The molecular etiology of breast cancer has proven to be remarkably complex. Most individual oncogenes are disregulated in only approximately 30% of breast tumors, indicating that either very few ...molecular alterations are common to the majority of breast cancers, or that they have not yet been identified. In striking contrast, we now show that 19 of 19 stage I breast tumors tested with the functional unscheduled DNA synthesis assay exhibited a significant deficiency of DNA nucleotide excision repair (NER) capacity relative to normal epithelial tissue from disease-free controls (n = 23). Loss of DNA repair capacity, including the complex, damage-comprehensive NER pathway, results in genomic instability, a hallmark of carcinogenesis. By microarray analysis, mRNA expression levels for 20 canonical NER genes were reduced in representative tumor samples versus normal. Significant reductions were observed in 19 of these genes analyzed by the more sensitive method of RNase protection. These results were confirmed at the protein level for five NER gene products. Taken together, these data suggest that NER deficiency may play an important role in the etiology of sporadic breast cancer, and that early-stage breast cancer may be intrinsically susceptible to genotoxic chemotherapeutic agents, such as cis-platinum, whose damage is remediated by NER. In addition, reduced NER capacity, or reduced expression of NER genes, could provide a basis for the development of biomarkers for the identification of tumorigenic breast epithelium.
Tamoxifen has been approved for breast cancer risk reduction in high-risk women, but how raloxifene compares with tamoxifen is unknown.
To compare the differences in patient-reported outcomes, ...quality of life QOL, and symptoms in Study of Tamoxifen and Raloxifene (STAR) participants by treatment assignment.
STAR was a double-blind, randomized phase 3 prevention trial designed to evaluate the relative efficacy of raloxifene vs tamoxifen in reducing the incidence of invasive breast cancer in high-risk postmenopausal women. Between July 1, 1999, and November 4, 2004, 19,747 participants were enrolled at centers throughout North America, with a median potential follow-up time of 4.6 years (range, 1.2-6.5 years). Patient-reported symptoms were collected from all participants using a 36-item symptom checklist. Quality of life was measured with the Medical Outcomes Study Short-Form Health Survey (SF-36), the Center for Epidemiologic Studies-Depression (CES-D), and the Medical Outcomes Study Sexual Activity Questionnaire in a substudy of 1983 participants, median potential follow-up 5.4 years (range, 4.6-6.0 years). Questionnaires were administered before treatment, every 6 months for 60 months and at 72 months.
Primary QOL end points were the SF-36 physical (PCS) and mental (MCS) component summaries.
Among women in the QOL analysis, mean PCS, MCS, and CES-D scores worsened modestly over the study's 60 months, with no significant difference between the tamoxifen (n = 973) and raloxifene (n = 1010) groups (P>.2). Sexual function was slightly better for participants assigned to tamoxifen (age-adjusted repeated measure odds ratio, 1.22%; 95% CI, 1.01-1.46). Of the women in the symptom assessment analyses, the 9769 in the raloxifene group reported greater mean symptom severity over 60 months of assessments than the 9743 in the tamoxifen group for musculoskeletal problems (1.15 vs 1.10, P = .002), dyspareunia (0.78 vs 0.68, P<.001), and weight gain (0.82 vs 0.76, P<.001). Women in the tamoxifen group reported greater mean symptom severity for gynecological problems (0.29 vs 0.19, P<.001), vasomotor symptoms (0.96 vs 0.85, P<.001), leg cramps (1.10 vs 0.91, P<.001), and bladder control symptoms (0.88 vs 0.73, P<.001).
No significant differences existed between the tamoxifen and raloxifene groups in patient-reported outcomes for physical health, mental health, and depression, although the tamoxifen group reported better sexual function. Although mean symptom severity was low among these postmenopausal women, those in the tamoxifen group reported more gynecological problems, vasomotor symptoms, leg cramps, and bladder control problems, whereas women in the raloxifene group reported more musculoskeletal problems, dyspareunia, and weight gain.
clinicaltrials.gov Identifier: NCT00003906.
