National Health Insurance group both in overall survival (P = 0.001) and recurrence-free survival (P = 0.006). The Medical Aid group showed higher proportion of patients with tumor size > 2 cm (P = 0.022), more advanced stage (P = 0.039), age > 50 years (P = 0.003), and low education level (P = 0.003). The Medical Aid group showed higher proportion of patients who received mastectomy (P < 0.001) and those who received no radiation therapy (P = 0.013). The Medical Aid group showed a higher rate of distant recurrence (P = 0.014) and worse prognosis for the triple negative subtype (P = 0.006). Medical insurance status was a significant independent prognostic factor in both univariate analysis and multivariate analysis. Conclusion The Medical Aid group had worse prognosis compared to the National Health Insurance group. Medical insurance status was a strong independent prognostic factor in breast cancer. Unfavorable clinicopathologic features could explain the worse prognosis for the Medical Aid group. Careful consideration should be given to medical insurance status as one of important prognostic factors for breast cancer patients.

Abstract A08: Epigenetic heterogeneity in triple-negative breast cancer

Abstract Triple-negative breast cancer (TNBC) is defined by the absence of estrogen/progesterone receptor (ER/PgR) expression and HER2 amplification. Patients with TNBC have a higher rate of distant recurrence and a poorer prognosis than women with other breast cancer subtypes, since targeted therapy is not available for them. TNBC is a highly heterogeneous group of tumors and the underlying biology of these tumors should be substantially different. Stratification is essential for selection of appropriate therapy. We have previously identified key regulators that define basal-like (ER-/PgR-/HER2-) and luminal (ER+/PgR+ and/or HER2+) breast cancer cell phenotypes by using combined somatic cell genetic and integrative epigenomic approaches (Su et al., Cell Reports 2015). We found that common core epigenetic programs in luminal tumors are defined by FOXA1 super-enhancers; however, apart from displaying extinguished luminal features, the basal-like phenotype is not defined by a specific epigenetic state and displays a high degree of heterogeneity. In this study, we aimed to identify a key regulator that can classify TNBCs into two groups, so that it could help improve our understanding of biology and explain the epigenetic heterogeneity in TNBC. We first reanalyzed our original multi-omics data of hetero-fusion cells in the previous study and also performed an integrated analysis of genomic, transcriptomic, and epigenomic data obtained from the TCGA project. We finally focused on a transcription factor (TF-X), whose function is currently unknown. TF-X is upregulated in a subset of TNBCs and the expression level of the gene is associated with poor prognosis in TNBC. Knockdown of TF-X decreased cell survival rate and changed cellular morphology of the cells. We are currently doing further functional analysis of TF-X. Our findings seem to imply that TF-X is one of the key regulators that govern cellular property of TNBC. Note: This abstract was not presented at the conference. Citation Format: Reo Maruyama, Liying Yang, Kohei Kumegawa. Epigenetic heterogeneity in triple-negative breast cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr A08.

Prognostic factors and patterns of recurrence in lymphovascular space invasion positive women with stage IIIC endometriod endometrial cancer.

The purpose of this study was to determine the prognostic factors and patterns of failure in lymphovascular space invasion (LVSI)-positive women with stage IIIC endometrioid endometrial cancer (EC). A multicenter, retrospective, department database review was performed to identify LVSI-positive patients with stage IIIC endometrioid EC at five gynecological oncology centers in Turkey. Demographic, clinicopathological and survival data were collected. We identified 172 LVSI-positive women with stage IIIC endometrioid EC during the study period; 75 (43.6%) were classified as Stage IIIC1 and 97 (56.4%) as Stage IIIC2 . The median age at diagnosis was 59 years, and the median duration of follow up was 34.5 months. The total number of recurrences was 46 (26.7%). We observed 14 (8.1%) locoregional recurrences, 12 (7.0%) retroperitoneal failures and 20 (11.6%) distant relapses. For the entire study cohort, 5-year progression-free survival (PFS) was 67.4%, while the 5-year overall survival (OS) rate was 75.1%. Grade 3 histology (hazard ratio [HR] 2.62, 95% confidence interval [CI] 1.34-5.12; P = 0.005), cervical stromal invasion (HR 2.33, 95% CI 1.09-4.99; P = 0.028) and myometrial invasion (MMI) ≥50% (HR 4.0, 95% CI 1.16-13.69; P = 0.028) were found to be independent prognostic factors for decreased OS. Uterine factors such as grade 3 disease, cervical stromal invasion and deep MMI seem to be independently associated with decreased OS in LVSI-positive women with stage IIIC endometrioid EC. The high distant recurrence rate in this subgroup of patients warrants further studies in order to identify the most effective treatment strategy for those patients.

Prognostic influence of Korean public medical insurance system on breast cancer patients.

