Baseline breast tissue characteristics determine the effect of tamoxifen on mammographic density change.

Tamoxifen prevents recurrence of breast cancer and is also approved for preventive, risk-reducing, therapy. Tamoxifen alters the breast tissue composition and decreases the mammographic density. We aimed to test if baseline breast tissue composition influences tamoxifen-associated density change. This biopsy-based study included 83 participants randomised to 6 months daily intake of placebo, 20, 10, 5, 2.5, or 1 mg tamoxifen. The study is nested within the double-blinded tamoxifen dose-determination trial Karolinska Mammography Project for Risk Prediction of Breast Cancer Intervention (KARISMA) Study. Ultrasound-guided core-needle breast biopsies were collected at baseline before starting treatment. Biopsies were quantified for epithelial, stromal, and adipose distributions, and epithelial and stromal expression of proliferation marker Ki67, oestrogen receptor (ER) and progesterone receptor (PR). Mammographic density was measured using STRATUS. We found that greater mammographic density at baseline was positively associated with stromal area and inversely associated with adipose area and stromal expression of ER. Premenopausal women had greater mammographic density and epithelial tissue, and expressed more epithelial Ki67, PR, and stromal PR, compared to postmenopausal women. In women treated with tamoxifen (1-20 mg), greater density decrease was associated with higher baseline density, epithelial Ki67, and stromal PR. Women who responded to tamoxifen with a density decrease had on average 17% higher baseline density and a 2.2-fold higher PR expression compared to non-responders. Our results indicate that features in the normal breast tissue before tamoxifen exposure influences the tamoxifen-associated density decrease, and that the age-associated difference in density change may be related to age-dependant differences in expression of Ki67 and PR.

Comparing the diagnostic accuracy, reading time, and inter-rater agreement of breast MRI abbreviated and full protocols: a multi-reader study.

BACKGROUND: Earlier studies have shown that abbreviated protocol magnetic resonance imaging (AB-MRI) has similar diagnostic accuracy as the full protocol (Full MRI). PURPOSE: To compare the diagnostic accuracy, reading time, and inter-rater agreement of AB-MRI to Full MRI among women without known increased familial risk of breast cancer or prior biopsy. MATERIAL AND METHODS: In total, 395 MRI examinations were included in this study. Three readers were blinded to all patient information. The AB-MRI and Full MRI were read separately and in a different random order for each of the readers. Scores 1-2 were considered test negative while scores 3-5 were test positive. A positive reference test was the diagnosis of malignancy; a negative reference test was the absence of a diagnosis of breast cancer within a two-year follow-up. We used a generalized estimating equations approach to compare sensitivity and specificity between the two protocols. We used t-tests to compare the average reading time and Krippendorff's alpha to compare inter-rater agreement. RESULTS: MRI examinations of 395 women (median age=56 years) were evaluated. For AB-MRI and Full MRI, respectively, the sensitivity was 93.0% (95% CI=90.6-95.0) vs. 92.0% (95% CI=89.4-94.1), the specificity was 91.7% (95% CI=90.3-92.9) vs. 94.3% (95% CI=93.2-95.3), average reading time was 67 vs. 126 s, and the inter-rater agreement 0.79 vs. 0.83. The difference in sensitivity was not statistically significant (P=0.840), but the difference in specificity was significant (P=0.003). CONCLUSION: AB-MRI has similar sensitivity, but somewhat lower specificity. The average reading time for the abbreviated protocol is lower, as is inter-rater agreement.

Effects of tamoxifen on normal breast tissue histological composition: Results from a randomised six-arm placebo-controlled trial in healthy women.

Tamoxifen prevents recurrence of breast cancer and is suggested for preventive risk-reducing therapy. Tamoxifen reduces mammographic density, a proxy for therapy response, but little is known about its effects in remodelling normal breast tissue. Our study, a substudy within the double-blinded dose-determination trial KARISMA, investigated tamoxifen-specific changes in breast tissue composition and histological markers in healthy women. We included 83 healthy women randomised to 6 months daily intake of 20, 10, 5, 2.5, 1 mg of tamoxifen or placebo. The groups were combined to "no dose" (0-1 mg), "low-dose" (2.5-5 mg) or "high-dose" (10-20 mg) of tamoxifen. Ultrasound-guided biopsies were collected before and after tamoxifen exposure. In each biopsy, epithelial, stromal and adipose tissues was quantified, and expression of epithelial and stromal Ki67, oestrogen receptor (ER) and progesterone receptor (PR) analysed. Mammographic density using STRATUS was measured at baseline and end-of-tamoxifen-exposure. We found that different doses of tamoxifen reduced mammographic density and glandular-epithelial area in premenopausal women and associated with reduced epithelium and increased adipose tissue. High-dose tamoxifen also decreased epithelial ER and PR expressions in premenopausal women. Premenopausal women with the greatest reduction in proliferation also had the greatest epithelial reduction. In postmenopausal women, high-dose tamoxifen decreased the epithelial area with no measurable density decrease. Tamoxifen at both low and high doses influences breast tissue composition and expression of histological markers in the normal breast. Our findings connect epithelial proliferation with tissue remodelling in premenopausal women and provide novel insights to understanding biological mechanisms of primary prevention with tamoxifen.

