Pathogenic variants (PVs) in
are relatively common, but the scope and magnitude of risk remains uncertain. This study aimed to estimate
PV cancer risks independent of family cancer history. This ...analysis included patients referred for hereditary cancer testing with a multi-gene panel (
= 627,742). Cancer risks for
PV carriers (
= 4,607) were adjusted for family history using multivariable logistic regression and reported as ORs with 95% confidence intervals (CIs). Subanalyses of the c.7271T>G missense PV were conducted. Moderate-to-high risks for pancreatic (OR, 4.21; 95% CI, 3.24-5.47), prostate (OR, 2.58; 95% CI, 1.93-3.44), gastric (OR, 2.97; 95% CI, 1.66-5.31), and invasive ductal breast (OR, 2.03; 95% CI, 1.89-2.19) cancers were estimated for
PV carriers. Notably, c.7271T>G was associated with higher invasive ductal breast cancer risk (OR, 3.76; 95% CI, 2.76-5.12) than other missense and truncating
PVs. Low-to-moderate risks were seen for ductal carcinoma
(OR, 1.80; 95% CI, 1.61-2.02), male breast cancer (OR, 1.72; 95% CI, 1.08-2.75), ovarian cancer (OR, 1.57; 95% CI, 1.35-1.83), colorectal cancer (OR, 1.49; 95% CI, 1.24-1.79), and melanoma (OR, 1.46; 95% CI, 1.18-1.81).
PVs are associated with multiple cancer risks and, while professional society guidelines support that carriers are eligible for increased breast and pancreatic cancer screening, increased screening for prostate and gastric cancer may also be warranted. c.7271T>G is associated with high risk for breast cancer, with a 3- to 4-fold risk increase that supports consideration of strategies for prevention and/or early detection. PREVENTION RELEVANCE: This study estimated risks for multiple cancers associated with
pathogenic variants independent of family history. These results indicate that some common variants may be associated with higher breast cancer risks than previously appreciated and increased screening for prostate and gastric cancer may be warranted for carriers of
pathogenic variants.
The practice of genetic testing for hereditary breast and/or ovarian cancer (HBOC) is rapidly evolving owing to the recent introduction of multigene panels. While these tests may identify 40% to 50% ...more individuals with hereditary cancer gene mutations than does testing for BRCA1/2 alone, whether finding such mutations will alter clinical management is unknown.
To define the potential clinical effect of multigene panel testing for HBOC in a clinically representative cohort.
Observational study of patients seen between 2001 and 2014 in 3 large academic medical centers. We prospectively enrolled 1046 individuals who were appropriate candidates for HBOC evaluation and who lacked BRCA1/2 mutations.
We carried out multigene panel testing on all participants, then determined the clinical actionability, if any, of finding non-BRCA1/2 mutations in these and additional comparable individuals.
We evaluated the likelihood of (1) a posttest management change and (2) an indication for additional familial testing, considering gene-specific consensus management guidelines, gene-associated cancer risks, and personal and family history.
Among 1046 study participants, 40 BRCA1/2-negative patients (3.8%; 95% CI, 2.8%-5.2%) harbored deleterious mutations, most commonly in moderate-risk breast and ovarian cancer genes (CHEK2, ATM, and PALB2) and Lynch syndrome genes. Among these and an additional 23 mutation-positive individuals enrolled from our clinics, most of the mutations (92%) were consistent with the spectrum of cancer(s) observed in the patient or family, suggesting that these results are clinically significant. Among all 63 mutation-positive patients, additional disease-specific screening and/or prevention measures beyond those based on personal and family history alone would be considered for most (33 52% of 63; 95% CI, 40.3%-64.2%). Furthermore, additional familial testing would be considered for those with first-degree relatives (42 72% of 58; 95% CI, 59.8%-82.2%) based on potential management changes for mutation-positive relatives. This clinical effect was not restricted to a few of the tested genes because most identified genes could change clinical management for some patients.
In a clinically representative cohort, multigene panel testing for HBOC risk assessment yielded findings likely to change clinical management for substantially more patients than does BRCA1/2 testing alone. Multigene testing in this setting is likely to alter near-term cancer risk assessment and management recommendations for mutation-affected individuals across a broad spectrum of cancer predisposition genes.
