Search

Inflammatory myofibroblastic tumors (IMTs) are intermediate-grade mesenchymal neoplasms commonly characterized by chromosomal rearrangements causing constitutive activation of anaplastic lymphoma kinase (ALK) and/or ALK mutations causing reduced sensitivity to ALK tyrosine kinase inhibitors (TKI). We present a patient with an IMT who initially responded to first-line alectinib, but who later suffered disease relapse and presently survives with moderate residual disease after receiving second-line lorlatinib. Biopsy specimens were analyzed using next generation sequencing (DNA-seq and RNA-seq) and reverse phase protein microarray (RPPA) as part of an institutional Molecular Tumor Board (MTB) study. An EML4-ALK rearrangement and EGFR activation (pEGFRY1068) were present in both the primary and recurrent tumors, while a secondary ALK I1171N mutation was exclusive to the latter. EGFR signaling in the background of a secondary ALK mutation is correlated with reduced ALK TKI sensitivity in vitro, implicating an important mechanism of drug resistance development in this patient. The RPPA results also critically demonstrate that ALK signaling (ALKY1604) was not activated in the recurrent tumor, thereby indicating that standard-of-care use of third- or fourth-line ALK TKI would not likely be efficacious or durable. These results underscore the importance of real-time clinical integration of functional protein drug target activation data with NGS in the MTB setting for improving selection of patient-tailored therapy.

103 Background: Disparities in cancer care due to race and ethnicity are prevalent in both the care patients receive and patient outcomes. The evaluation of next generation sequencing (NGS) results from patients with advanced cancer by a molecular tumor board (MTB) has become standard practice in many institutions for the identification of additional treatment options and targeted therapies. We sought to compare the racial distribution of patients evaluated by our MTB with our institutional cancer registry (CR). Methods: We tabulated the racial distribution of 560 MTB patients chosen for presentation in a bimonthly case conference based on physician request or clinical interest from more than 2,500 NGS reports of patients with advanced cancer from 2016 through 2020. Self-identified race from patients with stage 4 cancer within our institutional CR from the same time interval was compared to the MTB population from each year using the Chi-Squared test. The Cochran-Mantel-Haenszel test was used to analyze the relationship between race and MTB/CR after controlling for year. Race categories were defined as Asian, Black/African-American (AA), White/Caucasian, and other. Results: We identified 4,151 CR patients with stage 4 cancer from 2016 through 2020, 573 of whom identified as Black/AA (13.8%). Of the 560 MTB patients, 55 were Black/AA (9.8%). When controlling for year, Black/AA patients were less frequently included in the MTB compared to the CR (p = 0.0128). Conclusions: Black/AA patients with advanced cancer are under-represented in our MTB. Larger studies are warranted to examine underlying causes of this discrepancy including implicit bias, generalizability of this finding to other minorities and institutions, and potential remedies to ensure equitable access to state-of-the-art cancer care.[Table: see text]

Patient engagement in medical decision-making improves patient related outcomes through compliance and patient satisfaction. The Inova Schar Cancer Institute has a weekly molecular tumor board (MTB) to match comprehensive genomic sequencing results with targeted therapies for patients. Primary oncologists extended MTB invitations to their patients. Ultimately, 20 of the 139 patients attended and completed pre- and post MTB surveys. There was a statistically significant change from the pre- to post- survey for the question "I am satisfied with how well informed I am about targeted therapy" with P = 0.016. Patients who attended MTB reported higher levels of satisfaction with their knowledge of targeted therapy after MTB as compared to before. A more holistic method of studying this practice would include sampling a larger patient population and a formal evaluation of the physicians' experience with patients attending.