Breast cancer patient-derived whole-tumor cell culture model for efficient drug profiling and treatment response prediction.

Breast cancer (BC) is a complex disease comprising multiple distinct subtypes with different genetic features and pathological characteristics. Although a large number of antineoplastic compounds have been approved for clinical use, patient-to-patient variability in drug response is frequently observed, highlighting the need for efficient treatment prediction for individualized therapy. Several patient-derived models have been established lately for the prediction of drug response. However, each of these models has its limitations that impede their clinical application. Here, we report that the whole-tumor cell culture (WTC) ex vivo model could be stably established from all breast tumors with a high success rate (98 out of 116), and it could reassemble the parental tumors with the endogenous microenvironment. We observed strong clinical associations and predictive values from the investigation of a broad range of BC therapies with WTCs derived from a patient cohort. The accuracy was further supported by the correlation between WTC-based test results and patients' clinical responses in a separate validation study, where the neoadjuvant treatment regimens of 15 BC patients were mimicked. Collectively, the WTC model allows us to accomplish personalized drug testing within 10 d, even for small-sized tumors, highlighting its potential for individualized BC therapy. Furthermore, coupled with genomic and transcriptomic analyses, WTC-based testing can also help to stratify specific patient groups for assignment into appropriate clinical trials, as well as validate potential biomarkers during drug development.

Topical Endoxifen for Mammographic Density Reduction-A Randomized Controlled Trial.

Although breast cancer incidence is increasing, there are few primary preventive initiatives. Tamoxifen can reduce breast cancer incidence but is rarely used for primary prevention due to adverse events and tolerance issues. We tested if endoxifen, a tamoxifen metabolite, applied directly to the skin of the breast, could reduce mammographic density, a proxy for therapy response. Ninety women were randomized to placebo, 10 and 20 mg of topical Z-endoxifen for 6 months. Mammographic density and symptoms were measured at baseline and study exit. Despite a high discontinuation rate, driven by skin rashes, we found a significant mammographic density decrease, a dose-dependent increase in the concentration of plasma Z-endoxifen but no systemic side effects. Topical application of tamoxifen metabolites has the potential to decrease breast cancer incidence without major systemic side effects. However, endoxifen may not be suitable for topical administration and is unlikely to be used for breast cancer prevention.

Time to Mammographic Density Decrease After Exposure to Tamoxifen.

Mammographic density change has proven to be a reliable proxy for tamoxifen therapy response. The primary aim of this study was to identify time to tamoxifen-induced mammographic density change. We also analyzed side effects and adherence to therapy. In all, 42 women were randomized to 10 or 20 mg of daily oral tamoxifen. Mammograms were taken at baseline, 3, 6, and 9 months. Mammographic density change was measured using the automated STRATUS tool. Adverse events were monitored through a web-based questionnaire based on the FACT-ES tool. Nine out of the 42 (21%) participants discontinued therapy due to adverse events leaving 33 women in the study. A significant decrease in density was seen after 3 months of therapy. Dose did not seem to affect density change, side effects or adherence. Given the size of the study, additional studies are needed to confirm our data.

[It is time for individual breast cancer prevention]. / Det är dags att skräddarsy bröstcancerpreventionen.

Breast cancer prevention must include interventions aiming at both reducing the risk of breast cancer (primary prevention) and identifying cancers at an early stage (secondary prevention). Sweden has one of the best breast cancer screening programs globally, but women are still screened without taking risk of breast cancer or difficulties diagnosing a cancer into consideration. Today it is possible to identify women at high risk of breast cancer and those women that have high mammographic density. These women should be offered individualised screening.  Women at very high risk of breast cancer should be offered primary preventive initiatives.

Mammographic microcalcifications and risk of breast cancer.

