Biothera (United States)

531 Background: The Breast Cancer Index (BCI) is a validated gene expression assay that provides an individualized risk of late distant recurrence and predicts the likelihood of benefit from extended endocrine therapy (EET) in HR+ early-stage breast cancer. The objective of this analysis was to assess the influence of BCI on clinical decision-making regarding EET. Methods: The BCI Registry study is a prospective, multi-institutional study investigating the long-term clinical outcome, decision impact, and quality of life in HR+ breast cancer patients receiving BCI testing as part of routine clinical care. Physicians and patients completed pre- and post-BCI test questionnaires to assess physician decision-making; physician confidence; and patient preferences and concerns for EET. Pre- and post-BCI responses were compared using McNemar’s test and the Wilcoxon signed rank test. The BCI Registry Study is registered on ClinicalTrials.gov under NCT04875351. Results: In the current analysis,pre- and post-BCI testing questionnaires were completed for 2850 physicians and 2832 patients. 88.6% of patients were postmenopausal, 76.5% N0, 73.0% T1, 53.5% G2, and 13.0% HER2-positive. Following BCI testing, physicians changed treatment recommendations for EET in 41.2% (1175/2850) of patients (p<0.001). In cases where physicians recommended EET prior to BCI testing, 49.8% (775/1555) changed their recommendation to not treat with EET, while 31.2% (400/1280) of those who did not recommend EET prior to BCI testing changed their recommendation in favor of EET. Following BCI testing, 43.9% (1250/2850) of physicians felt more confident in their recommendation (p<0.001) and 43.2% (1223/2832) of patients felt more comfortable with their EET decision (p<0.001). The percentage of physicians having high confidence levels (confident or strongly confident) increased from 63.6% (N=1813) pre-BCI testing to 88.2% (N=2515) post-BCI testing. The percentage of physicians having low confidence levels (not at all confident, not confident, or ambivalent) decreased from 33.1% (N=943) pre-BCI testing to 11.0%(N=313) post-BCI testing. In BCI (H/I)-Low patients, 48.9% (868/1776) showed a decreased preference for EET (p<0.001). In BCI (H/I)-High patients, 34.6% (365/1056) showed an increased EET preference (p<0.001). After BCI testing, significantly more patients were less concerned about cost (23.9%, p<0.001), drug safety (25.7%, p<0.001), and EET benefit (30.9%, p<0.001). No significant change in concern regarding side-effects was observed (p=0.58). Conclusions: Incorporating BCI into clinical practice resulted in significant changes in physician recommendations for EET, while at the same time increasing physician confidence. Knowledge of the BCI result improved patient preference, satisfaction and reduced patient concerns regarding cost, drug safety and benefit of EET.

456 Background: CUP is a rare and heterogenous clinicopathologic syndrome with unidentifiable origin at time of diagnosis. Based on immunophenotyping, specifically PAX8 staining, CUP with Renal profile (RCUP) is emerging as a distinct clinical subset. In addition to clinical presentation and immunohistochemistry (IHC), molecular profiling for tissue of origin may aid defining CUP subsets. Precision in diagnosis impacts therapeutics given that cytotoxic chemotherapy options for CUP do not overlap with tyrosine kinase inhibitors or checkpoint inhibitors used for renal cell carcinoma. Methods: We retrospectively (2018-2022) evaluated patients with CUP composed of cases (renal profile, N=100, clear cell or papillary) or controls (non-renal, N=200) identified using the 92-gene assay (CancerTYPE ID), a validated classifier for predicting tissue of origin. Clinicopathologic data including IHC and molecular profiling results were collected using pathology specimens and reports. Results: Baseline characteristics (age, gender, tumor grade) of cases and controls were comparable, except for histology, wherein adenocarcinoma was less common with RCUP (27% vs 48%, p<0.001). Median number of IHC stains performed was 11 (range 0-30) vs 9 (0-29) (p=0.04) in RCUP vs non-renal cases, respectively. While PAX8 was tested in 64% vs 39% (p<0.001) of cases, it was found to be strongly or focally positive in 87.5% vs 21.8% (p<0.001), respectively. In contrast to non-renal CUP, RCUP patients were more likely to have bone biopsies (24% vs 11.5%, OR 2.4, p=0.007), less likely to have high-TMB (2.8% vs 28.2%, OR 0.07, p=0.001), and had a lower proportion of TP53 mutations (18.8% vs 89.2%, OR 0.028, p<0.001), KRAS mutations (13.3% vs 77.4%, OR 0.045, p<0.001) and BRAF mutations (0% vs 42%, OR 0, p=0.015). Conclusions: RCUP appears to be a distinct subset of CUP with variable diagnostic workup. Critical IHC markers may be omitted in a considerable number of cases and despite positivity, may still confer an uncertain diagnosis. Key molecular factors appear to be different and may require tailored therapeutic approaches. This study further supports the clinical utility of GEP-based cancer classification with the 92-gene assay to predict RCUP and may be an important adjunct to IHC to improve diagnostic accuracy for CUP and to guide treatment selection for better clinical outcomes. RCUP (N=100) Non-renal CUP (N=200) IHC Cases Tested (%) Cases Positive (%) Cases Tested (%) Cases Positive (%) CK7 83 47 81 75* CK20 75 11 77 24* PAX8 64* 88* 39 22 Napsin 29 28* 25 8 RCC 26* 31 4 13 Vimentin 17 94 5.5 73 *Significantly (p<0.05) greater proportion of cases.

