Impact of genomic testing and patient-reported outcomes on receipt of adjuvant chemotherapy

Practice guidelines incorporate genomic tumor profiling, using results such as the Oncotype DX Recurrence Score (RS), to refine recurrence risk estimates for the large proportion of breast cancer patients with early-stage, estrogen receptor-positive disease. We sought to understand the impact of receiving genomic recurrence risk estimates on breast cancer patients’ well-being and the impact of these patient-reported outcomes on receipt of adjuvant chemotherapy. Participants were 193 women (mean age 57) newly diagnosed with early-stage breast cancer. Women were interviewed before and 2–3 weeks after receiving the RS result between 2011 and 2015. We assessed subsequent receipt of chemotherapy from chart review. After receiving their RS, perceived pros (t = 4.27, P < .001) and cons (t = 8.54, P <.001) of chemotherapy increased from pre-test to post-test, while perceived risk of breast cancer recurrence decreased (t = 2.90, P = .004). Women with high RS tumors were more likely to receive chemotherapy than women with low RS tumors (88 vs. 5 %, OR 0.01, 0.00–0.02, P < .001). Higher distress (OR 2.19, 95 % CI 1.05–4.57, P < .05) and lower perceived cons of chemotherapy (OR 0.50, 95 % CI 0.26–0.97, P < .05) also predicted receipt of chemotherapy. Distressed patients who saw few downsides of chemotherapy received this treatment. Clinicians should consider these factors when discussing chemotherapy with breast cancer patients

Attenuation of RNA polymerase II pausing mitigates BRCA1-associated R-loop accumulation and tumorigenesis.

Most BRCA1-associated breast tumours are basal-like yet originate from luminal progenitors. BRCA1 is best known for its functions in double-strand break repair and resolution of DNA replication stress. However, it is unclear whether loss of these ubiquitously important functions fully explains the cell lineage-specific tumorigenesis. In vitro studies implicate BRCA1 in elimination of R-loops, DNA-RNA hybrid structures involved in transcription and genetic instability. Here we show that R-loops accumulate preferentially in breast luminal epithelial cells, not in basal epithelial or stromal cells, of BRCA1 mutation carriers. Furthermore, R-loops are enriched at the 5' end of those genes with promoter-proximal RNA polymerase II (Pol II) pausing. Genetic ablation of Cobra1, which encodes a Pol II-pausing and BRCA1-binding protein, ameliorates R-loop accumulation and reduces tumorigenesis in Brca1-knockout mouse mammary epithelium. Our studies show that Pol II pausing is an important contributor to BRCA1-associated R-loop accumulation and breast cancer development

Psychosocial and Quality of Life in Women Receiving the 21-Gene Recurrence Score Assay: The Impact of Decision Style in Women with Intermediate RS

Multigene assays such as the 21-gene recurrence score (RS) quantify risk for recurrence and potential benefit from chemotherapy in early-stage, ER+ breast cancers. Few studies have assessed the impact of testing on patient-reported outcomes such as cancer-related distress or quality of life. The few studies that have assessed these outcomes do not consider potential modifiers, such as the patients’ level of involvement in the treatment decision-making process. In the current study, 81 breast cancer patients who received the RS assay completed cross-sectional surveys. We used linear multiple regression to assess whether test result, decision-making role (passive versus shared/active), and their interaction contributed to current levels of distress, quality of life, and decisional conflict. There were no associations between these variables and test result or decision-making role. However, women who received an intermediate RS and took a passive role in their care reported higher-cancer-related distress and cancer worry and lower quality of life than those who took a shared or active role. These data should be confirmed in prospective samples, as these poorer outcomes could be amenable to intervention

The effect of S-substitution at the O6-guanine site on the structure and dynamics of a DNA oligomer containing a G:T mismatch

The effect of S-substitution on the O6 guanine site of a 13-mer DNA duplex containing a G:T mismatch is studied using molecular dynamics. The structure, dynamic evolution and hydration of the S-substituted duplex are compared with those of a normal duplex, a duplex with Ssubstitution on guanine, but no mismatch and a duplex with just a G:T mismatch. The S-substituted mismatch leads to cell death rather than repair. One suggestion is that the G:T mismatch recognition protein recognises the S-substituted mismatch (GS:T) as G:T. This leads to a cycle of futile repair ending in DNA breakage and cell death. We find that some structural features of the helix are similar for the duplex with the G:T mismatch and that with the S-substituted mismatch, but differ from the normal duplex, notably the helical twist. These differences arise from the change in the hydrogen-bonding pattern of the base pair. However a marked feature of the S-substituted G:T mismatch duplex is a very large opening. This showed considerable variability. It is suggested that this enlarged opening would lend support to an alternative model of cell death in which the mismatch protein attaches to thioguanine and activates downstream damage-response pathways. Attack on the sulphur by reactive oxygen species, also leading to cell death, would also be aided by the large, variable opening

Rapid progression of prostate cancer in men with a BRCA2 mutation.

