BRE12-158: A Postneoadjuvant, Randomized Phase II Trial of Personalized Therapy Versus Treatment of Physician's Choice for Patients With Residual Triple-Negative Breast Cancer

PURPOSE Patients with triple-negative breast cancer (TNBC) with residual disease after neoadjuvant chemotherapy (NAC) have high risk of recurrence with prior data suggesting improved outcomes with capecitabine. Targeted agents have demonstrated activity across multiple cancer types. BRE12-158 was a phase II, multicenter trial that randomly allocated patients with TNBC with residual disease after NAC to genomically directed therapy versus treatment of physician choice (TPC). PATIENTS AND METHODS From March 2014 to December 2018, 193 patients were enrolled. Residual tumors were sequenced using a next-generation sequencing test. A molecular tumor board adjudicated all results. Patients were randomly allocated to four cycles of genomically directed therapy (arm A) versus TPC (arm B). Patients without a target were assigned to arm B. Primary end point was 2-year disease-free survival (DFS) among randomly assigned patients. Secondary/exploratory end points included distant disease-free survival, overall survival, toxicity assessment, time-based evolution of therapy, and drug-specific outcomes. RESULTS One hundred ninety-three patients were randomly allocated or were assigned to arm B. The estimated 2-year DFS for the randomized population only was 56.6% (95% CI, 0.45 to 0.70) for arm A versus 62.4% (95% CI, 0.52 to 0.75) for arm B. No difference was seen in DFS, distant disease-free survival, or overall survival for the entire or randomized populations. There was increased uptake of capecitabine for TPC over time. Patients randomly allocated later had less distant recurrences. Circulating tumor DNA status remained a significant predictor of outcome with some patients demonstrating clearance with postneoadjuvant therapy. CONCLUSION Genomically directed therapy was not superior to TPC for patients with residual TNBC after NAC. Capecitabine should remain the standard of care; however, the activity of other agents in this setting provides rationale for testing optimal combinations to improve outcomes. Circulating tumor DNA should be considered a standard covariate for trials in this setting.

Dramatic Reduction of Distant Pancreatic Metastases Using Local Light Activation of Verteporfin with Nab-Paclitaxel

Despite substantial drug development efforts, pancreatic adenocarcinoma (PDAC) remains a difficult disease to treat, and surgical resection is the only potentially curative option. Unfortunately, 80% of patients are ineligible for surgery due to the presence of invasive disease and/or distant metastases at the time of diagnosis. Treatment strategies geared towards reclassifying these patients as surgical candidates by reducing metastatic burden represents the most promising approach to improve long-term survival. We describe a photodynamic therapy (PDT) based approach that, in combination with the first-line chemotherapeutic nab-paclitaxel, effectively addresses distant metastases in three separate orthotopic PDAC models in immunodeficient mice. In addition to effectively controlling local tumor growth, PDT plus nab-paclitaxel primes the tumor to elicit systemic effects and reduce or abrogate metastases. This combination dramatically inhibits (up to 100%) the eventual development of metastases in models of early stage PDAC, and completely eliminates metastasis in 55% of animals with already established distant disease in late-stage models. Our findings suggest that this light activation process initiates local biological and/or physiological changes within the tumor microenvironment that can be leveraged to treat both localized and distant disease, and potentially reclassify patients with previously inoperable disease as surgical candidates.

A phase II study of talimogene laherparepvec for patients with inoperable locoregional recurrence of breast cancer