Cancer of unknown primary (CUP) is a syndrome comprising metastatic cancers without a clinically identified primary site. Although patients with CUP have an unfavorable prognosis, treatment with site-specific therapies guided by clinical features, standard pathology, and molecular assays can improve overall survival. The 92-gene assay (CancerTYPE ID) is a gene expression-based classifier that helps identify the tissue of origin for metastatic cancers with unknown or uncertain diagnoses. This study reports the frequency of selected molecular aberrations of oncogenes, including KRAS, IDH1/2, BRCA1/2, and BRAF, in patients with CUP in the MOSAIC database to highlight potential treatment options. MOSAIC is a database of patients with CUP submitted for CancerTYPE ID testing and NeoTYPE biomarker testing. Tumor biopsy samples were analyzed by CancerTYPE ID for tumor type identification and further tested for molecular aberrations of oncogenes, including KRAS, IDH1/2, BRCA1/2, and BRAF. CancerTYPE ID identified a specific tumor type in 92.5% (2,929 of 3,168) of CUP cases in the MOSAIC database. The most commonly identified histological type was adenocarcinoma (75.4%), with pancreaticobiliary being the most common molecularly diagnosed cancer (24.9%). Aberrations in KRAS, IDH1/2, BRCA, and BRAF genes were identified in 18.8% (n = 597) of biopsies. A cancer-specific US Food and Drug Administration (FDA)-approved or investigational targeted therapy was potentially available for 24.6% (n = 147) of these patients. This retrospective analysis supports incorporating CancerTYPE ID into the evaluation for patients with CUP to help determine the tissue of origin and identify actionable genetic alterations. This approach may allow more patients with CUP to benefit from site-specific FDA-approved targeted therapies or enrollment into clinical trials.

Adjuvant ovarian function suppression (OFS) with oral endocrine therapy improves outcomes for premenopausal patients with hormone receptor-positive (HR+) breast cancer but adds adverse effects. A genomic biomarker for selecting patients most likely to benefit from OFS-based treatment is lacking. To assess the predictive and prognostic performance of the Breast Cancer Index (BCI) for OFS benefit in premenopausal women with HR+ breast cancer. This prospective-retrospective translational study used all available tumor tissue samples from female patients from the Suppression of Ovarian Function Trial (SOFT). These individuals were randomized to receive 5 years of adjuvant tamoxifen alone, tamoxifen plus OFS, or exemestane plus OFS. BCI testing was performed blinded to clinical data and outcome. The a priori hypothesis was that BCI HOXB13/IL17BR ratio (BCI[H/I])-high tumors would benefit more from OFS and high BCI portended poorer prognosis in this population. Settings spanned multiple centers internationally. Participants included premenopausal female patients with HR+ early breast cancer with specimens in the International Breast Cancer Study Group tumor repository available for RNA extraction. Data were collected from December 2003 to April 2021 and were analyzed from May 2022 to October 2022. Primary end points were breast cancer-free interval (BCFI) for the predictive analysis and distant recurrence-free interval (DRFI) for the prognostic analyses. Tumor specimens were available for 1718 of the 3047 female patients in the SOFT intention-to-treat population. The 1687 patients (98.2%) who had specimens that yielded sufficient RNA for BCI testing represented the parent trial population. The median (IQR) follow-up time was 12 (10.5-13.4) years, and 512 patients (30.3%) were younger than 40 years. Tumors were BCI(H/I)-low for 972 patients (57.6%) and BCI(H/I)-high for 715 patients (42.4%). Patients with tumors classified as BCI(H/I)-low exhibited a 12-year absolute benefit in BCFI of 11.6% from exemestane plus OFS (hazard ratio [HR], 0.48 [95% CI, 0.33-0.71]) and an absolute benefit of 7.3% from tamoxifen plus OFS (HR, 0.69 [95% CI, 0.48-0.97]) relative to tamoxifen alone. In contrast, patients with BCI(H/I)-high tumors did not benefit from either exemestane plus OFS (absolute benefit, -0.4%; HR, 1.03 [95% CI, 0.70-1.53]; P for interaction = .006) or tamoxifen plus OFS (absolute benefit, -1.2%; HR, 1.05 [95% CI, 0.72-1.54]; P for interaction = .11) compared with tamoxifen alone. BCI continuous index was significantly prognostic in the N0 subgroup for DRFI (n = 1110; P = .004), with 12-year DRFI of 95.9%, 90.8%, and 86.3% in BCI low-risk, intermediate-risk, and high-risk N0 cancers, respectively. In this prospective-retrospective translational study of patients enrolled in SOFT, BCI was confirmed as prognostic in premenopausal women with HR+ breast cancer. The benefit from OFS-containing adjuvant endocrine therapy was greater for patients with BCI(H/I)-low tumors than BCI(H/I)-high tumors. BCI(H/I)-low status may identify premenopausal patients who are likely to benefit from this more intensive endocrine therapy.

