Validation Study on Risk-Reduction Activities after Exposure to a Personalized Breast Cancer Risk-Assessment Education Tool in High-Risk Women in the WISDOM Study.

We performed a 318-participant validation study of an individualized risk assessment tool in women identified as having high- or highest-risk of breast cancer in the personalized arm of the Women Informed to Screen Depending on Measures of risk (WISDOM) trial. Per protocol, these women were educated about their risk and risk reducing options using the Breast Health Decisions (BHD) tool, which uses patient-friendly visuals and 8th grade reading level language to convey risk and prevention options. Prior to exposure to the educational tool, 4.7% of women were already taking endocrine risk reduction, 38.7% were reducing alcohol intake, and 62.6% were exercising. Three months after initial use of BHD, 8.4% of women who considered endocrine risk reduction, 33% of women who considered alcohol reduction, and 46% of women who considered exercise pursued the risk-reducing activities. Unlike lifestyle interventions which are under the control of the patient, additional barriers at the level of the healthcare provider may be impeding the targeted use of endocrine risk reduction medications in women with elevated breast cancer risk.

Guiding principles for the responsible development of artificial intelligence tools for healthcare.

Several principles have been proposed to improve use of artificial intelligence (AI) in healthcare, but the need for AI to improve longstanding healthcare challenges has not been sufficiently emphasized. We propose that AI should be designed to alleviate health disparities, report clinically meaningful outcomes, reduce overdiagnosis and overtreatment, have high healthcare value, consider biographical drivers of health, be easily tailored to the local population, promote a learning healthcare system, and facilitate shared decision-making. These principles are illustrated by examples from breast cancer research and we provide questions that can be used by AI developers when applying each principle to their work.

Positive margins after mastectomy in patients with invasive lobular carcinoma of the breast: Incidence and management strategies.

BACKGROUND: Surgical treatment of invasive lobular carcinoma (ILC) is challenging due to its diffuse growth pattern, and the positive margin rate after mastectomy is poorly described. METHODS: We retrospectively determined the positive margin rate in those with stage I-III ILC undergoing mastectomy. We evaluated the relationship between management strategy and recurrence free survival (RFS). RESULTS: In 357 patients, the positive margin rate was 10.6% overall and 18.7% in those with T3 tumors. Having a positive margin was associated with significantly shorter RFS on multivariate analysis (p = 0.01). Undergoing additional local treatment (radiation or re-excision) for a positive margin was significantly associated with improved RFS (p = 0.004). Older women with positive margins were significantly less likely to undergo additional local therapy. CONCLUSIONS: Even mastectomy fails to clear margins in a high proportion of patients with large ILC tumors, a finding which may warrant testing neoadjuvant strategies even prior to planned mastectomy.

Assessment of 25-Year Survival of Women With Estrogen Receptor-Positive/ERBB2-Negative Breast Cancer Treated With and Without Tamoxifen Therapy: A Secondary Analysis of Data From the Stockholm Tamoxifen Randomized Clinical Trial.