Talimogene laherparepvec (T-VEC) is an immunotherapy that generates local tumor lysis and systemic antitumor immune response. We studied the efficacy of intratumoral administration of T-VEC as monotherapy for inoperable locoregional recurrence of breast cancer. T-VEC was injected intratumorally at 106 PFU/mL on day 1 (cycle 1), 108 PFU/mL on day 22 (cycle 2), and 108 PFU/mL every 2 weeks thereafter (cycles ≥ 3). Nine patients were enrolled, 6 with only locoregional disease and 3 with both locoregional and distant disease. No patient completed the planned 10 cycles or achieved complete or partial response. The median number of cycles administered was 4 (range, 3–8). Seven patients withdrew prematurely because of uncontrolled disease progression, 1 withdrew after cycle 3 because of fatigue, and 1 withdrew after cycle 4 for reasons unrelated to study treatment. Median progression-free survival and overall survival were 77 days (95% CI, 63–NA) and 361 days (95% CI, 240–NA). Two patients received 8 cycles with clinically stable disease as the best response. The most common grade 2 or higher adverse event was injection site reaction (n = 7, 78%). Future studies could examine whether combining intratumoral T-VEC with concurrent systemic therapy produces better outcomes.

Metastatic Medullary Thyroid Cancer: The Role of 68Gallium-DOTA-Somatostatin Analogue PET/CT and Peptide Receptor Radionuclide Therapy

Context Metastatic medullary thyroid cancer (MTC) is a rare malignancy with minimal treatment options. Many, but not all, MTCs express somatostatin receptors. Objective Our aim was to explore the role of 68Ga-DOTA-somatostatin analogue (SSA) PET/CT in patients with metastatic MTC, and to determine their eligibility for peptide receptor radionuclide therapy (PRRT). Methods We retrospectively identified patients with metastatic MTC who had 68Ga-DOTA-SSA PET/CT at five centers. We collected characteristics on contrast-enhanced CT, 68Ga-DOTA-SSA and 18F-FDG PET/CT. The efficacy of PRRT was explored in a subgroup of patients. Kaplan-Meier analysis was used to estimate time to treatment failure (TTF) and overall survival (OS). Results Seventy-one patients were included (10 local recurrence, 61 distant disease). Of the patients with distant disease, 16 (26%) had ≥50% of disease sites with tracer avidity greater than background liver, including 10 (10/61, 16%) with >90%. In 19 patients with contemporaneous contrast-enhanced CT, no disease regions were independently identified on 68Ga-DOTA-SSA PET/CT. Thirty-five patients had an 18F-FDG PET/CT, with 18F-FDG positive/ 68Ga-DOTA-SSA negative metastases identified in 15 (43%). Twenty-one patients had PRRT with a median TTF of 14 months (95%CI 8-25) and a median OS of 63 months (95%CI 21–not reached). Of the entire cohort, the median OS was 323 months (95%CI 152-not reached). Predictors of poorer overall survival included a short calcitonin doubling-time (≤24 months), strong 18F-FDG avidity and age ≥60 years. Conclusions The prevalence of high tumour avidity on 68Ga-DOTA-SSA PET/CT is low in the setting of metastatic MTC; nevertheless, PRRT may still be a viable treatment option in select patients.

Repeated porphyrin lipoprotein-based photodynamic therapy controls distant disease in mouse mesothelioma via the abscopal effect

While photodynamic therapy (PDT) can induce acute inflammation in the irradiated tumor site, a sustained systemic, adaptive immune response is desirable, as it may control the growth of nonirradiated distant disease. Previously, we developed porphyrin lipoprotein (PLP), a ∼20 nm nanoparticle photosensitizer, and observed that it not only efficiently eradicated irradiated primary VX2 buccal carcinomas in rabbits, but also induced regression of nonirradiated metastases in a draining lymph node. We hypothesized that PLP-mediated PDT can induce an abscopal effect and we sought to investigate the immune mechanism underlying such a response in a highly aggressive, dual subcutaneous AE17-OVA+ mesothelioma model in C57BL/6 mice. Four cycles of PLP-mediated PDT was sufficient to delay the growth of a distal, nonirradiated tumor four-fold relative to controls. Serum cytokine analysis revealed high interleukin-6 levels, showing a 30-fold increase relative to phosphate-buffered solution (PBS) treated mice. Flow cytometry revealed an increase in CD4+ T cells and effector memory CD8+ T cells in non-irradiated tumors. Notably, PDT in combination with PD-1 antibody therapy prolonged survival compared to monotherapy and PBS. PLP-mediated PDT shows promise in generating a systemic immune response that can complement other treatments, improving prognoses for patients with metastatic cancers.