Older adults with advanced cancer who have high pretreatment symptom severity often experience adverse events during cancer treatments. Unsupervised machine learning may help stratify patients into ...different risk groups.
To evaluate whether clusters identified from baseline patient-reported symptom severity were associated with adverse outcomes.
This secondary analysis of the Geriatric Assessment Intervention for Reducing Toxicity in Older Patients With Advanced Cancer (GAP70+) Trial (2014-2019) included patients who completed the National Cancer Institute Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) before starting a new cancer treatment regimen and received care at community oncology sites across the United States. An unsupervised machine learning algorithm (k-means with Euclidean distance) clustered patients based on similarities of baseline symptom severities. Clustering variables included severity items of 24 PRO-CTCAE symptoms (range, 0-4; corresponding to none, mild, moderate, severe, and very severe). Total severity score was calculated as the sum of 24 items (range, 0-96). Whether the clusters were associated with unplanned hospitalization, death, and toxic effects was then examined. Analyses were conducted in January and February 2022.
Symptom severity.
Unplanned hospitalization over 3 months (primary), all-cause mortality over 1 year, and any clinician-rated grade 3 to 5 toxic effect over 3 months.
Of 718 enrolled patients, 706 completed baseline PRO-CTCAE and were included (mean SD age, 77.2 5.5 years, 401 56.8% male patients; 51 7.2% Black and 619 87.8% non-Hispanic White patients; 245 34.7% with gastrointestinal cancer; 175 24.8% with lung cancer; mean SD impaired Geriatric Assessment domains, 4.5 1.6). The algorithm classified 310 (43.9%), 295 (41.8%), and 101 (14.3%) into low-, medium-, and high-severity clusters (within-cluster mean SD severity scores: low, 6.3 3.4; moderate, 16.6 4.3; high, 29.8 7.8; P < .001). Controlling for sociodemographic variables, clinical factors, study group, and practice site, compared with patients in the low-severity cluster, those in the moderate-severity cluster were more likely to experience hospitalization (risk ratio, 1.36; 95% CI, 1.01-1.84; P = .046). Moderate- and high-severity clusters were associated with a higher risk of death (moderate: hazard ratio, 1.31; 95% CI, 1.01-1.69; P = .04; high: hazard ratio, 2.00; 95% CI, 1.43-2.78; P < .001), but not toxic effects.
In this study, unsupervised machine learning partitioned patients into distinct symptom severity clusters; patients with higher pretreatment severity were more likely to experience hospitalization and death.
ClinicalTrials.gov Identifier: NCT02054741.
Oncologists estimate patients' prognosis to guide care. Evidence suggests oncologists tend to overestimate life expectancy, which can lead to care with questionable benefits. Information obtained ...from geriatric assessment may improve prognostication for older adults. In this study, we created a geriatric assessment-based prognostic model for older adults with advanced cancer and compared its performance to alternative models.
We conducted a secondary analysis of a trial (URCC 13070; PI: Mohile) capturing geriatric assessment and vital status up to one year for adults age ≥ 70 years with advanced cancer. Oncologists estimated life expectancy as 0–6 months, 7–12 months, and > 1 year. Three statistical models were developed: (1) a model including age, sex, cancer type, and stage (basic model), (2) basic model + Karnofsky Performance Status (≤50, 60–70, and 80+) (KPS model), and (3) basic model +16 binary indicators of geriatric assessment impairments (GA model). Cox regression was used to model one-year survival; c-indices and time-dependent c-statistics assessed model discrimination and stratified survival curves assessed model calibration.
We included 484 participants; mean age was 75; 48% had gastrointestinal or lung cancer. Overall, 43% of patients died within one year. Oncologists classified prognosis accurately for 55% of patients, overestimated for 35%, and underestimated for 10%. C-indices were 0.61 (basic model), 0.62 (KPS model), and 0.63 (GA model). The GA model was well-calibrated.
