Tumor mutational burden and PTEN alterations as molecular correlates of response to PD-1/L1 blockade in metastatic triple-negative breast cancer

Purpose: Few patients with metastatic triple-negative breast cancer (mTNBC) benefit from immune checkpoint inhibitors (ICI). On the basis of immunotherapy response correlates in other cancers, we evaluated whether high tumor mutational burden (TMB) ≥10 nonsynonymous mutations/megabase and PTEN alterations, defined as nonsynonymous mutations or 1 or 2 copy deletions, were associated with clinical benefit to anti-PD-1/L1 therapy in mTNBC. Experimental design: We identified patients with mTNBC, who consented to targeted DNA sequencing and were treated with ICIs on clinical trials between April 2014 and January 2019 at Dana-Farber Cancer Institute (Boston, MA). Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were correlated with tumor genomic features. Results: Sixty-two women received anti-PD-1/L1 inhibitors alone (23%) or combined with targeted therapy (19%) or chemotherapy (58%). High TMB (18%) was associated with significantly longer PFS (12.5 vs. 3.7 months; P = 0.04), while PTEN alterations (29%) were associated with significantly lower ORR (6% vs. 48%; P = 0.01), shorter PFS (2.3 vs. 6.1 months; P = 0.01), and shorter OS (9.7 vs. 20.5 months; P = 0.02). Multivariate analyses confirmed that these associations were independent of performance status, prior lines of therapy, therapy regimen, and visceral metastases. The survival associations were additionally independent of PD-L1 in patients with known PD-L1 and were not found in mTNBC cohorts treated with chemotherapy (n = 90) and non-ICI regimens (n = 169). Conclusions: Among patients with mTNBC treated with anti-PD-1/L1 therapies, high TMB and PTEN alterations were associated with longer and shorter survival, respectively. These observations warrant validation in larger datasets

Cancer Pathology Turnaround Time at Queen Elizabeth Central Hospital, the Largest Referral Center in Malawi for Oncology Patients

Purpose In all settings, a need exists for expedited pathology processing for patients with a suspected cancer diagnosis. In low- and middle-income countries (LMICs) with limited resources, processing pathology samples is particularly challenging, so the measurement of turnaround times (TATs) for pathology results is an important quality metric. We explored the pathology TAT for suspected cancer patients at Queen Elizabeth Central Hospital in Malawi to determine whether a difference exists when patients paid an out-of-pocket fee (paid for [PF] v nonpaid for [NPF]) to facilitate sample processing. Methods and Population This retrospective descriptive study included all patients with suspected cancer (N = 544) who underwent incisional and excisional biopsy in 2010 at Queen Elizabeth Central Hospital, a teaching hospital in Malawi. Data were abstracted from patient charts and administrative forms to build a database and determine the TAT for PF and NPF samples. Results: The median TAT for the 544 patients was 71 days (interquartile range [IQR], 31 to 118 days). The median pathology processing time was 31 days (IQR, 15 to 52 days) and was shorter for PF versus NPF samples. The median TAT was 43 days for PF samples (IQR, 27 to 69 days) versus 101 days for NPF samples (IQR, 31 to 118 days), which was significantly different by the Wilcoxon rank sum test (P < .01). Conclusion: The TAT for pathology samples among patients with suspected cancer was longer than reported for other African countries during the study period, was longer than considered acceptable in high-income countries, and differed between PF and NPF samples

Compulsory Licenses for Cancer Drugs: Does Circumventing Patent Rights Improve Access to Oncology Medications?

Worldwide, there are enormous inequities in cancer control that cause poor outcomes among patients with cancer who live in low- and middle-income countries (LMICs). One of the biggest challenges that oncology faces today is how to increase patient access to expensive, but life-saving, therapies in LMICs. Access to cancer medications in LMICs is a major problem, especially in recent years, as the costs of these therapies continue to rise exponentially. One mechanism available to LMICs to improve access to cancer medications allows a country to pursue a compulsory license for a given drug. Here, we will review how the legal framework in the World Trade Organization's Trade-Related Aspects of Intellectual Property Rights Agreement and the Doha Declaration supports countries to circumvent patent laws and acquire compulsory licenses for essential medicines. We will also discuss the current and future role of compulsory licenses in oncology and how compulsory licenses may improve access to cancer drugs in LMICs

Are rare cancer survivors at elevated risk of subsequent new cancers?