IMPORTANCE: Contralateral prophylactic mastectomy (CPM) use is increasing among women with unilateral breast cancer, but little is known about treatment decision making or physician interactions in ...diverse patient populations. OBJECTIVE: To evaluate patient motivations, knowledge, and decisions, as well as the impact of surgeon recommendations, in a large, diverse sample of patients who underwent recent treatment for breast cancer. DESIGN, SETTING, AND PARTICIPANTS: A survey was sent to 3631 women with newly diagnosed, unilateral stage 0, I, or II breast cancer between July 2013 and September 2014. Women were identified through the population-based Surveillance Epidemiology and End Results registries of Los Angeles County and Georgia. Data on surgical decisions, motivations for those decisions, and knowledge were included in the analysis. Logistic and multinomial logistic regression of the data were conducted to identify factors associated with (1) CPM vs all other treatments combined, (2) CPM vs unilateral mastectomy (UM), and (3) CPM vs breast-conserving surgery (BCS). Associations between CPM receipt and surgeon recommendations were also evaluated. All statistical models and summary estimates were weighted to be representative of the target population. MAIN OUTCOMES AND MEASURES: Receipt of CPM was the primary dependent variable for analysis and was measured by a woman’s self-report of her treatment. RESULTS: Of the 3631 women selected to receive the survey, 2578 (71.0%) responded and 2402 of these respondents who did not have bilateral disease and for whom surgery type was known constituted the final analytic sample. The mean (SD) age was 61.8 (12) years at the time of the survey. Overall, 1301 (43.9%) patients considered CPM (601 24.8% considered it very strongly or strongly); only 395 (38.1%) of them knew that CPM does not improve survival for all women with breast cancer. Ultimately, 1466 women (61.6%) received BCS, 508 (21.2%) underwent UM, and 428 (17.3%) received CPM. On multivariable analysis, factors associated with CPM included younger age (per 5-year increase: odds ratio OR, 0.71; 95% CI, 0.65-0.77), white race (black vs white: OR, 0.50; 95% CI, 0.34-0.74), higher educational level (OR, 1.69; 95% CI, 1.20-2.40), family history (OR, 1.63; 95% CI, 1.22-2.17), and private insurance (Medicaid vs private insurance: OR, 0.47; 95% CI, 0.28-0.79). Among 1569 patients (65.5%) without high genetic risk or an identified mutation, 598 (39.3%) reported a surgeon recommendation against CPM, of whom only 12 (1.9%) underwent CPM, but among the 746 (46.8%) of these women who received no recommendation for or against CPM from a surgeon, 148 (19.0%) underwent CPM. CONCLUSIONS AND RELEVANCE: Many patients consider CPM, but knowledge about the procedure is low and discussions with surgeons appear to be incomplete. Contralateral prophylactic mastectomy use is substantial among patients without clinical indications but is low when patients report that their surgeon recommended against it. More effective physician-patient communication about CPM is needed to reduce potential overtreatment.
Background
Extending endocrine therapy from 5 to 10 years is recommended for women with invasive estrogen receptor (ER)‐positive breast cancers. We evaluated the benefits and harms of the five ...additional years of therapy.
Methods
An established Cancer Intervention and Surveillance Network (CISNET) model used a lifetime horizon with national and clinical trial data on treatment efficacy and adverse events and other‐cause mortality among multiple birth cohorts of U.S. women ages 25–79 newly diagnosed with ER+, non‐metastatic breast cancer. We assumed 100% use of therapy. Outcomes included life years (LYs), quality‐adjusted life years (QALYs), and breast cancer mortality. Results were discounted at 3%. Sensitivity analyses tested a 15‐year time horizon and alternative assumptions.
Results
Extending tamoxifen therapy duration among women ages 25–49 reduced the lifetime probability of breast cancer death from 11.9% to 9.3% (absolute difference 2.6%). This translates to a gain of 0.77 LYs (281 days)/woman (undiscounted). Adverse events reduce this gain to 0.44 QALYs and after discounting, gains are 0.20 QALYs (73 days)/woman. Extended aromatase inhibitor therapy in women 50–79 had small absolute benefits and gains were offset by adverse events (loss of 0.06 discounted QALYs). There were greater gains with extended endocrine therapy for women with node‐positive versus negative cancers, but only women ages 25–49 and 50–59 had a net QALY gain. All gains were reduced with less than 100% treatment completion.
Conclusion
The extension of endocrine therapy from 5 to 10 years modestly improved lifetime breast cancer outcomes, but in some women, treatment‐related adverse events may outweigh benefits.
Simulation modeling was used to evaluate extended endocrine therapy for women with hormone receptor‐positive non‐metastatic breast cancer. Results indicate that extension of endocrine therapy from 5 to 10 years modestly improves life years in some groups but adverse events may outweigh benefits.
Genetic testing is important for breast and ovarian cancer risk reduction and treatment, yet little is known about its evolving use.
