Discerning the clinical relevance of biomarkers in early stage breast cancer

Purpose Prior data suggest that breast cancer patients accept significant toxicity for small benefit. It is unclear whether personalized estimations of risk or benefit likelihood that could be provided by biomarkers alter treatment decisions in the curative setting. Methods A choice-based conjoint (CBC) survey was conducted in 417 HER2-negative breast cancer patients who received chemotherapy in the curative setting. The survey presented pairs of treatment choices derived from common taxane- and anthracycline-based regimens, varying in degree of benefit by risk of recurrence and in toxicity profile, including peripheral neuropathy (PN) and congestive heart failure (CHF). Hypothetical biomarkers shifting benefit and toxicity risk were modeled to determine whether this knowledge alters choice. Previously identified biomarkers were evaluated using this model. Results Based on CBC analysis, a non-anthracycline regimen was the most preferred. Patients with prior PN had a similar preference for a taxane regimen as those who were PN naïve, but more dramatically shifted preference away from taxanes when PN was described as severe/irreversible. When modeled after hypothetical biomarkers, as the likelihood of PN increased, the preference for taxane-containing regimens decreased; similarly, as the likelihood of CHF increased, the preference for anthracycline regimens decreased. When evaluating validated biomarkers for PN and CHF, this knowledge did alter regimen preference. Conclusions Patients faced with multi-faceted decisions consider personal experience and perceived risk of recurrent disease. Biomarkers providing information on likelihood of toxicity risk do influence treatment choices, and patients may accept reduced benefit when faced with higher risk of toxicity in the curative setting

Identification of germline cancer predisposition variants during clinical ctDNA testing

Next-generation sequencing of circulating tumor DNA (ctDNA) is a non-invasive method to guide therapy selection for cancer patients. ctDNA variant allele frequency (VAF) is commonly reported and may aid in discerning whether a variant is germline or somatic. We report on the fidelity of VAF in ctDNA as a predictor for germline variant carriage. Two patient cohorts were studied. Cohort 1 included patients with known germline variants. Cohort 2 included patients with any variant detected by the ctDNA assay with VAF of 40–60%. In cohort 1, 36 of 91 (40%) known germline variants were identified through ctDNA analysis with a VAF of 39–87.6%. In cohort 2, 111 of 160 (69%) variants identified by ctDNA analysis with a VAF between 40 and 60% were found to be germline. Therefore, variants with a VAF between 40 and 60% should induce suspicion for germline status but should not be used as a replacement for germline testing

Implications of Incidental Germline Findings Identified In the Context of Clinical Whole Exome Sequencing for Guiding Cancer Therapy

PURPOSE Identification of incidental germline mutations in the context of next-generation sequencing is an unintended consequence of advancing technologies. These data are critical for family members to understand disease risks and take action. PATIENTS AND METHODS A retrospective cohort analysis was conducted of 1,028 adult patients with metastatic cancer who were sequenced with tumor and germline whole exome sequencing (WES). Germline variant call files were mined for pathogenic/likely pathogenic (P/LP) variants using the ClinVar database and narrowed to high-quality submitters. RESULTS Median age was 59 years, with 16% of patients ≤ 45 years old. The most common tumor types were breast cancer (12.5%), colorectal cancer (11.5%), sarcoma (9.3%), prostate cancer (8.4%), and lung cancer (6.6%). We identified 3,427 P/LP variants in 471 genes, and 84% of patients harbored one or more variant. One hundred thirty-two patients (12.8%) carried a P/LP variant in a cancer predisposition gene, with BRCA2 being the most common (1.6%). Patients with breast cancer were most likely to carry a P/LP variant (19.2%). One hundred ten patients (10.7%) carried a P/LP variant in a gene that would be recommended by the American College of Medical Genetics and Genomics to be reported as a result of clinical actionability, with the most common being ATP7B (2.7%), BRCA2 (1.6%), MUTYH (1.4%), and BRCA1 (1%). Of patients who carried a P/LP variant in a cancer predisposition gene, only 53% would have been offered correct testing based on current clinical practice guidelines. Of 471 mutated genes, 231 genes had a P/LP variant identified in one patient, demonstrating significant genetic heterogeneity. CONCLUSION The majority of patients undergoing clinical cancer WES harbor a pathogenic germline variation. Identification of clinically actionable germline findings will create additional burden on oncology clinics as broader WES becomes common

Characterizing the heterogeneity of triple-negative breast cancers using microdissected normal ductal epithelium and RNA-sequencing

Triple-negative breast cancers (TNBCs) are a heterogeneous set of tumors defined by an absence of actionable therapeutic targets (ER, PR, and HER-2). Microdissected normal ductal epithelium from healthy volunteers represents a novel comparator to reveal insights into TNBC heterogeneity and to inform drug development. Using RNA-sequencing data from our institution and The Cancer Genome Atlas (TCGA) we compared the transcriptomes of 94 TNBCs, 20 microdissected normal breast tissues from healthy volunteers from the Susan G. Komen for the Cure Tissue Bank, and 10 histologically normal tissues adjacent to tumor. Pathway analysis comparing TNBCs to optimized normal controls of microdissected normal epithelium versus classic controls composed of adjacent normal tissue revealed distinct molecular signatures. Differential gene expression of TNBC compared with normal comparators demonstrated important findings for TNBC-specific clinical trials testing targeted agents; lack of over-expression for negative studies and over-expression in studies with drug activity. Next, by comparing each individual TNBC to the set of microdissected normals, we demonstrate that TNBC heterogeneity is attributable to transcriptional chaos, is associated with non-silent DNA mutational load, and explains transcriptional heterogeneity in addition to known molecular subtypes. Finally, chaos analysis identified 146 core genes dysregulated in >90 % of TNBCs revealing an over-expressed central network. In conclusion, use of microdissected normal ductal epithelium from healthy volunteers enables an optimized approach for studying TNBC and uncovers biological heterogeneity mediated by transcriptional chaos