Most thoracic cancers arise via a series of stepwise somatic alterations driven by a well-defined carcinogen (ie, tobacco or asbestos for lung cancer and mesothelioma, respectively). A small proportion can emerge on a background of pathogenic germline variants (PGVs), which have the property of heritability. In general, PGVs may be initially suspected on the basis of the presence of specific clinical features. Such gene × environment interactions significantly increase the risk of developing lung cancer (1.5- to 3.2-fold). PGVs have been discovered involving the actionable driver oncogene, epidermal growth factor receptor (EGFR), with an EGFR T790M PGV rate of 0.3%-0.9% in the nonsquamous non-small-cell lung cancer subtype. Its appearance during routine somatic DNA sequencing in those patients who have not had a previous tyrosine kinase inhibitor should raise suspicion. In patients with sporadic mesothelioma, BAP1 is the most frequently mutated tumor driver, with a PGV rate between 2.8% and 8%, associated with a favorable prognosis. BAP1 PGVs accelerate mesothelioma tumorigenesis after asbestos exposure in preclinical models and may be partly predicted by clinical criteria. At present, routine germline genetic testing for thoracic cancers is not a standard practice. Expert genetic counseling is, therefore, required for patients who carry a PGV. Ongoing studies aim to better understand the natural history of patients harboring PGVs to underpin future cancer prevention, precise counseling, and cancer management with the goal of improving the quality and length of life.