Impact of Socioeconomic Status on Paranasal Sinus Cancer Disease-Specific and Conditional Survival

Objective Socioeconomic status (SES) is often used to quantify social determinants of health. This study uses the National Cancer Institute SES index to examine the effect of SES on disease-specific survival and 5-year conditional disease-specific survival (CDSS; the change in life expectancy with increasing survivorship) in paranasal sinus cancer Study Design Cross-sectional analysis. Setting National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) program. Methods A study of adults with sinus cancer between 1973 and 2015 was performed. The Yost index, a census tract–level composite score of SES, was used to categorize patients. Kaplan-Meier analysis and Cox regression for disease-specific survival were stratified by SES. CDSS was calculated with simplified models. Logistic regression was conducted to identify risk factors for advanced stage at diagnosis, multimodal therapy, and diagnosis of squamous cell carcinoma. Results There were 3437 patients analyzed. In Cox models adjusting for patient-specific factors, the lowest SES tertile exhibited worse mortality (hazard ratio, 1.22; 95% CI, 1.07-1.39; P < .01). After addition of treatment and pathology, SES was not significant ( P = .07). The lowest SES tertile was more often diagnosed at later stages (odds ratio [OR], 1.52; 95% CI, 1.12-2.06; P < .01). For those with regional/distant disease, the middle tertile (OR, 0.75; 95% CI, 0.63-0.90; P < .01) and lowest tertile (OR, 0.75; 95% CI, 0.62-0.91; P < .01) were less likely to receive multimodal therapy. SES tertiles primarily affected 5-year CDSS for regional/distant disease. CDSS for all stages converged over time. Conclusion Lower SES is associated with worse outcomes in paranasal sinus cancer. Research should be devoted toward understanding factors that contribute to such disparities, including tumor pathology and treatment course.

Cerebellar metastasis of a Liposarcoma: Case report and literature review

Background: Liposarcoma (LPS) is a rare type of tumor; they come from the adipose tissue. It is the most common type of soft-tissue sarcoma. Every type of LPS has morphological features, immunophenotypic, and molecular pathogenesis characteristics of their own. In this case, we are going to report a cerebellar metastatic disease from a well-differentiated liposarcoma (WDL) with pleomorphic component, not found in our literature research. Case Description: A 72-year-old woman with progressive pain and inflammation in the left knee with functional limitation when climbing stairs. MRI shows a tumor in the vastus medialis of the left thigh. Pathology result was pleomorphic and WDL, Stage III and negative for MDM2 and CDK4. Extension study was carried out, finding nodular lesion in the right cerebellar hemisphere with mass effect and partial obliteration of the fourth ventricle, suspicious of distant disease. Conclusion: Cerebellar metastasis of LPS is uncommon; there are only a few cases reports with the literature reviews describing orbital or skull base metastases, but not in the cerebellum. Our case allows us to remember that neurological symptoms, no matter how subtle, in patients diagnosed with LPS, a secondary affectation of the central nervous system must be ruled out, even though it is a rare location. The findings of distant disease in LPSs, allow planning oncological treatment options and targeted radiotherapeutic.