Importance: Clinically used breast cancer markers, such as tumor size, tumor grade, progesterone receptor (PR) status, and Ki-67 status, are known to be associated with short-term survival, but the association of these markers with long-term (25-year) survival is unclear. Objective: To assess the association of clinically used breast cancer markers with long-term survival and treatment benefit among postmenopausal women with lymph node-negative, estrogen receptor [ER]-positive and ERBB2-negative breast cancer who received tamoxifen therapy. Design, Setting, and Participants: This study was a secondary analysis of data from a subset of 565 women with ER-positive/ERBB2-negative breast cancer who participated in the Stockholm tamoxifen (STO-3) randomized clinical trial. The STO-3 clinical trial was conducted from 1976 to 1990 and comprised 1780 postmenopausal women with lymph node-negative breast cancer who were randomized to receive adjuvant tamoxifen therapy or no endocrine therapy. Complete 25-year follow-up data through December 31, 2016, were obtained from Swedish national registers. Immunohistochemical markers were reannotated in 2014. Data were analyzed from April to December 2020. Interventions: Patients in the original STO-3 clinical trial were randomized to receive 2 years of tamoxifen therapy vs no endocrine therapy. In 1983, patients who received tamoxifen therapy without cancer recurrence during the 2-year treatment and who consented to continued participation in the STO-3 study were further randomized to receive 3 additional years of tamoxifen therapy or no endocrine therapy. Main Outcomes and Measures: Distant recurrence-free interval (DRFI) by clinically used breast cancer markers was assessed using Kaplan-Meier and multivariable Cox proportional hazards analyses adjusted for age, period of primary diagnosis, tumor size (T1a and T1b [T1a/b], T1c, and T2), tumor grade (1-3), PR status (positive vs negative), Ki-67 status (low vs medium to high), and STO-3 clinical trial arm (tamoxifen treatment vs no adjuvant treatment). A recursive partitioning analysis was performed to evaluate which markers were able to best estimate long-term DRFI. Results: The study population comprised 565 postmenopausal women (mean [SD] age, 62.0 [5.3] years) with lymph node-negative, ER-positive/ERBB2-negative breast cancer. A statistically significant difference in long-term DRFI was observed by tumor size (88% for T1a/b vs 76% for T1c vs 63% for T2 tumors; log-rank P < .001) and tumor grade (81% for grade 1 vs 77% for grade 2 vs 65% for grade 3 tumors; log-rank P = .02) but not by PR status or Ki-67 status. Patients with smaller tumors (hazard ratio [HR], 0.31 [95% CI, 0.17-0.55] for T1a/b tumors and 0.58 [95% CI, 0.38-0.88] for T1c tumors) and grade 1 tumors (HR, 0.48; 95% CI, 0.24-0.95) experienced a significant reduction in the long-term risk of distant recurrence compared with patients with larger (T2) tumors and grade 3 tumors, respectively. A significant tamoxifen treatment benefit was observed among patients with larger tumors (HR, 0.53 [95% CI, 0.32-0.89] for T1c tumors and 0.34 [95% CI, 0.16-0.73] for T2 tumors), lower tumor grades (HR, 0.24 [95% CI, 0.07-0.82] for grade 1 tumors and 0.50 [95% CI, 0.31-0.80] for grade 2 tumors), and PR-positive status (HR, 0.38; 95% CI, 0.24-0.62). The recursive partitioning analysis revealed that tumor size was the most important characteristic associated with long-term survival, followed by clinical trial arm among patients with larger tumors. Conclusions and Relevance: This secondary analysis of data from the STO-3 clinical trial indicated that, among the selected subgroup of patients, tumor size followed by tumor grade were the markers most significantly associated with long-term survival. Furthermore, a significant long-term tamoxifen treatment benefit was observed among patients with larger tumors, lower tumor grades, and PR-positive tumors.

Development and pilot of an online, personalized risk assessment tool for a breast cancer precision medicine trial.

Breast cancer risk reduction has been validated by large-scale clinical trials, but uptake remains low. A risk communication tool could provide personalized risk-reduction information for high-risk women. A low-literacy-friendly, visual, and personalized tool was designed as part of the Women Informed to Screen Depending On Measures of risk (WISDOM) study. The tool integrates genetic, polygenic, and lifestyle factors, and quantifies the risk-reduction from undertaking medication and lifestyle interventions. The development and design process utilized feedback from clinicians, decision-making scientists, software engineers, and patient advocates. We piloted the tool with 17 study participants, collecting quantitative and qualitative feedback. Overall, participants felt they better understood their personalized breast cancer risk, were motivated to reduce their risk, and considered lifestyle interventions. The tool will be used to evaluate whether risk-based screening leads to more informed decisions and higher uptake of risk-reduction interventions among those most likely to benefit.

Use of 18F-FDG PET/CT as an Initial Staging Procedure for Stage II-III Breast Cancer: A Multicenter Value Analysis.

BACKGROUND: Metastatic staging imaging is not recommended for asymptomatic patients with stage I-II breast cancer. Greater distant metastatic disease risk may warrant baseline imaging in patients with stage II-III with high-risk biologic subtypes. NCCN Guidelines recommend considering CT of the chest, abdomen, and pelvis (CT CAP) and bone scan in appropriate patients. CT CAP and bone scan are considered standard of care (SoC), although PET/CT is a patient-centered alternative. METHODS: Data were available for 799 high-risk patients with clinical stage II-III disease who initiated screening for the I-SPY2 trial at 4 institutions. A total of 564 complete records were reviewed to compare PET/CT versus SoC. Costs were determined from the payer perspective using the national 2018 Medicare Physician Fee Schedule and representative reimbursements to the University of California, San Francisco (UCSF). Incremental cost-effectiveness ratio (ICER) measured cost of using PET/CT per percent of patients who avoided a false-positive (FP). RESULTS: The de novo metastatic disease rate was 4.6%. Imaging varied across the 4 institutions (P<.0001). The FP rate was higher using SoC versus PET/CT (22.1% vs 11.1%; P=.0009). Mean time between incidental finding on baseline imaging to FP determination was 10.8 days. Mean time from diagnosis to chemotherapy initiation was 44.3 days with SoC versus 37.5 days with PET/CT (P=.0001). Mean cost per patient was $1,132 (SoC) versus $1,477 (PET/CT) using the Medicare Physician Fee Schedule, with an ICER of $31. Using representative reimbursements to UCSF, mean cost per patient was $1,236 (SoC) versus $1,073 (PET/CT) for Medicare, and $3,083 (SoC) versus $1,656 (PET/CT) for a private payer, with ICERs of -$15 and -$130, respectively. CONCLUSIONS: Considerable variation exists in metastatic staging practices. PET/CT reduced FP risk by half and decreased workup of incidental findings, allowing for earlier treatment start. PET/CT may be cost-effective, and at one institution was shown to be cost-saving. Better alignment is needed between hospital pricing strategies and payer coverage policies to deliver high-value care.