Abstract Background: Extended endocrine therapy (EET) has shown modest gains in absolute benefit to reduce the long-term risk of recurrence in hormone receptor-positive (HR+) breast cancer but is accompanied by serious adverse events (AEs), such as bone and cardiovascular toxicities, endometrial cancer and other side effects that impair quality of life (QOL). Novel approaches that quantify the benefit-risk balance integrating both survival benefit and harm to determine a net health outcome would advance EET decision making. BCI is a gene expression-based assay that predicts benefit from endocrine therapy. Here, the ability of BCI by HOXB13/IL17BR (H/I) to predict the net benefit from 2.5 vs 5y of extended letrozole in patients treated in the IDEAL trial was examined by integrating both efficacy and toxicity outcomes into a single analysis. Methods: All IDEAL patients with available tumor specimens were eligible for this analysis. The Net Treatment Benefit (NTB) and the Win Ratio (WR) were examined using generalized pairwise comparisons to analyze both efficacy and safety wherein all possible patient pairs, one from each treatment arm, were compared based on several prioritized outcome measures scored as favorable, unfavorable, neutral or uninformative. The first prioritized outcome was recurrence-free survival (RFI) with a clinical threshold of ≥3 months; the second prioritized outcome was toxicity based on the highest grade of treatment related AEs. NTB was estimated as the difference in the proportions of favorable vs unfavorable pairs, representing the net probability of an improved health outcome with EET. WR was calculated as the ratio of favorable vs unfavorable pairs, representing the relative risk of an improvement in health outcomes with EET. AEs were evaluated in annual follow-up visits during the active treatment period. Bone-related AEs of ≥ grade 3 included arthralgia, osteoporosis, decreased joint range of motion, back pain and fracture. The most prevalent QOL-related AEs of ≥ grade 3 included hot flashes, fatigue, depression, insomnia and vaginal dryness. Results: 908 HR+ patients (73% pN+, median age 59y, 45% pT1, 48% pT2) were included, with 88% and 68% receiving prior treatment with an aromatase inhibitor (AI) or chemotherapy, respectively. When toxicity was assessed with treatment related AEs ≥ grade 2, no significant improvement in the benefit-risk was observed for EET in either BCI (H/I)-High or BCI (H/I)-Low group. However, when severe toxicity was assessed with AEs ≥ grade 3, significant benefit-risk improvements were observed for EET in BCI (H/I)-High patients (NTB=7.2%, WR=1.76, p=0.044), but not in BCI (H/I)-Low patients (NTB=-0.7%, WR=0.96, p=0.869). BCI (H/I)-High patients demonstrated significant NTB=7.7%/7.4%, WR=2.24/1.92 when analyzing bone-related and QOL-related toxicities, respectively (p=0.024, 0.024), while no significant results were observed in the BCI (H/I)-Low patients (p=0.902, 0.780, respectively). Prioritizing toxicity over efficacy produced similar results. Conclusion: Novel findings demonstrate that BCI not only significantly predicts preferential survival benefit from longer durations of endocrine therapy, but also significantly predicts the overall benefit/risk and likelihood of an improved health outcome from EET in HR+ patients treated with primary adjuvant AI, when severe AEs are considered. It should be noted that the results of our analysis could be biased due to a shorter AE recording period in the 2.5y arm, hence the true benefit/risk of EET could be larger than reported here. Quantification of a net treatment benefit when considering the impact of both efficacy and toxicity may represent a new paradigm for evaluation of the overall EET benefit and aid in patient selection for EET. Citation Format: Marc Buyse, Jenna Wong, Samuel Salvaggio, Jean-Christophe Chiem, Yi Zhang, Kai Treuner, Elma Meershoek-Klein Kranenbarg, Mickaël De Backer, Gerrit-Jan Liefers, Catherine A Schnabel. Breast Cancer Index and assessment of the Net Treatment Benefit (NTB) of extended endocrine therapy in HR+ 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 PD15-04.

Abstract Background: Hormone receptor-positive (HR+) is the most common molecular subtype of breast cancer accounting for approximately 2 out of every 3 patients. Adjuvant anti-estrogen therapy is the cornerstone of systemic therapy, underscoring the critical role of endocrine treatment which affects the majority of women with breast cancer. Furthering efforts to better understand endocrine response and resistance and implementing genomic tools to help individualize patient selection for endocrine therapy are of ongoing importance to improve outcomes. Breast Cancer Index (BCI) is a gene expression signature composed of the Molecular Grade Index (MGI) and HOXB13/IL17BR (H/I) that predicts the likelihood of extended endocrine benefit and quantifies the risk of both late (5-10 years) and overall (0-10 years) distant recurrence. BCI has recently been incorporated into the NCCN clinical practice guideline as a biomarker for prediction of benefit from extended endocrine therapy in patients with early-stage, HR+ breast cancer. The objective of the BCI Registry Study is to collect real-world evidence at a national level aimed at advancing patient care and optimizing duration of endocrine treatment and will be conducted in two phases. First, long-term patient outcomes and the impact of BCI on decision-making based on physician and patient reported outcomes as well as medication adherence to extended endocrine therapy will be assessed. Secondly, individual patient data on over 40 clinical variables will be collected and partnered with molecular profiling and genomic data for each patient to enable correlative analysis and novel biomarker research of endocrine sensitivity and resistance. Study Description: The BCI Registry Study is a prospective, multi-center, observational data registry and biospecimen repository for stage I-III HR+ breast cancer patients. The main objective of the Registry Study is prospective characterization of BCI predictive and prognostic performance. The primary endpoint is time to distant recurrence (TTDR), defined as the interval between the time of BCI testing and the first metastasis at distant organs. Secondary endpoints include time to any recurrences and medication adherence score over time. Eligibility criteria includes confirmed diagnosis of HR+ early-stage invasive breast carcinoma (ductal, lobular, or mixed ductal/lobular), either HER2 negative or positive and either node-negative or node-positive tumors with 1-3 positive lymph nodes (N1). Patients must have completed 4 to 7 years of primary adjuvant endocrine therapy and have pre-treatment tumor tissue available from a previous breast surgery or biopsy. Both physicians and patients will complete a pre- and post-test Decision Impact Questionnaire to assess the impact of BCI results on extended endocrine therapy decision-making. Patients who elect to complete 10 years of endocrine therapy will answer a Medication Adherence Questionnaire during annual follow-up visits. Follow-up of patients will end 10 years from initial breast cancer diagnosis. The Registry plans to enroll approximately 3,000 patients across approximately 40 study sites in the United States. Enrollment for the study began in Q2 2021, and 324 patients have been enrolled as of July 2021. For more information, please visit the ClinicalTrials.gov registration: NCT04875351. Citation Format: Joyce A O'Shaughnessy, Jenny R Fox, Carlos A Encarnación, Brandon O'Neal, Kai Treuner, Tara Sanft, Rachel C Jankowitz, Mark D Pegram, Catherine A Schnabel, Sami G Diab. The Breast Cancer Index registry study: A prospective multi-center observational study to evaluate patient outcome, clinical impact, and medication adherence in HR+ breast cancer patients considering treatment with extended endocrine therapy [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 OT1-10-01.