Men with BRCA2 mutations have been found to be at increased risk of developing prostate cancer. There is a recent report that BRCA2 carriers with prostate cancer have poorer survival than noncarrier prostate cancer patients. In this study, we compared survival of men with a BRCA2 mutation and prostate cancer with that of men with a BRCA1 mutation and prostate cancer. We obtained the age at diagnosis, age at death or current age from 182 men with prostate cancer from families with a BRCA2 mutation and from 119 men with prostate cancer from families with a BRCA1 mutation. The median survival from diagnosis was 4.0 years for men with a BRCA2 mutation vs 8.0 years for men with a BRCA1 mutation, and the difference was highly significant (P&lt;0.01). It may be important to develop targeted chemotherapies to treat prostate cancer in men with a BRCA2 mutation

A Comparison of Bilateral Breast Cancers in <i>BRCA</i> Carriers

Abstract Background: Women with breast cancer and a BRCA mutation have a high risk of developing a contralateral breast cancer. It is generally believed that the two cancers represent independent events. However, the extent of concordance between the first and second tumors with respect to hormone receptor expression and other pathologic features is unknown. Purpose: To determine the degree of concordance of estrogen receptor (ER) status, tumor grade, and histology in tumors from women with bilateral breast cancer and a BRCA mutation. Subjects and Methods: Women with a history of bilateral invasive breast cancers were selected from an international registry of women with BRCA1 or BRCA2 mutations. Medical records were reviewed to document the characteristics of each cancer and the treatments received. Results: Data were available for 286 women with bilateral breast cancer and a BRCA mutation (211 BRCA1; 75 BRCA2). The mean interval between first and second tumor was 5.1 years. The two tumors were concordant more often than expected for ER status (P &lt; 0.0001) and for grade (P &lt; 0.0001), but not for histology (P = 0.55). The ER status of the first tumor was highly predictive of the ER status of the second tumor (odds ratio, 8.7; 95% confidence interval, 3.5-21.5; P &lt; 0.0001). Neither age, menopausal status, oophorectomy nor tamoxifen use was predictive of the ER status of the second tumor. Conclusions: There is strong concordance in ER status and tumor grade between independent primary breast tumors in women with a BRCA mutation. The excess concordance may be due to common risk factors, genetic variation, or the existence of a preneoplastic lesion that is common to both tumors

Plasma levels of interleukin-6 mediate neurocognitive performance in older breast cancer survivors: The Thinking and Living With Cancer study.

BACKGROUND: Immune activation/inflammation markers (immune markers) were tested to explain differences in neurocognition among older breast cancer survivors versus noncancer controls. METHODS: Women &gt;60&nbsp;years old with primary breast cancer (stages 0-III) (n&nbsp;=&nbsp;400) were assessed before systemic therapy with frequency-matched controls (n&nbsp;=&nbsp;329) and followed annually to 60 months; blood was collected during annual assessments from 2016 to 2020. Neurocognition was measured by tests of attention, processing speed, and executive function (APE). Plasma levels of interleukin-6 (IL-6), IL-8, IL-10, tumor necrosis factor α (TNF-α), and interferon γ were determined using multiplex testing. Mixed linear models were used to compare results of immune marker levels by survivor/control group by time and by controlling for age, racial/ethnic group, cognitive reserve, and study site. Covariate-adjusted multilevel mediation analyses tested whether survivor/control group effects on cognition were explained by immune markers; secondary analyses examined the impact of additional covariates (e.g., comorbidity and obesity) on mediation effects. RESULTS: Participants were aged 60-90&nbsp;years (mean, 67.7&nbsp;years). Most survivors had stage I (60.9%) estrogen receptor-positive tumors (87.6%). Survivors had significantly higher IL-6 levels than controls before systemic therapy and at 12, 24, and 60 months (p&nbsp;≤&nbsp;.001-.014) but there were no differences for other markers. Survivors had lower adjusted APE scores than controls (p&nbsp;&lt;&nbsp;.05). Levels of IL-6, IL-10, and TNF-α were related to APE, with IL-6 explaining part of the relationship between survivor/control group and APE (p&nbsp;=&nbsp;.01). The magnitude of this mediation effect decreased but remained significant (p&nbsp;=&nbsp;.047) after the consideration of additional covariates. CONCLUSIONS: Older breast cancer survivors had worse long-term neurocognitive performance than controls, and this relationship was explained in part by elevated IL-6