Breast Cancer Screening: Can We Justify Deescalation?

Novel breast cancer screening methods that detect greater numbers of occult (nonpalpable) tumors have been rapidly incorporated into clinical practice, with the aim of reducing mortality. Yet, tumor detection has never been validated as a proper surrogate outcome measure for breast cancer mortality. Moreover, the detection of greater numbers of occult cancers increases the risk of overdiagnosis, which refers to detection of tumors that pose no threat to life and would never have been detected in the absence of screening. With recent advances in breast cancer therapy, many cancers that were previously curable only if detected as occult tumors with mammography screening are perhaps now curable even when detected as small palpable tumors, thereby giving us an opportunity to deescalate screening and mitigate the risk of overdiagnosis. Thus, a randomized trial comparing screening mammography versus screening clinical breast examination (CBE), with breast cancer mortality as the endpoint, is now warranted. In such a trial, hand-held ultrasound might aid in the interpretation of screening CBE findings. In conclusion, recent improvements in breast cancer therapy provide the justification to assess the deescalation of breast cancer screening. See related article by Farber et al., p. 671.

Non-surgical ablation for breast cancer: an emerging therapeutic option.

Non-surgical ablation is emerging as an alternative local therapy option for patients with early-stage breast cancer and encompasses two main types of percutaneous therapeutic procedures: radiofrequency ablation and cryoablation. Both techniques involve obliteration of a spherical lesion and feasibility studies have shown that complete tumour ablation is achievable with good or excellent cosmetic results. Although few clinical studies have directly compared non-surgical ablation with conventional surgical resection, observational studies indicate that clinical outcomes are favourable with acceptable rates of local control and no detriment to long-term survival. There remain outstanding issues with these percutaneous ablative techniques that require resolution before they could be incorporated into routine clinical practice. Hence, a consensus meeting was convened to discuss the challenges of non-surgical ablation and clarify indications for its use alongside clinical management pathways. In this Policy Review we will address some of the broader biological aspects of non-surgical ablation, including immune-modulatory effects and potential novel applications for the future.

mTOR inhibition abrogates human mammary stem cells and early breast cancer progression markers.

BACKGROUND: Mammary physiology is distinguished in containing adult stem/progenitor cells that are actively amending the breast tissue throughout the reproductive lifespan of women. Despite their importance in both mammary gland development, physiological maintenance, and reproduction, the exact role of mammary stem/progenitor cells in mammary tumorigenesis has not been fully elucidated in humans or animal models. The implications of modulating adult stem/progenitor cells in women could lead to a better understanding of not only their function, but also toward possible breast cancer prevention led us to evaluate the efficacy of rapamycin in reducing mammary stem/progenitor cell activity and malignant progression markers. METHODS: We analyzed a large number of human breast tissues for their basal and luminal cell composition with flow cytometry and their stem and progenitor cell function with sphere formation assay with respect to age and menopausal status in connection with a clinical study (NCT02642094) involving a low-dose (2 mg/day) and short-term (5-7 days) treatment of the mTOR inhibitor sirolimus. The expression of biomarkers in biopsies and surgical breast samples were measured with quantitative analysis of immunohistochemistry. RESULTS: Sirolimus treatment significantly abrogated mammary stem cell activity, particularly in postmenopausal patients. It did not affect the frequency of luminal progenitors but decreased their self-renewal capacity. While sirolimus had no effect on basal cell population, it decreased luminal cell population, particularly in postmenopausal patients. It also significantly diminished prognostic biomarkers associated with breast cancer progression from ductal carcinoma in situ to invasive breast cancer including p16INK4A, COX-2, and Ki67, as well as markers of the senescence-associated secretary phenotype, thereby possibly functioning in preventing early breast cancer progression. CONCLUSION: Overall, these findings indicate a link from mTOR signaling to mammary stem and progenitor cell activity and cancer progression. Trial registration This study involves a clinical trial registered under the ClinicalTrials.gov identifier NCT02642094 registered December 30, 2015.

National Economic Conditions May Impact the Financial Barriers to Travel for Cancer Operations.