Assessment of Long-term Distant Recurrence-Free Survival Associated With Tamoxifen Therapy in Postmenopausal Patients With Luminal A or Luminal B Breast Cancer.

IMPORTANCE: Patients with estrogen receptor (ER)-positive breast cancer have a long-term risk for fatal disease. However, the tumor biological factors that influence the long-term risk and the benefit associated with endocrine therapy are not well understood. OBJECTIVE: To compare the long-term survival from tamoxifen therapy for patients with luminal A or luminal B tumor subtype. DESIGN, SETTING, AND PARTICIPANTS: Secondary analysis of patients from the Stockholm Tamoxifen (STO-3) trial conducted from 1976 to 1990, which randomized postmenopausal patients with lymph node-negative breast cancer to receive adjuvant tamoxifen or no endocrine therapy. Tumor tissue sections were assessed in 2014 using immunohistochemistry and Agilent microarrays. Only patients with luminal A or B subtype tumors were evaluated. Complete long-term follow-up data up to the end of the STO-3 trial on December 31, 2012, were obtained from the Swedish National registers. Data analysis for the secondary analysis was conducted in 2017 and 2018. INTERVENTIONS: Patients were randomized to receive at least 2 years of tamoxifen therapy or no endocrine therapy; patients without recurrence who reconsented were further randomized to 3 additional years of tamoxifen therapy or no endocrine therapy. MAIN OUTCOMES AND MEASURES: Distant recurrence-free interval (DRFI) by luminal A and luminal B subtype and trial arm was assessed by Kaplan-Meier analyses and time-dependent flexible parametric models to estimate time-varying hazard ratios (HRs) that were adjusted for patient and tumor characteristics. RESULTS: In the STO-3 treated trial arm, 183 patients had luminal A tumors and 64 patients had luminal B tumors. In the untreated arm, 153 patients had luminal A tumors and 62 had luminal B tumors. Age at diagnosis ranged from 45 to 73 years. A statistically significant difference in DRFI by trial arm was observed (log rank, P < .001 [luminal A subtype, n = 336], P = .04 [luminal B subtype, n = 126]): the 25-year DRFI for luminal A vs luminal B subtypes was 87% (95% CI, 82%-93%) vs 67% (95% CI, 56%-82%) for treated patients, and 70% (95% CI, 62%-79%) vs 54% (95% CI, 42%-70%) for untreated patients, respectively. Patients with luminal A tumors significantly benefited from tamoxifen therapy for 15 years after diagnosis (HR, 0.57; 95% CI, 0.35-0.94), and those with luminal B tumors benefited from tamoxifen therapy for 5 years (HR, 0.38; 95% CI, 0.24-0.59). CONCLUSIONS AND RELEVANCE: Patients with luminal A subtype tumors had a long-term risk of distant metastatic disease, which was reduced by tamoxifen treatment, whereas patients with luminal B tumors had an early risk of distant metastatic disease, and tamoxifen benefit attenuated over time.

MRI, Clinical Examination, and Mammography for Preoperative Assessment of Residual Disease and Pathologic Complete Response After Neoadjuvant Chemotherapy for Breast Cancer: ACRIN 6657 Trial.