PurposeTo investigate the prognostic influence of Korean public medical insurance system on breast cancer patients.MethodsData of 1,068 patients with primary invasive breast cancer were analyzed. Korean public medical insurance status was classified into 2 groups: National Health Insurance and Medical Aid. Kaplan-Meier estimator and Cox proportional hazards model were used for survival analysis.ResultsThe Medical Aid group showed worse prognoses compared to the National Health Insurance group both in overall survival (P = 0.001) and recurrence-free survival (P = 0.006). The Medical Aid group showed higher proportion of patients with tumor size > 2 cm (P = 0.022), more advanced stage (P = 0.039), age > 50 years (P = 0.003), and low education level (P = 0.003). The Medical Aid group showed higher proportion of patients who received mastectomy (P < 0.001) and those who received no radiation therapy (P = 0.013). The Medical Aid group showed a higher rate of distant recurrence (P = 0.014) and worse prognosis for the triple negative subtype (P = 0.006). Medical insurance status was a significant independent prognostic factor in both univariate analysis and multivariate analysis.ConclusionThe Medical Aid group had worse prognosis compared to the National Health Insurance group. Medical insurance status was a strong independent prognostic factor in breast cancer. Unfavorable clinicopathologic features could explain the worse prognosis for the Medical Aid group. Careful consideration should be given to medical insurance status as one of important prognostic factors for breast cancer patients.

Treatment of locally advanced parotid malignancies with parotidectomy and temporal bone resection

PurposeIn this study we review our institution's experience and outcomes with temporal bone resection and parotidectomy in the treatment of advanced parotid malignancies. MethodsPatients undergoing lateral temporal bone resection and parotidectomy from 2007–2013 were identified in the EPIC electronic medical record. Primary tumor location, staging, surgical procedure, and patient demographic and outcome data were collected retrospectively. ResultsFifteen patients underwent combined temporal bone resection and parotidectomy for parotid malignancy. Carcinoma ex-pleomorphic and squamous cell carcinoma were the most common pathologies. Two year disease free survival was 40%. Distant metastases were the most common site of disease recurrence. Only nodal disease was predictive of reduced disease free survival, though pre-operative facial paralysis showed a trend towards significance. Margin status and operating for recurrent tumor did not influence outcome in our series. ConclusionLocal and regional tumor controls are attainable with combined skull base approaches to advanced parotid malignancies. Unfortunately these cases have a high rate of distant recurrence despite negative margins and local control.

Abstract B16: Lymphatics in triple-negative breast cancer: Contribution to chemotherapeutic efficacy in vitro and in vivo

Abstract Background: Triple-negative breast cancer (TNBC) accounts for approximately 15% of breast cancers and is associated with a poorer prognosis and higher rate of distant recurrence compared to receptor positive breast cancer. Due to an absence of effective targeted therapies, cytotoxic chemotherapy remains the standard of care for TNBC patients. However, the aggressive nature of these tumors makes preventing progression to metastatic disease a priority in therapeutic strategy. Inhibition of lymphatic activation represents an attractive approach to reduce peritumoral lymphatic vessel recruitment and attenuate cancer cell invasion to lymph nodes and subsequent metastasis to distant sites. However, little is currently known regarding the role of lymphatics in TNBC and how common therapeutic strategies can influence lymphatic reactivity. We hypothesized that inhibiting lymphatic activation in combination with standard of care chemotherapy will enhance therapeutic response in TNBC. Methods: Our lab has developed a novel 3D tissue-engineered tri-culture system that recapitulates the tumor-lymphatic interface within the breast tumor microenvironment. It consists of a porous tissue culture insert on which we seed human lymphatic endothelial cells (LECs) to form a monolayer on the underside. Atop the insert, we place Collagen I gel with human mammary fibroblasts and human breast cancer cells labeled with fluorescent Cell Tracker dye. After gelation, flow is applied via a pressure head and the system equilibrates overnight (16-18h). Drugs are applied via flow and then flushed from the system with basal media. After 48h from first application, gels are removed, dissociated, and analyzed via flow cytometry for death [Live/Dead and apoptosis (Caspase 3/7)], while the inserts are analyzed via microscopy for invaded cancer cells. Animal experiments were performed according to guidelines set forth by the UVA Animal Care and Use Committee. Twenty female Balb/c mice were implanted with 250,000 4T1 cells and treated with either anti-VEGFR3 antibody or IgG control and docetaxel (n=5 per group) or saline control once tumors were palpable. Tumors were dissected and dissociated once they reached 150 mm3, and analyzed via flow cytometry for stromal cell populations. Lungs were analyzed for metastases by cryosectioning and H&amp;E staining. Results: We used our in vitro system to screen the common chemotherapeutics docetaxel, doxorubicin, 5-FU, and carboplatin across three common TNBC cell lines MDAMB231, HCC1806, and HCC38. We found that the presence of LECs significantly increases TNBC cell survival and invasiveness, shifting EC50s for cell death 10-1000 fold (EC50 shift nonlinear regression, p&amp;lt;0.05 for +/- LECs) and doubling to tripling invasion of cancer cells (analysis by two-way ANOVA, p&amp;lt;0.05). This poor response to therapy can be attenuated by treatment with the VEGFR3 inhibitor MAZ51. In vivo, we have seen that adjuvant anti- VEGFR3 therapy can reduce lymphatic endothelial cell populations in the tumor stroma with and without docetaxel chemotherapy when analyzed by flow cytometry (n=4 per group, p&amp;lt;0.05). Additionally, combination-treated mice showed reduced metastasis to the lung. Conclusion: Together, these data could indicate the effectiveness of anti-VEGFR3 therapy as an addition to chemotherapy to reduce metastatic progression of TNBC by limiting tumor-induced and therapy-induced lymphangiogenesis. Studies are ongoing to optimize and understand the ability of this adjuvant therapeutic strategy to increase therapeutic efficacy in TNBC. Citation Format: Alexandra H. Harris, Jennifer M. Munson. Lymphatics in triple-negative breast cancer: Contribution to chemotherapeutic efficacy in vitro and in vivo. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr B16.