SEER records of women of age ≥ 20 years diagnosed with breast or ...ovarian cancer from 2013 to 2017 in California or Georgia were linked to the results of clinical germline testing through 2019. We measured testing trends, rates of variants of uncertain significance (VUS), and pathogenic variants (PVs).
One quarter (25.2%) of 187,535 patients with breast cancer and one third (34.3%) of 14,689 patients with ovarian cancer were tested; annually, testing increased by 2%, whereas the number of genes tested increased by 28%. The prevalence of test results by gene category for breast cancer cases in 2017 were
PVs 5.2%, and VUS 0.8%; breast cancer-associated genes or ovarian cancer-associated genes (
and
), PVs 3.7%, and VUS 12.0%; other actionable genes (
and
) PVs 0.6%, and VUS 0.5%; and other genes, PVs 0.3%, and VUS 2.6%. For ovarian cancer cases in 2017, the prevalence of test results were
, PVs 11.0%, and VUS 0.9%; breast or ovarian genes, PVs 4.0%, and VUS 12.6%; other actionable genes, PVs 0.7%, and VUS 0.4%; and other genes, PVs 0.3%, and VUS 0.6%. VUS rates doubled over time (2013 diagnoses: 11.2%; 2017 diagnoses: 26.8%), particularly for racial or ethnic minorities (47.8% Asian and 46.0% Black,
24.6% non-Hispanic White patients;
< .001).
A testing gap persists for patients with ovarian cancer (34.3% tested
nearly all recommended), whereas adding more genes widened a racial or ethnic gap in VUS results. Most PVs were in 20 breast cancer-associated genes or ovarian cancer-associated genes; testing other genes yielded mostly VUS. Quality improvement should focus on testing indicated patients rather than adding more genes.
IMPORTANCE: Bilateral mastectomy is increasingly used to treat unilateral breast cancer. Because it may have medical and psychosocial complications, a better understanding of its use and outcomes is ...essential to optimizing cancer care. OBJECTIVE: To compare use of and mortality after bilateral mastectomy, breast-conserving therapy with radiation, and unilateral mastectomy. DESIGN, SETTING, AND PARTICIPANTS: Observational cohort study within the population-based California Cancer Registry; participants were women diagnosed with stages 0-III unilateral breast cancer in California from 1998 through 2011, with median follow-up of 89.1 months. MAIN OUTCOMES AND MEASURES: Factors associated with surgery use (from polytomous logistic regression); overall and breast cancer–specific mortality (from propensity score weighting and Cox proportional hazards analysis). RESULTS: Among 189 734 patients, the rate of bilateral mastectomy increased from 2.0% (95% CI, 1.7%-2.2%) in 1998 to 12.3% (95% CI, 11.8%-12.9%) in 2011, an annual increase of 14.3% (95% CI, 13.1%-15.5%); among women younger than 40 years, the rate increased from 3.6% (95% CI, 2.3%-5.0%) in 1998 to 33% (95% CI, 29.8%-36.5%) in 2011. Bilateral mastectomy was more often used by non-Hispanic white women, those with private insurance, and those who received care at a National Cancer Institute (NCI)–designated cancer center (8.6% 95% CI, 8.1%-9.2% among NCI cancer center patients vs 6.0% 95% CI, 5.9%-6.1% among non-NCI cancer center patients; odds ratio OR, 1.13 95% CI, 1.04-1.22); in contrast, unilateral mastectomy was more often used by racial/ethnic minorities (Filipina, 52.8% 95% CI, 51.6%-54.0%; OR, 2.00 95% CI, 1.90-2.11 and Hispanic, 45.6% 95% CI, 45.0%-46.2%; OR, 1.16 95% CI, 1.13-1.20 vs non-Hispanic white, 35.2% 95% CI, 34.9%-35.5%) and those with public/Medicaid insurance (48.4% 95% CI, 47.8%-48.9%; OR, 1.08 95% CI, 1.05-1.11 vs private insurance, 36.6% 95% CI, 36.3%-36.8%). Compared with breast-conserving surgery with radiation (10-year mortality, 16.8% 95% CI, 16.6%-17.1%), unilateral mastectomy was associated with higher all-cause mortality (hazard ratio HR, 1.35 95% CI, 1.32-1.39; 10-year mortality, 20.1% 95% CI, 19.9%-20.4%). There was no significant mortality difference compared with bilateral mastectomy (HR, 1.02 95% CI, 0.94-1.11; 10-year mortality, 18.8% 95% CI, 18.6%-19.0%). Propensity analysis showed similar results. CONCLUSIONS AND RELEVANCE: Use of bilateral mastectomy increased significantly throughout California from 1998 through 2011 and was not associated with lower mortality than that achieved with breast-conserving surgery plus radiation. Unilateral mastectomy was associated with higher mortality than were the other 2 surgical options.