OBJECTIVE: The objective of our study was to determine the accuracy of preoperative measurements for detecting pathologic complete response (CR) and assessing residual disease after neoadjuvant chemotherapy (NACT) in patients with locally advanced breast cancer. SUBJECTS AND METHODS: The American College of Radiology Imaging Network 6657 Trial prospectively enrolled women with ≥ 3 cm invasive breast cancer receiving NACT. Preoperative measurements of residual disease included longest diameter by mammography, MRI, and clinical examination and functional volume on MRI. The accuracy of preoperative measurements for detecting pathologic CR and the association with final pathology size were assessed for all lesions, separately for single masses and nonmass enhancements (NMEs), multiple masses, and lesions without ductal carcinoma in situ (DCIS). RESULTS: In the 138 women with all four preoperative measures, longest diameter by MRI showed the highest accuracy for detecting pathologic CR for all lesions and NME (AUC = 0.76 and 0.84, respectively). There was little difference across preoperative measurements in the accuracy of detecting pathologic CR for single masses (AUC = 0.69-0.72). Longest diameter by MRI and longest diameter by clinical examination showed moderate ability for detecting pathologic CR for multiple masses (AUC = 0.78 and 0.74), and longest diameter by MRI and longest diameter by mammography showed moderate ability for detecting pathologic CR for tumors without DCIS (AUC = 0.74 and 0.71). In subjects with residual disease, longest diameter by MRI exhibited the strongest association with pathology size for all lesions and single masses (r = 0.33 and 0.47). Associations between preoperative measures and pathology results were not significantly influenced by tumor subtype or mammographic density. CONCLUSION: Our results indicate that measurement of longest diameter by MRI is more accurate than by mammography and clinical examination for preoperative assessment of tumor residua after NACT and may improve surgical planning.

Total skin-sparing mastectomy and immediate breast reconstruction: an evolution of technique and assessment of outcomes.

BACKGROUND: Total skin-sparing mastectomy (TSSM) with preservation of the breast and nipple-areolar complex (NAC) skin was developed to improve aesthetic outcomes for mastectomy. Over time, indications for TSSM broadened and our technique has evolved with a series of systematic improvements. METHODS: We reviewed all cases of TSSM with immediate breast reconstruction performed from 2005 to 2012. Patient comorbidities, treatment characteristics, postoperative complications, and outcomes were obtained prospectively and through medical chart review. Locoregional recurrences, distant recurrences, and patient survival were analyzed with Kaplan-Meier methods. RESULTS: During this 8-year period, 633 patients (981 cases) underwent TSSM with median follow-up time of 29 (interquartile range 14-54) months. Immediate breast reconstruction was performed with tissue expander placement (89 %), pedicle TRAM (5 %), free flap (5 %), permanent implant (0.3 %), or latissimus flap (0.2 %). The incidences of postoperative complications decreased significantly over time. In 2012, these were down to 3.5 % for superficial nipple necrosis, 1.0 % for complete nipple necrosis, 3.0 % for minor skin flap necrosis, 4.4 % for major skin flap necrosis, 13.3 % for infections requiring oral antibiotics, 9.9 % for infections requiring intravenous antibiotics, 3.4 % for infections requiring operative intervention, and 8.5 % for expander/implant. Overall 5-year cumulative incidences of recurrence were 3.0 % (locoregional) and 4.2 % (distant), and there were no recurrences in the NAC skin. CONCLUSIONS: Systematic changes in our technique of TSSM and immediate breast reconstruction have decreased postoperative complications over time. Oncologic outcomes of locoregional and distal recurrences remain similar to skin-sparing mastectomy techniques.

Aggregate cost of mammography screening in the United States: comparison of current practice and advocated guidelines.

BACKGROUND: Controversy exists over how often and at what age mammography screening should be implemented. Given that evidence supports less frequent screening, the cost differences among advocated screening policies should be better understood. OBJECTIVE: To estimate the aggregate cost of mammography screening in the United States in 2010 and compare the costs of policy recommendations by professional organizations. DESIGN: A model was developed to estimate the cost of mammography screening in 2010 and 3 screening strategies: annual (ages 40 to 84 years), biennial (ages 50 to 69 years), and U.S. Preventive Services Task Force (USPSTF) guidelines (biennial for those aged 50 to 74 years and personalized based on risk for those younger than 50 years and based on comorbid conditions for those 75 years and older). SETTING: United States. PATIENTS: Women aged 40 to 85 years. INTERVENTION: Mammography annually, biennially, or following USPSTF guidelines. MEASUREMENTS: Cost of screening per year, using Medicare reimbursements. RESULTS: The estimated cost of mammography screening in the United States in 2010 was $7.8 billion, with approximately 70% of women screened. The simulated cost of screening 85% of women was $10.1 billion, $2.6 billion, and $3.5 billion for annual, biennial, and USPSTF guidelines, respectively. The largest drivers of cost (in order) were screening frequency, percentage of women screened, cost of mammography, percentage of women screened with digital mammography, and percentage of mammography recalls. LIMITATION: Cost estimates and assumptions used in the model were conservative. CONCLUSION: The cost of mammography varies by at least $8 billion per year on the basis of screening strategy. The USPSTF guidelines are based on the scientific evidence to date to maximize patient benefit and minimize harm but also result in far more effective use of resources. PRIMARY FUNDING SOURCE: University of California and the Safeway Foundation.