Background: Better cancer-related outcomes are associated with physicians and hospitals with higher case volume. This serves as an incentive to refer patients requiring complex cancer operations to large referral centers, which may require increased travel for patients. However, barriers exist for patients to travel for cancer care, some of which may be aggravated or alleviated by factors relating to the health of the national economy. This impact may be reflected in variability of travel distances for cancer operations over time particularly for complex operation such as pancreatectomy and esophagectomy compared with less complex resections such as those for breast cancer or melanoma. Methods: We obtained the estimated travel distance for patients undergoing operations for cancer of the pancreas, esophagus, skin (melanoma), and breast from the National Cancer Database from 2004 to 2017 and correlated them with economic factors obtained from public sources. We then examined the impact of unemployment rates, gas prices, and inflation on travel distances regarding disadvantaged groups. Correlations were measured by the (rank-based, nonparametric) Spearman's correlation coefficient, and the corresponding P value is obtained by the asymptotic distribution of the coefficient. A P value of 0.05 equates to an absolute correlation value of 0.532. To adjust for multiple tests, a more restrictive P value of 0.01 was also assessed, which equates to correlation coefficients of absolute value greater than 0.661. Results: There were 4,222,380 cases in the dataset, of which 1,781,056 remained after exclusion. The economic factors that were associated most strongly with the distance patients traveled for all cancer operation types were the labor force participation rate, personal savings, consumer price index, and changes in gasoline prices. Inflation and rising gasoline prices were often inversely related with travel distance in lower-income and less well-educated regions and African American patients. Conclusions: Several macroeconomic factors correlate with the travel distance for operations, suggesting that the economic health of the nation may aggravate or alleviate the financial barriers to travel for cancer operations. Financially disadvantaged groups may be particularly vulnerable to changes in gasoline prices and inflation. Organizations serving these populations may need to increase patient support services during times of economic hardship to avoid the exacerbation of health care disparities.

State Variation in Racial and Ethnic Disparities in Incidence of Triple-Negative Breast Cancer Among US Women.

Importance: There are few data on state variation in racial and ethnic disparities in incidence of triple-negative breast cancer (TNBC) in the US, limiting the ability to inform state-level health policy developments toward breast cancer equity. Objective: To quantify between and within racial and ethnic disparities in TNBC incidence rates (IRs) among US women across states. Design, Setting, and Participants: This cohort study using population-based cancer registry data included data for all women with TNBC diagnosed from January 1, 2015, to December 31, 2019, identified in the US Cancer Statistics Public Use Research Database. Data were analyzed from July through November 2022. Exposures: State and race and ethnicity (Hispanic, non-Hispanic American Indian or Alaska Native, non-Hispanic Asian or Pacific Islander, non-Hispanic Black, or non-Hispanic White) abstracted from medical records. Main Outcomes and Measures: The main outcomes were diagnosis of TNBC, age-standardized IR per 100 000 women, state-specific incidence rate ratios (IRRs) using the rate among White women in each state as a reference for between-population disparities, and state-specific IRRs using the race and ethnicity-specific national rate as a reference for within-population disparities. Results: The study included data for 133 579 women; 768 (0.6%) were American Indian or Alaska Native; 4969 (3.7%), Asian or Pacific Islander; 28 710 (21.5%), Black; 12 937 (9.7%), Hispanic; and 86 195 (64.5%), White. The TNBC IR was highest among Black women (25.2 per 100 000 women), followed by White (12.9 per 100 000 women), American Indian or Alaska Native (11.2 per 100 000 women), Hispanic (11.1 per 100 000 women), and Asian or Pacific Islander (9.0 per 100 000 women) women. Racial and ethnic group-specific and state-specific rates substantially varied, ranging from less than 7 per 100 000 women among Asian or Pacific Islander women in Oregon and Pennsylvania to greater than 29 per 100 000 women among Black women in Delaware, Missouri, Louisiana, and Mississippi. Compared with White women, IRRs were statistically significantly higher in 38 of 38 states among Black women, ranging from 1.38 (95% CI, 1.10-1.70; IR, 17.4 per 100 000 women) in Colorado to 2.32 (95% CI, 1.90-2.81; IR, 32.0 per 100 000 women) in Delaware; lower in 22 of 22 states among Asian or Pacific Islander women, varying from 0.50 (95% CI, 0.34-0.70; IR, 5.7 per 100 000 women) in Oregon to 0.82 (95% CI, 0.75-0.90; IR, 10.5 per 100 000 women) in New York; and did not differ among Hispanic and American Indian or Alaska Native women in 22 of 35 states and 5 of 8 states, respectively. State variations within each racial and ethnic population were smaller but still substantial. For example, among White women, compared with the national rate, IRRs varied from 0.72 (95% CI, 0.66-0.78; IR, 9.2 per 100 000 women) in Utah to 1.18 (95% CI, 1.11-1.25; IR, 15.2 per 100 000 women) in Iowa, 1.15 (95% CI, 1.07-1.24; IR, 14.8 per 100 000 women) in Mississippi, and 1.15 (95% CI, 1.07-1.24; IR, 14.8 per 100 000 women) in West Virginia. Conclusions and Relevance: In this cohort study, there were substantial state variations in racial and ethnic disparities in TNBC incidence, with Black women in Delaware, Missouri, Louisiana, and Mississippi having the highest rates among all states and racial and ethnic populations. The findings suggest that more research is needed to identify factors contributing to the substantial geographic variations in racial and ethnic disparities in TNBC incidence to develop effective preventive measures and that social determinants of health contribute to the geographic disparities in TNBC risk.