Abstract PD9-10: BRE12-158: A post-neoadjuvant, randomized phase 2 trial of personalized therapy vs. treatment of physician’s choice for patients with residual triple negative breast cancer

Abstract 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 2, multicenter trial that randomized TNBC patients with residual disease after NAC to genomically-directed therapy vs. treatment of physician choice (TPC). Patients and Methods: From March 2014 to December 2018, 197 patients were enrolled. Residual tumors were sequenced using a next generation sequencing (NGS) test. A molecular tumor board adjudicated all results. Patients were randomized to 4 cycles of genomically-directed therapy (arm A) vs. TPC (arm B). Patients without a target were assigned to arm B. Primary endpoint was 2-year disease free survival (DFS) among randomized patients. Secondary/exploratory endpoints included: distant disease free survival (DDFS), overall survival (OS), toxicity assessment, time-based evolution of therapy, and drug-specific outcomes. Results: 193 patients were randomized or were assigned to arm B. The estimated 2-year DFS was 56.6% (95%CI:0.45-0.70) for arm A vs. 62.4% (95%CI:0.52-0.75) for randomized arm B. No difference was seen in DFS, DDFS, or OS for the entire or randomized populations. There was increased uptake of capecitabine for TPC over time. Patients randomized later had less distant recurrences. ctDNA status remained a significant predictor of outcome with some patients demonstrating clearance with post-neoadjuvant 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 for this high-risk population. ctDNA should be considered a standard covariate for trials in this setting. Citation Format: Bryan P Schneider, Guanglong Jiang, Tarah J Ballinger, Fei Shen, Christopher Chitambar, Rita Nanda, Carla Falkson, Filipa C Lynce, Christopher Gallagher, Claudine Isaacs, Marcelo Blaya, Elisavet Paplomata, Radhika Walling, Karen Daily, Reshma Mahtani, Michael A Thompson, Robert Graham, Maureen E Cooper, Dean C Pavlick, Lee A Albacker, Jeffery Gregg, Jeffery P Solzak, Yu-Hsiang Chen, Casey L Bales, Erica Cantor, Bradley A Hancock, Nawal Kassem, Paul Helft, Bert O'Neil, Anna Maria Storniolo, Sunil Badve, Kathy D Miller, Milan Radovich. BRE12-158: A post-neoadjuvant, randomized phase 2 trial of personalized therapy vs. treatment of physician’s choice for patients with residual triple negative breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD9-10

BRE12-158: A postneoadjuvant, randomized phase II trial of personalized therapy versus treatment of physician\u27s 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

NCCN Guidelines® Insights: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 2.2024.

The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic focus primarily on assessment of pathogenic/likely pathogenic (P/LP) variants associated with increased risk of breast, ovarian, pancreatic, and prostate cancer, including BRCA1, BRCA2, CDH1, PALB2, PTEN, and TP53, and recommended approaches to genetic counseling/testing and care strategies in individuals with these P/LP variants. These NCCN Guidelines Insights summarize important updates regarding: (1) a new section for transgender, nonbinary and gender diverse people who have a hereditary predisposition to cancer focused on risk reduction strategies for ovarian cancer, uterine cancer, prostate cancer, and breast cancer; and (2) testing criteria and management associated with TP53 P/LP variants and Li-Fraumeni syndrome

Informal Cairo: Between Islamist Insurgency & the Neglectful State?

From the late 1980s, Islamist militants established a ‘state within the state’ in the Egyptian capital Cairo, situated in ‘informal’ neighbourhoods developed without official authorization, planning or public services. After government security forces in late 1992 crushed these efforts in the neighbourhood of Munira Gharbiyya, informal Cairo became pathologized in public discourse as ashwa’iyyat (‘random’ or ‘haphazard’ areas), a zone of socio-spatial disorder threatening Egypt as a whole and demanding state intervention. However, this securitizing move did not lead to heavy-handed intervention against informal Cairo more generally. Following the suppression of the militants, the Mubarak government instead returned to long-term patterns of indifference and neglect that had allowed informal neighbourhoods to flourish since the 1960s. In part, the absence of intervention can be explained in terms of resource constraints and risk avoidance. More profoundly, however, it reflects numerous linkages between informal urbanization and the Egyptian state. The ashwa’iyyat are, to a significant degree, both a consequence of an authoritarian political order and embedded in the informal control stratagems used by Egyptian governments to bolster their rule. Informal Cairo should thus not be understood as a disorderly zone of subaltern dissidence. Rather, the Egyptian state is best seen as facing its own oblique reflection