Cost-effectiveness analysis of intraoperative radiation therapy for early-stage breast cancer.

BACKGROUND: Shortened courses of radiation therapy have been shown to be similarly effective to whole-breast external-beam radiation therapy (WB-EBRT) in terms of local control. We sought to analyze, from a societal perspective, the cost-effectiveness of two radiation strategies for early-stage invasive breast cancer: single-dose intraoperative radiation therapy (IORT) and the standard 6-week course of WB-EBRT. METHODS: We developed a Markov decision-analytic model to evaluate these treatment strategies in terms of life expectancy, quality-adjusted life years (QALYs), costs, and the incremental cost-effectiveness ratio over 10 years. RESULTS: IORT single-dose intraoperative radiation therapy was the dominant, more cost-effective strategy, providing greater quality-adjusted life years at a decreased cost compared with 6-week WB-EBRT. The model was sensitive to health state utilities and recurrence rates, but not costs. IORT was either the preferred or dominant strategy across all sensitivity analyses. The two-way sensitivity analyses demonstrate the need to accurately determine utility values for the two forms of radiation treatment and to avoid indiscriminate use of IORT. CONCLUSIONS: With less cost and greater QALYs than WB-EBRT, IORT is the more valuable strategy. IORT offers a unique example of new technology that is less costly than the current standard of care option but offers similar efficacy. Even when considering the capital investment for the equipment ($425 K, low when compared with the investments required for robotic surgery or high-dose-rate brachytherapy), which could be recouped after 3-4 years conservatively, these results support IORT as a change in practice for treating early-stage invasive breast cancer.

Breast cancer risk assessment and prevention: a framework for shared decision-making consultations.

Options for breast cancer prevention, used in combination with screening and surveillance, include lifestyle modifications, chemoprevention with tamoxifen, and prophylactic surgery. Preventive health decisions are often preference driven: patients typically must choose whether to initiate effective treatments that hold the possibility of side effects that can negatively impact quality of life. This situation demands that patients be well informed and have a full understanding of the risks associated with each option. Investigators have developed a comprehensive decision-making framework designed to support breast cancer prevention consultations within a shared decision-making setting. The framework integrates predictive information from current risk models within the context of a woman's general health to appropriately frame breast cancer risk management consultations and outlines the application of available treatments and emerging biomarker information to individual patient decisions. Using an evidence-based approach, specialized risk-benefit projections can be provided in the clinical setting. A more comprehensive individualized risk profile allows for tailored medical management plans and can better prepare patients to make informed decisions. The framework is intended to encourage a shared decision-making approach to prevention consultations, a method for researchers to increase accrual to trials, and to more quickly incorporate new findings into the routine of practice.

Evaluation of breast cancer risk assessment techniques: a cost-effectiveness analysis.

OBJECTIVE: Assess the effectiveness and cost-effectiveness of using biomarkers and risk assessment tools to stratify women for breast cancer preventive interventions. METHODS: A Markov model was developed to compare risk management strategies for high-risk women considering chemoprevention. Annual screening is compared to the use of chemoprevention for all women and the use of risk assessment technologies to stratify patients for chemoprevention. The biomarker atypia was used to stratify women by risk. Random fine-needle aspiration (rFNA) and ductal lavage (DL) were evaluated and compared as the risk assessment tools used to discover atypia. Sensitivity analyses explore assumptions regarding the prognostic and predictive characteristics of atypia, both the relative breast cancer risk and benefit from chemoprevention women with atypia incur. RESULTS: Risk assessment strategies using rFNA or DL in combination with chemoprevention are found to be cost-effective (<$50,000 per life year saved) in high-risk groups under most scenarios. Both strategies were more effective and less costly in younger cohorts. Effectiveness of the risk assessment strategies increased when higher risk and increased benefit from chemoprevention were associated with atypia. Within the scenarios tested, rFNA is less costly than DL. CONCLUSION: rFNA and DL appear to be cost-effective in high-risk women, assuming women with detected atypia choose tamoxifen. The tools are largely effective for women who are not motivated to take tamoxifen but would be if atypia were found. As biomarker risk assessment tools better predict the risk of breast cancer and or benefit of interventions, their cost-effectiveness increases.