Tools for Contralateral Prophylactic Mastectomy Decision Making.

PURPOSE: Women with unilateral breast cancer are increasingly opting for the removal of not only the involved breast, but also for the removal of the opposite uninvolved breast (contralateral prophylactic mastectomy [CPM]), although the risk of contralateral breast cancer (CBC) has decreased in recent years. Models to predict the absolute risk of CBC can help a woman decide whether to undergo CPM. Our objective is to illustrate that a better decision can be made if the patient and doctor also have estimates of the absolute risks of regional and distant recurrences and mortality from non-breast cancer causes. MATERIALS AND METHODS: We based our analyses on two published models for CBC and published information on the hazards of regional and distant recurrences and non-breast cancer mortality. Assuming that CPM eliminates CBC but has no effect on other events, we calculated how much CPM reduces a woman's CBC risk and total risk from all these events for 10 hypothetical women with various subtypes of breast cancer and risk factors. RESULTS: The risk of CBC and total risk vary greatly, depending on the breast cancer subtype. In some cases, a decision for or against CPM can be based on CBC risk alone, but in others, additional consideration of total risk may cause a woman to decline CPM. CONCLUSION: There is a potential to develop more informative tools for deciding on CPM. Realizing this potential will require more and better data to validate existing models of absolute CBC risk and to characterize the hazards of regional and distant recurrences and deaths from non-breast cancer causes for women with various subtypes of breast cancers and risk factors.

The antidepressant imipramine inhibits breast cancer growth by targeting estrogen receptor signaling and DNA repair events.

Aberrant activities of various cell cycle and DNA repair proteins promote cancer growth and progression and render them resistant to therapies. Here, we demonstrate that the anti-depressant imipramine blocks growth of triple-negative (TNBC) and estrogen receptor-positive (ER+) breast cancers by inducing cell cycle arrest and by blocking heightened homologous recombination (HR) and non-homologous end joining-mediated (NHEJ) DNA repair activities. Our results reveal that imipramine inhibits the expression of several cell cycle- and DNA repair-associated proteins including E2F1, CDK1, Cyclin D1, and RAD51. In addition, we show that imipramine inhibits the growth of ER + breast cancers by inhibiting the estrogen receptor- α (ER-α) signaling. Our studies in preclinical mouse models and ex vivo explants from breast cancer patients show that imipramine sensitizes TNBC to the PARP inhibitor olaparib and endocrine resistant ER + breast cancer to anti-estrogens. Our studies suggest that repurposing imipramine could enhance routine care for breast cancer patients. Based on these results, we designed an ongoing clinical trial, where we are testing the efficacy of imipramine for treating patients with triple-negative and estrogen receptor-positive breast cancer. Since aberrant DNA repair activity is used by many cancers to survive and become resistant to therapy, imipramine could be used alone and/or with currently used drugs for treating many aggressive cancers.