Outcomes with definitive local treatment to the primary site in non-nasopharyngeal head and neck squamous cell carcinoma patients with synchronous distant metastasis.

e18014 Background: Data on the efficacy of including definitive local therapy to the primary head and neck disease (PHN) for non-nasopharyngeal head and neck squamous cell carcinoma (HNSCC) patients with synchronous distant metastasis are lacking. Methods: In this single institution retrospective study, we evaluated the outcomes of patients treated from 2000-2020 at UPMC for non-nasopharyngeal HNSCC with synchronous distant metastasis whose therapy included definitive therapy to the PHN. We evaluated overall survival (OS), calculated as date of diagnosis to date of death and progression free survival (PFS), calculated as date of diagnosis to date of death or progression. Based on an initial univariate analysis, the potential significant predictors were evaluated further in the multiple covariates Cox model via stepwise procedures. The relative mortality rates were summarized with hazard ratio (HR), with HR > 1.0 corresponding to increased mortality. Results: A total of 40 patients met inclusion criteria. The median age was 61, primary sites included 52.5% oropharynx (48% HPV +), 40% larynx/hypopharynx, 7.5% oral cavity, and 85% had a solitary metastatic lesion, most commonly in the lung. Definitive treatment of the PHN was with surgery (55%) or chemoradiation (45%), and 45% also underwent local treatment for all distant disease. The median PFS was 8.6 months (95% CI, 6.4-11.6), and OS was 14.2 months (95% CI, 10.9-27.5). In the 28% of patients that received induction therapy, there was a two-fold increase in median OS to 27.5 vs. 13.7 months, p = 0.06. In the 33% of patients that received anti-PD-1 mAb immunotherapy (IO), the median OS was significantly increased to 41.7 months (95% CI, 8.7-NR) vs. 12.1 months (95% CI, 8.4-14.4), p = 0.01, with a numeric increase in PFS as well (11.3 vs. 8.2 months respectively, p = 0.07). Notably no difference in PFS or OS was seen with type of local therapy to the PHN, receipt of local treatment to all distant disease, by HPV status, or year of diagnosis. In multivariate analysis including induction and other variables significant in univariate analysis (age, number of metastatic sites), IO was independently associated with improved OS (HR 3.123 (No IO vs. IO) (95% CI, 1.198-8.137), p = 0.02), as was age and number of metastatic sites. In the patients that received IO started as part of induction the median PFS and OS were 19.5 and 45.5 months respectively. Conclusions: We observed impressive survival in select non-nasopharyngeal HNSCC patients with synchronous distant metastasis treated with definitive local therapy to the primary head and neck disease in addition to induction and/or IO, with IO independently associated with improved OS. To our knowledge this is the first evaluation of the efficacy of definitive local therapy and IO in this population. Prospective evaluation is warranted.

Treatment and survival outcomes for Medicaid patients with pancreatic, colon-rectosigmoid, and liver cancers at a national comprehensive cancer center.

e18524 Background: Treatment and survival disparities faced by Medicaid patients are documented for pancreatic, colon-rectosigmoid, and liver cancers at a national level. Studies show these disparities persist at academic medical centers. We assessed Medicaid treatment and survival outcomes among University of Wisconsin-Health (UWH) pancreatic, colon-rectosigmoid, and liver cancer patients to determine whether national trends persisted at this academic medical center. Methods: We included UWH registry data for 1567 pancreatic, 2313 colon-rectosigmoid, and 1027 liver cancer patients ages 18+ from 2004-2016. We performed multivariable logistic regression to estimate odds ratios (ORs) to assess insurance disparities in intended resection and Cox Proportional regression to estimate hazard ratios (HRs) to assess all-cause mortality disparities for each cancer, adjusting for age, sex, race/ethnicity, BMI, comorbidity, stage, rurality, and insurance. Results: Median overall survival was 6.5 months (range 0.1-147.5) for pancreatic, 12.8 months (0.1-167.5) for colon-rectosigmoid, and 12.5 months (0.1-168.7) for liver cancer patients. 3% of pancreatic, 5% of colon-rectosigmoid, and 9% of liver cancer patients had Medicaid Insurance. Medicaid patients were less likely to be older and non-Hispanic White than private insurance (private) patients for each cancer. Medicaid patients were diagnosed with more distant disease for colon-rectosigmoid and liver cancers and less distant disease for pancreatic cancer. Medicaid patients were less likely to receive surgery vs private patients for pancreatic (OR 0.41, 95% CI 0.16-1.08) and liver (OR 0.62, 0.26-1.49) cancers, though confidence intervals were wide. Insurance was not associated with surgery in colon-rectosigmoid cancer patients (OR 0.97, 0.48-1.97). Medicaid patients had a higher risk of death vs private patients for colon rectosigmoid cancer (HR 1.50, 1.12-2.01). Risk of death was modestly elevated for Medicaid vs private patients for pancreatic (HR 1.35, 0.97-1.87) but not liver (HR 1.07, 0.77-1.48) cancer. Conclusions: Medicaid pancreatic and liver cancer patients may be less likely to receive surgery than private patients in our one center study. Results suggested that Medicaid pancreatic and colon-rectosigmoid cancer patients may have a slightly elevated risk of death vs private patients, though this needs confirmation in larger samples. Future studies should explore at which local, state, and regional levels Medicaid pancreatic, colon-rectosigmoid, and liver cancer patients experience treatment and survival disparities vs private insurance patients. These studies, combined with Medicaid expansion studies, can guide healthcare leaders and policy makers to design context-appropriate interventions to reduce insurance-related disparities in cancer treatment and outcomes.