Abstract Background Although rare cancers account for 27% of cancer diagnoses in the US, there is insufficient research on survivorship issues in these patients. An important issue cancer survivors face is an elevated risk of being diagnosed with new primary cancers. The primary aim of this analysis was to assess whether a history of rare cancer increases the risk of subsequent cancer compared to survivors of common cancers. Methods This was a prospective cohort study of 16,630 adults with personal and/or family history of cancer who were recruited from cancer clinics at 14 geographically dispersed US academic centers of the NIH-sponsored Cancer Genetics Network (CGN). Participants’ self-reported cancer histories were collected at registration to the CGN and updated annually during follow-up. At enrollment, 14% of participants reported a prior rare cancer. Elevated risk was assessed via the cause-specific hazard ratio on the time to a subsequent cancer diagnosis. Results After a median follow-up of 7.9 years, relative to the participants who were unaffected at enrollment, those with a prior rare cancer had a 23% higher risk of subsequent cancer (95% CI: -1 to 52%), while those with a prior common cancer had no excess risk. Patients having two or more prior cancers were at a 53% elevated risk over those with fewer than two (95% CI: 21 to 94%) and if the multiple prior cancers were rare cancers, risk was further elevated by 47% (95% CI: 1 to 114%). Conclusion There is evidence suggesting that survivors of rare cancers, especially those with multiple cancer diagnoses, are at an increased risk of a subsequent cancer. There is a need to study this population more closely to better understand cancer pathogenesis

Cancer burden in individuals with single versus double pathogenic variants in cancer susceptibility genes

Purpose: As panel testing expands, more individuals with double pathogenic variants (DPVs) in cancer susceptibility genes are likely to be identified. Little is known about the effects of DPVs on cancer phenotype, although this information is crucial for genetic counseling and risk management. We sought to describe the cancer phenotype among individuals with DPVs in cancer susceptibility genes. Methods: A retrospective study of individuals with DPVs identified through a single testing laboratory from 2012 to 2017 was conducted. DPV combinations were enumerated. For DPV gene combinations that occurred >10 times, cancer histories of individuals with DPVs were compared with cancer histories of controls with a single PV matched by gene. Results: Among 644 individuals with DPVs, combinations that included the ATM, BRCA1, BRCA2, CHEK2, and PALB2 genes occurred >10 times. There were 8883 matched controls for a single PV in these genes. The median age of first cancer diagnosis was younger with ATM+CHEK2 (43), compared with ATM (47, P = .016) or CHEK2 (47, P = .015) alone. Similar findings were observed when comparing age at first breast cancer (BC) for the ATM+CHEK2 with single-gene controls. Individuals with 2 CHEK2 PVs also were younger at first cancer diagnosis (40) compared with single CHEK2 PV controls (47, P = .0038). This difference was not driven by age at first BC diagnosis among females. Conclusion: Individuals with ATM+CHEK2 or 2 CHEK2 PVs have a greater cancer burden than single gene controls. These findings can be used to counsel individuals with DPVs and their families and inform cancer screening recommendations

Inequities in referrals to a breast cancer risk assessment and prevention clinic: a mixed methods study

Abstract Background Inequitable access to personalized breast cancer screening and prevention may compound racial and ethnic disparities in outcomes. The Breast Cancer Personalized Risk Assessment, Education and Prevention (B-PREP) program, located within the Brigham and Women’s Hospital (BWH) Comprehensive Breast Health Center (BHC), provides care to patients at high risk for developing breast cancer. We sought to characterize the differences between BWH primary care patients referred specifically to B-PREP for risk evaluation and those referred to the BHC for benign breast conditions. Through interviews with primary care clinicians, we sought to explore contributors to potentially inequitable B-PREP referral patterns. Methods We used electronic health record data and the B-PREP clinical database to identify patients referred by primary care clinicians to the BHC or B-PREP between 2017 and 2020. We examined associations with likelihood of referral to B-PREP for risk assessment. Semi-structured interviews were conducted with nine primary care clinicians from six clinics to explore referral patterns. Results Of 1789 patients, 78.0% were referred for benign breast conditions, and 21.5% for risk assessment. In multivariable analyses, Black individuals were less likely to be referred for risk than for benign conditions (OR 0.38, 95% CI:0.23–0.63) as were those with Medicaid/Medicare (OR 0.72, 95% CI:0.53–0.98; OR 0.52, 95% CI:0.27–0.99) and those whose preferred language was not English (OR 0.26, 95% CI:0.12–0.57). Interviewed clinicians described inconsistent approaches to risk assessment and variable B-PREP awareness. Conclusions In this single-site evaluation, among individuals referred by primary care clinicians for specialized breast care, Black, publicly-insured patients, and those whose preferred language was not English were less likely to be referred for risk assessment. Larger studies are needed to confirm these findings. Interventions to standardize breast cancer risk assessment in primary care may improve equity