e16259 Background: Advanced PDAC is associated with a poor prognosis and median survivals of less than one year. FOLFIRINOX and Gemcitabine/Nab-Paclitaxel are both considered standard of care in the first line setting, though there is considerable variability among oncologists regarding sequencing of these regimens. Pre-clinical and clinical data support the use of platinum therapy in HRD+ PDAC, but little is known about how this translates into best practices regarding sequencing of treatment or clinical benefit relevant to Gemcitabine based therapies in this population. Methods: Using the cancer registry and Inova molecular tumor board database, we retrospectively reviewed all patients from January 2015 until November 2021 with unresectable PDAC who had NGS performed and stratified by the presence or absence of HRD mutation. HRD mutations included by BRCA1, BRCA2, PALB2, ATM, ATR, CHEK2, ARID1A, FANCA, FANCL. We analyzed for RR to Folfirinox/Folfox and Gemcitabine based therapies, adjusted time to progression on Folfirinox/Folfox (time from first dose of oxaliplatin based combination to first dose of gemcitabine to account for those who stopped oxaliplatin early for neuropathy or received maintenance therapy), and time on gemcitabine based therapy. Results: 142 consecutive patients with advanced PDAC were examined, including 20 with HRD variants. When excluding those who eventually received surgery and those who never received platinum therapy, we were left with 87 (74 in Control and 13 in HRD) for analysis. RR to Folfirinox/Folfox was 60% in HRD+ and 31.25% in control (p = 0.71) (Table). Mean adjusted time to progression on Folfirinox/Folfox was 320.0 days in HRD+ group and 252.9 in the control group (p = 0.57) (Table 2). The time on treatment for gemcitabine based combination therapy was 260.7 in HRD+ and 165.1 in control group. Conclusions: HRD+ patients had longer durations of treatment on both 5-FU based therapy and Gemcitabine based combinations. These data challenges the importance of first line platinum therapy in HRD+ patients, and further exploration should be considered.[Table: see text]

10581 Background: MSI-H colorectal cancer is most often a result of deleterious mutations in mismatch repair genes, but can also occur through repressed gene transcription due to hypermethylation of the MLH1 promoter, often associated with BRAF V600E mutations. However, there is a subset of patients who have a “constitutional epimutation”, resulting in hypermethylation of MLH1 throughout normal tissue. We observed a young patient develop a second primary Lynch associated malignancy (see Table 1) who was found to have a constitutional epimutation in MLH1 that prompted us to review the frequency with which the test was ordered and the positivity rate, as well as outline the clinical history in the positive cases. Methods: We reviewed all of the testing ordered for MLH1 hypermethylation of peripheral blood (MLHPB) at the Mayo Clinic Laboratory between 09/01/2020 and 09/01/2021. To the best of our knowledge, this is the only clinically available testing lab in the United States. We reviewed positive casesfor characteristics including the number of malignancies, age of diagnosis, and family history. Results: 33 MLHPB total tests were ordered in the United States at the Mayo Clinic laboratories between 09/01/2020 and 09/01/2021. Three of the tests were positive, including the single test ordered by our institution, and one of the two additional positive tests was available for detailed review. Our institution’s positive test case was a 41 year old women who developed T4N2M0 colorectal cancer 5 years after being treated for endometrial cancer. She had endometrial cancer with absence of MLH1 and PMS2 staining and had a negative germline cancer risk panel at age 36. Five years later, she developed a T4N2 colorectal cancer after which repeat germline testing with RNA sequencing was negative and she was found to have constitutional MLH1 promoter hypermethylation. We were able to obtain clinical information about two of the three individuals with positive tests (See Table). Conclusions: Recognition of constitutional MLH1 hypermethylation may allow for earlier recognition of Lynch related malignancies in affected patients and families. Testing appears infrequent and this condition often goes unrecognized. Specific consensus guidelines may improve recognition and cancer screening in this population. [Table: see text]

3561 Background: BRAF V600E+, MSS mCRC patients comprise up to 10% of advanced CRC. They have a poor prognosis with median survivals typically

129 Background: KRAS and NRAS (RAS) mutations are considered driver mutations in gastrointestinal malignancies such as colorectal and pancreatic cancer. Our institution obtains broad molecular testing (commercial panels with full exon coverage of at least 300 genes) for all stage IV gastrointestinal malignancies that are reviewed at an internal molecular tumor board (MTB). The MTB subjectively felt there was less benefit from comprehensive molecular testing in RAS mutant tumors and wished to quantify this using standardized analysis according to validated guidelines. Methods: We performed a retrospective cohort study of 209 consecutive genomic sequencing results of advanced gastrointestinal malignancies at our institution dating from March 2016 until December 2019. We compared the number of “targetable” mutations in the RAS mutant and wild type (WT) malignancies, as analyzed by an interpretation service according to the Association of Molecular Pathology (AMP) guidelines. A lower AMP score corresponds to a higher level of evidence as a predictive biomarker. We also compared molecular tumor board specific recommendations for each group (excluding recommendations regarding RAS such as EGFR mAbs). Results: There were 134 RAS mutant and 75 RAS WT cases. Alterations with AMP scores of 1A,1B, and 1C were more commonly seen in the RAS WT population 18/75 and 9/134 respectively (24.0% versus 6.7% p-value=0.0004). 39 of 75 cases in RAS WT and 27/134 in RAS mutant (52.0 versus 20.1%, p-value