IMPORTANCE: Given recent advances in screening mammography and adjuvant therapy (treatment), quantifying their separate and combined effects on US breast cancer mortality reductions by molecular ...subtype could guide future decisions to reduce disease burden. OBJECTIVE: To evaluate the contributions associated with screening and treatment to breast cancer mortality reductions by molecular subtype based on estrogen-receptor (ER) and human epidermal growth factor receptor 2 (ERBB2, formerly HER2 or HER2/neu). DESIGN, SETTING, AND PARTICIPANTS: Six Cancer Intervention and Surveillance Network (CISNET) models simulated US breast cancer mortality from 2000 to 2012 using national data on plain-film and digital mammography patterns and performance, dissemination and efficacy of ER/ERBB2-specific treatment, and competing mortality. Multiple US birth cohorts were simulated. EXPOSURES: Screening mammography and treatment. MAIN OUTCOMES AND MEASURES: The models compared age-adjusted, overall, and ER/ERBB2-specific breast cancer mortality rates from 2000 to 2012 for women aged 30 to 79 years relative to the estimated mortality rate in the absence of screening and treatment (baseline rate); mortality reductions were apportioned to screening and treatment. RESULTS: In 2000, the estimated reduction in overall breast cancer mortality rate was 37% (model range, 27%-42%) relative to the estimated baseline rate in 2000 of 64 deaths (model range, 56-73) per 100 000 women: 44% (model range, 35%-60%) of this reduction was associated with screening and 56% (model range, 40%-65%) with treatment. In 2012, the estimated reduction in overall breast cancer mortality rate was 49% (model range, 39%-58%) relative to the estimated baseline rate in 2012 of 63 deaths (model range, 54-73) per 100 000 women: 37% (model range, 26%-51%) of this reduction was associated with screening and 63% (model range, 49%-74%) with treatment. Of the 63% associated with treatment, 31% (model range, 22%-37%) was associated with chemotherapy, 27% (model range, 18%-36%) with hormone therapy, and 4% (model range, 1%-6%) with trastuzumab. The estimated relative contributions associated with screening vs treatment varied by molecular subtype: for ER+/ERBB2−, 36% (model range, 24%-50%) vs 64% (model range, 50%-76%); for ER+/ERBB2+, 31% (model range, 23%-41%) vs 69% (model range, 59%-77%); for ER−/ERBB2+, 40% (model range, 34%-47%) vs 60% (model range, 53%-66%); and for ER−/ERBB2−, 48% (model range, 38%-57%) vs 52% (model range, 44%-62%). CONCLUSIONS AND RELEVANCE: In this simulation modeling study that projected trends in breast cancer mortality rates among US women, decreases in overall breast cancer mortality from 2000 to 2012 were associated with advances in screening and in adjuvant therapy, although the associations varied by breast cancer molecular subtype.
Breast cancer incidence is higher among black women than white women before age 40 years, but higher among white women than black women after age 40 years (black-white crossover). We used newly ...available population-based data to examine whether the age-specific incidences of breast cancer subtypes vary by race and ethnicity.
We classified 91908 invasive breast cancers diagnosed in California between January 1, 2006, and December 31, 2009, by subtype based on tumor expression of estrogen receptor (ER) and progesterone receptor (PR)-together referred to as hormone receptor (HR)-and human epidermal growth factor receptor 2 (HER2). Breast cancer subtypes were classified as ER or PR positive and HER2 negative (HR(+)/HER2(-)), ER or PR positive and HER2 positive (HR(+)/HER2(+)), ER and PR negative and HER2 positive (HR(-)/HER2(+)), and ER, PR, and HER2 negative (triple-negative). We calculated and compared age-specific incidence rates, incidence rate ratios, and 95% confidence intervals by subtype and race (black, white, Hispanic, and Asian). All P values are two-sided.
We did not observe an age-related black-white crossover in incidence for any molecular subtype of breast cancer. Compared with white women, black women had statistically significantly higher rates of triple-negative breast cancer at all ages but statistically significantly lower rates of HR(+)/HER2(-) breast cancers after age 35 years (all P < .05). The age-specific incidence of HR(+)/HER2(+) and HR(-)/HER2(+) subtypes did not vary markedly between white and black women.
The black-white crossover in breast cancer incidence occurs only when all breast cancer subtypes are combined and relates largely to higher rates of triple-negative breast cancers and lower rates of HR(+)/HER2(-) breast cancers in black vs white women.
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