Inflammatory myofibroblastic tumor: A multi-institutional study from the pediatric surgical oncology research collaborative.

10024 Background: Inflammatory myofibroblastic tumor (IMT) is a mesenchymal neoplasm of intermediate malignancy, predominantly seen in children and young adults. Given its rarity, data are limited. We describe the largest cohort of patients with IMT to date, with an aim to further characterize this poorly understood tumor. Methods: A multi-institutional review was performed at 18 North American hospitals participating in the Pediatric Surgical Oncology Research Collaborative to identify IMT patients ≤39 years, diagnosed from 2000-2018. Descriptive statistics are described as median and interquartile range. Multivariable analysis was used to identify predictors of event free survival (EFS). Results: 182 patients were identified with a median age of 11 years (5-17); 52% were female. 33% of tumors were thoracic, 26% abdominal/pelvic, 20% head/neck, and 14% genitourinary. Common presenting symptoms included pain (29%), respiratory symptoms (24%), weight loss (12%), and a palpable mass (10%). Median tumor size was 3.9 cm (1.9-6.5). Anaplastic lymphoma kinase (ALK) overexpression was identified via immunohistochemistry in 53% of patients tested. One third of patients had abnormal cytogenetics, with 12% of the entire cohort having an ALK mutation. 7% of patients had distant disease at diagnosis. 13% of patients received neoadjuvant therapy including chemotherapy (3%), ALK inhibitor (4%), radiation (0.5%), non-steroidal anti-inflammatories (NSAIDs) (7%), or steroids (2%). Of those who underwent resection with known margin status (n = 158), 66% had complete resection, 20% had microscopic positive margins, and 14% had gross residual disease. Just over 40% of patients had an en bloc resection of involved organs, most commonly lung (26%). 21% of patients received adjuvant therapy, including chemotherapy (3%), ALK inhibitor (9%), radiation (0.5%), NSAIDs (8%), or steroids (5%). 12% of all patients received an ALK inhibitor: 24% neoadjuvant, 62% adjuvant, and 14% without surgery. Median follow-up time was 36 months (14-69). Overall 5-year survival (OS) was 95% and 5-year EFS was 80%. Predictors of recurrence included respiratory symptoms, larger tumor size, or distant disease at diagnosis. Gender, race, age and primary site were not predictive of EFS. Likewise, there was no association of ALK overexpression or ALK mutation with EFS. The presence of gross or microscopic margins following resection was not associated with recurrence. Conclusions: IMT is a rare tumor with favorable OS. Five year recurrence rate was 20%. Presenting with respiratory symptoms, larger tumor size, or metastatic disease was associated with recurrence, while ALK positivity was not. Notably, a positive margin after resection was not associated with increased recurrence, indicating that aggressive attempts at surgical resection that would compromise form or function may not be warranted.