BackgroundAlthough recent advances in immunotherapy have transformed the treatment landscape for many anatomically defined cancers, these therapies are currently not approved for patients diagnosed with cancer of unknown primary (CUP). Molecular cancer classification using gene expression profiling (GEP) assays has the potential to identify tumor type and putative primary cancers and thereby may allow consideration of immune checkpoint inhibitor (ICI) therapy options for a subset of patients with CUP. Herein, we evaluated and characterized the ability of a 92‐gene assay (CancerTYPE ID) to provide a molecular diagnosis and identify putative tumor types that are known to be sensitive to ICI therapies in patients with CUP or uncertain diagnosis.FindingsA total of 24,426 cases from a large‐scale research database of 92‐gene assay clinical cases were classified, of which 9,350 (38%) were predicted to have an ICI‐eligible tumor type. All ICIs with approved indications as of March 2020 were included in the analysis. Non‐small cell lung cancer (NSCLC) was the most frequent molecular diagnosis and accounted for 33% of the ICI‐eligible tumor types identified and 13% of the overall reportable results. In addition to NSCLC, the assay also frequently identified urothelial carcinomas, gastric cancer, and head and neck squamous cell carcinoma. The distributions of identified tumor types with indications for ICI therapy were similar across age and gender.ConclusionsResults suggest that molecular profiling with the 92‐gene assay identifies a subset of ICI‐eligible putative primary cancers in patients with CUP. We propose a treatment strategy based on available tests, including clinicopathologic features, GEP, and ICI biomarkers of response.

555 Background: Identification of N+ breast cancer patients with a limited risk of recurrence improves selection of those for which chemotherapy and/or extended endocrine therapy (EET) may be most appropriate to reduce overtreatment. BCIN+ integrates gene expression with tumor size and grade, and is highly prognostic for overall (0-10yr) and late (5-10yr) distant recurrence (DR) in N1 patients. Clinical Treatment Score post-5-years (CTS5) is a prognostic model based on clinicopathological factors (nodes, age, tumor size and grade) and significantly prognostic for late DR. The current analysis compares BCIN+ and CTS5 for risk of late DR in N1 patients. Methods: 349 women with HR+, N1 disease and recurrence-free for ≥5 years were included. BCIN+ results were determined blinded to clinical outcome. CTS5 was calculated as previously described (Dowsett et al, JCO 2018; 36:1941). Kaplan-Meier analysis and Cox proportional hazards regression for late DR (5-15y) were evaluated. Results: 64% of patients were > 50 years old, 34% with tumors > 2cm, 79% received adjuvant chemotherapy and 64% received up to 5 years of ET. BCIN+ stratified 23% of patients as low-risk with 1.3% risk for late DR vs those classified as high-risk with 16.1% [HR 12.4 (1.7-90.4), p = 0.0014]. CTS5 classified patients into 3 risk groups: 29% of patients as low-risk (4.2% DR), 37% as intermediate-risk (10.6% DR), and 34% as high-risk (22.1% DR) [HR intermediate vs. low: 2.3 (0.7-7.0), p = 0.16; high vs. low: 5.3 (1.8-15.5), p = 0.002]. In a subset of patients who completed 5 years of ET (N = 223), BCIN+ identified 22% of patients as low-risk with a late DR rate of 2.1%, while CTS5 identified 29% and 37% of patients as low- and intermediate-risk with late DR rates of 5.2% and 10.3%, respectively. Conclusions: BCIN+ classified N1 patients into binary risk groups and identified 20% patients with limited risk of late DR ( < 2%) that may be advised to forego EET and its attendant toxicities/side effects. In comparison, CTS5 classified patients into 3 risk groups, with low- and intermediate-risk of late DR of 4-5% and 10%, wherein the risk-benefit profile for extension of endocrine therapy is less clear.