Disparities in Cancer Genetic Testing and Variants of Uncertain Significance in the Hispanic Population of South Texas.

PURPOSE: Racial and ethnic disparities have included a lack of access to both genetic testing and research, resulting in poor understanding of the genomic architecture in under-represented populations. The South Texas population is primarily of Hispanic background and has been largely devoid of genetic services. We extended access to this underserved population and uncovered genetic variants previously not observed, emphasizing the need to continually improve both genomic databases and clarification of variant significance to provide meaningful patient counseling. METHODS: This study consisted of a retrospective cohort review of patients seen through a cancer genetics education and service program across 24 counties in South Texas. In total, 1,595 individuals were identified as appropriate for cancer genetic counseling and 1,377 completed genetic testing. RESULTS: Eighty percent of those receiving genetic counseling self-identified as Hispanic, 16% as non-Hispanic White (NHW), 3% as African American, and 1% as other race/ethnicity. Of reported variants, 18.8% were pathogenic and 13.7% were reported as a variant of uncertain significance (VUS). VUS was reported in 17.2% of the Hispanic individuals compared with 9% NHW (P = .005). CONCLUSION: Individuals of Hispanic ethnicity were significantly more likely to harbor a VUS compared with NHW. The extended reach into our regional communities revealed a gap in the ability to accurately interpret genomic variation with implications for advising patients on screening, prevention, and management strategies. A higher percentage of VUS also emphasizes the challenge of continued follow-up amid existing barriers that led to disparities in access. As understanding of the variants develops, hopefully gaps in knowledge of the genomic landscape will be lessened with increased clarity to provide accurate cancer risk assessment and recommendations for implementing prevention initiatives.

Targeting aberrant replication and DNA repair events for treating breast cancers.

The major limitations of DNA-targeting chemotherapy drugs include life-threatening toxicity, acquired resistance and occurrence of secondary cancers. Here, we report a small molecule, Carbazole Blue (CB), that binds to DNA and inhibits cancer growth and metastasis by targeting DNA-related processes that tumor cells use but not the normal cells. We show that CB inhibits the expression of pro-tumorigenic genes that promote unchecked replication and aberrant DNA repair that cancer cells get addicted to survive. In contrast to chemotherapy drugs, systemic delivery of CB suppressed breast cancer growth and metastasis with no toxicity in pre-clinical mouse models. Using PDX and ex vivo explants from estrogen receptor (ER) positive, ER mutant and TNBC patients, we further demonstrated that CB effectively blocks therapy-sensitive and therapy-resistant breast cancer growth without affecting normal breast tissue. Our data provide a strong rationale to develop CB as a viable therapeutic for treating breast cancers.

Mitigating Cancer Overdiagnosis.

Overdiagnosis refers to the detection of cancers that pose no threat to life and would never have been detected in the absence of screening. It is now a major public health concern throughout the world because advancements in screening technology have substantially increased the detection rates of non-lethal cancers. Cancer overdiagnosis leads to unnecessary treatments, putting patients unnecessarily at risk for the potential morbidity and mortality that may arise from those treatments, and it wastes healthcare resources. Patients may also suffer unnecessary anxiety, job discrimination, financial hardships, and other detrimental effects on quality-of-life following cancer overdiagnosis. In this article, I provide examples of cancer overdiagnosis as a consequence of screening for thyroid, breast, and pancreatic cancers. To mitigate the adverse effects of cancer overdiagnosis, we should adopt only those screening strategies that have been shown in randomized trials to reduce cancer mortality, and we should inform patients about the potential benefits and risks of cancer screening, particularly the risk for overdiagnosis.