The GA model showed moderate discrimination for survival, similar to alternative models, but calibration was improved. Further research is needed to optimize geriatric assessment-based prognostic models for use in older adults with advanced cancer.
Laboratory and epidemiologic evidence suggest that nonsteroidal anti-inflammatory drug (NSAID) use may be inversely related to the risk of breast cancer; however, the mechanism by which NSAIDs may ...protect against the development of this disease is uncertain. The objective of this observational study was to assess the relationship between current NSAID use and endogenous estradiol levels, an established breast cancer risk factor. To evaluate this aim, we conducted a cross-sectional investigation among 260 postmenopausal women who were not recently exposed to exogenous hormones. Information on current NSAID use (aspirin, cyclooxygenase-2 inhibitors, and other NSAIDs combined) was collected using a questionnaire at the time of blood draw. Estradiol was quantified in serum by radioimmunoassay. General linear models were used to evaluate the association between NSAID use and serum total estradiol. The age-adjusted and body mass index-adjusted geometric mean serum estradiol concentration among NSAID users (n = 124) was significantly lower than nonusers of NSAIDs (n = 136; 17.8 versus 21.3 pmol/L; P = 0.03). Further adjustment for additional potential confounding factors did not substantially alter estimates (17.7 versus 21.2 pmol/L; P = 0.03). To our knowledge, this report is the first to examine the relationship between NSAID use and serum estradiol in postmenopausal women. These cross-sectional findings suggest that NSAID use may be associated with lower circulating estradiol levels, potentially representing one mechanism through which NSAIDs exert protective effects on breast cancer.
Oncologists have a critical opportunity to utilize risk assessment and cancer prevention strategies to interrupt the initiation or progression of cancer in cancer survivors and individuals at high ...risk of developing cancer. Expanding knowledge about the natural history and prognosis of cancers positions oncologists to advise patients regarding the risk of second malignancies and treatment-related cancers. In addition, as recognized experts in the full spectrum of cancer care, oncologists are afforded opportunities for involvement in community-based cancer prevention activities. Although oncologists are currently providing many cancer prevention and risk assessment services to their patients, economic barriers exist, including inadequate or lack of insurance, that may compromise uniform patient access to these services. Additionally, insufficient reimbursement for existing and developing interventions may discourage patient access to these services. The American Society of Clinical Oncology (ASCO), the medical society representing cancer specialists involved in patient care and clinical research, is committed to supporting oncologists in their wide-ranging involvement in cancer prevention. This statement on risk assessment and prevention counseling, although not intended to be a comprehensive overview of cancer prevention describes the current role of oncologists in risk assessment and prevention; provides examples of risk assessment and prevention activities that should be offered by oncologists; identifies potential opportunities for coordination between oncologists and primary care physicians in prevention education and coordination of care for cancer survivors; describes ASCO's involvement in education and training of oncologists regarding prevention; and proposes improvement in the payment environment to encourage patient access to these services.
Caregiver-oncologist concordance regarding the patient's prognosis is associated with worse caregiver outcomes (e.g., depressive symptoms), but mechanisms underpinning these associations are unclear. ...We explored whether caregiving esteem mediates these associations.
At enrollment, caregivers and oncologists used a 5-point ordinal scale to estimate patient survival; identical responses were considered concordant. At 4–6 weeks, caregivers completed an assessment of the extent to which caregiving imparts self-esteem (Caregiver Reaction Assessment self-esteem subscale; range 0–5; higher score indicates greater esteem). They also completed Patient Health Questionnaire-2 (PHQ-2) for depressive symptoms, Distress Thermometer, and 12-Item Short Form Survey for quality of life (QoL). Mediation analysis with bootstrapping (PROCESS macro by Hayes) was used to estimate the extent to which caregiving mediated the effects of prognostic concordance on caregiver outcomes through caregiving esteem.
Prognostic concordance occurred in 28% the caregiver-oncologist dyads; 85% of the discordance were due to caregivers estimating a longer patient's survival. At 4–6 weeks, mean caregiving esteem score was 4.4 (range 1.5–5.0). Lower caregiving esteem mediated the associations of concordance with higher PHQ-2 indirect effect = 0.12; 95% Confidence Interval (CI) 0.03, 0.27, greater distress (indirect effect =0.25; 95% CI 0.08, 0.48), and poorer QoL (indirect effect = −1.50; 95% CI −3.06, −0.41). Caregiving esteem partially mediated 39%, 64%, and 48% of the associations between caregiver-oncologist concordance and PHQ-2, distress, and SF-12, respectively.
Caregiver-oncologist concordance was associated with lower caregiving esteem. Lower caregiving esteem mediated the negative relationship between caregiver-oncologist concordance and caregiver outcomes.
Risk for breast cancer can be easily and rapidly assessed using validated, quantitative models. Multiple randomized studies show that the selective estrogen response modifiers (SERMs) tamoxifen and ...raloxifene can safely reduce the risk of invasive breast cancer in both pre- and postmenopausal women. Treatment resulted in a 38% reduction in breast cancer incidence, and 42 women would need to be treated to prevent one breast cancer event in the first 10 years of follow-up. Reduction was larger in the first 5 years of follow-up than in years 5 to 10, but no studies treated patients for longer than 5 years. Thromboembolic events were significantly increased with all SERMs, whereas vertebral fractures were reduced. Tamoxifen provides net benefit to all premenopausal women who are at increased risk, whereas raloxifene reduces risk nearly as much in postmenopausal women and offers increased safety. Both tamoxifen and raloxifene reduce the incidence of in situ cancers. Lasofoxifene reduced the risk of breast cancer by 79% in postmenopausal women with osteoporosis. The MAP3 trial showed a 65% reduction in the annual incidence of invasive breast cancer in postmenopausal women who were at moderately increased risk for breast cancer who took the aromatase inhibitor exemestane. The IBIS-II trial showed a 53% reduction in the risk of invasive breast cancer in postmenopausal women aged 40 to 70 who took the aromatase inhibitor anastrozole. Of the 50 million white women in the United States aged 35 to 79, 2.4 million would have a positive benefit/risk index for chemoprevention.
The present study was undertaken to gain insights into the molecular mechanism of cell death (apoptosis) by guggulsterone, a constituent of Ayurvedic medicinal plant Commiphora mukul, using PC-3 ...human prostate cancer cells as a model. The viability of PC-3 cells, but not a normal prostate epithelial cell line (PrEC), was reduced significantly on treatment with guggulsterone in a concentration-dependent manner. Guggulsterone-mediated suppression of PC-3 cell proliferation was not due to perturbation in cell cycle progression but caused by apoptosis induction characterized by appearance of subdiploid cells and cytoplasmic histone-associated DNA fragmentation. Guggulsterone-induced apoptosis was associated with induction of multidomain proapoptotic Bcl-2 family members Bax and Bak. Interestingly, the expression of antiapoptotic proteins Bcl-2 and Bcl-xL was initially increased in guggulsterone-treated PC-3 cells but declined markedly following a 16- to 24-hour treatment with guggulsterone. Ectopic expression of Bcl-2 in PC-3 cells failed to confer significant protection against guggulsterone-induced cell death. On the other hand, SV40 immortalized mouse embryonic fibroblasts derived from Bax-Bak double knockout mice were significantly more resistant to guggulsterone-induced cell killing compared with wild-type cells. Guggulsterone treatment resulted in cleavage (activation) of caspase-9, caspase-8, and caspase-3, and guggulsterone-induced cell death was significantly attenuated in the presence of general caspase inhibitor as well as specific inhibitors of caspase-9 and caspase-8. In conclusion, the present study indicates that caspase-dependent apoptosis by guggulsterone is mediated in part by Bax and Bak.
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