BACKGROUND: Mammographic microcalcifications are considered early signs of breast cancer (BC). We examined the association between microcalcification clusters and the risk of overall and subtype-specific BC. Furthermore, we studied how mammographic density (MD) influences the association between microcalcification clusters and BC risk. METHODS: We used a prospective cohort (n = 53,273) of Swedish women with comprehensive information on BC risk factors and mammograms. The total number of microcalcification clusters and MD were measured using a computer-aided detection system and the STRATUS method, respectively. Cox regressions and logistic regressions were used to analyse the data. RESULTS: Overall, 676 women were diagnosed with BC. Women with ≥3 microcalcification clusters had a hazard ratio [HR] of 2.17 (95% confidence interval [CI] = 1.57-3.01) compared to women with no clusters. The estimated risk was more pronounced in premenopausal women (HR = 2.93; 95% CI = 1.67-5.16). For postmenopausal women, microcalcification clusters and MD had a similar influence on BC risk. No interaction was observed between microcalcification clusters and MD. Microcalcification clusters were significantly associated with in situ breast cancer (odds ratio: 2.03; 95% CI = 1.13-3.63). CONCLUSIONS: Microcalcification clusters are an independent risk factor for BC, with a higher estimated risk in premenopausal women. In postmenopausal women, microcalcification clusters have a similar association with BC as baseline MD.

Low-Dose Tamoxifen for Mammographic Density Reduction: A Randomized Controlled Trial.

PURPOSE: Tamoxifen prevents breast cancer in high-risk women and reduces mortality in the adjuvant setting. Mammographic density change is a proxy for tamoxifen therapy response. We tested whether lower doses of tamoxifen were noninferior to reduce mammographic density and associated with fewer symptoms. PATIENTS AND METHODS: Women, 40-74 years of age, participating in the Swedish mammography screening program were invited to the 6-month double-blind six-arm randomized placebo-controlled noninferiority dose-determination KARISMA phase II trial stratified by menopausal status (EudraCT 2016-000882-22). In all, 1,439 women were accrued with 1,230 participants accessible for intention-to-treat analysis. The primary outcome was proportion of women treated with placebo, 1, 2.5, 5, and 10 mg whose mammographic density decreased at least as much as the median reduction in the 20 mg arm. The noninferior margin was 17%. Secondary outcome was reduction of symptoms. Post hoc analyses were performed by menopausal status. Per-protocol population and full population were analyzed in sensitivity analysis. RESULTS: The 1,439 participants, 566 and 873 pre- and postmenopausal women, respectively, were recruited between October 1, 2016, and September 30, 2019. The participants had noninferior mammographic density reduction following 2.5, 5, and 10 mg tamoxifen compared with the median 10.1% decrease observed in the 20 mg group, a reduction confined to premenopausal women. Severe vasomotor symptoms (hot flashes, cold sweats, and night sweats) were reduced by approximately 50% in the 2.5, 5, and 10 mg groups compared with the 20 mg group. CONCLUSION: Premenopausal women showed noninferior magnitude of breast density decrease at 2.5 mg of tamoxifen, but fewer side effects compared with the standard dose of 20 mg. Future studies should test whether 2.5 mg of tamoxifen reduces the risk of primary breast cancer.

Predictors of mammographic microcalcifications.

We examined the association between established risk factors for breast cancer and microcalcification clusters and their asymmetry. A cohort study of 53 273 Swedish women aged 30 to 80 years, with comprehensive information on breast cancer risk factors and mammograms, was conducted. Total number of microcalcification clusters and the average mammographic density area were measured using a Computer Aided Detection system and the STRATUS method, respectively. A polygenic risk score for breast cancer, including 313 single nucleotide polymorphisms, was calculated for those women genotyped (N = 7387). Odds ratios (ORs) and 95% confidence intervals (CIs), with adjustment for potential confounders, were estimated. Age was strongly associated with microcalcification clusters. Both high mammographic density (>40 cm2 ), and high polygenic risk score (80-100 percentile) were associated with microcalcification clusters, OR = 2.08 (95% CI = 1.93-2.25) and OR = 1.22 (95% CI = 1.06-1.48), respectively. Among reproductive risk factors, life-time breastfeeding duration >1 year was associated with microcalcification clusters OR = 1.22 (95% CI = 1.03-1.46). The association was confined to postmenopausal women. Among lifestyle risk factors, women with a body mass index ≥30 kg/m2 had the lowest risk of microcalcification clusters OR = 0.79 (95% CI = 0.73-0.85) and the association was stronger among premenopausal women. Our results suggest that age, mammographic density, genetic predictors of breast cancer, having more than two children, longer duration of breast-feeding are significantly associated with increased risk of microcalcification clusters. However, most lifestyle risk factors for breast cancer seem to protect against presence of microcalcification clusters. More research is needed to study biological mechanisms behind microcalcifications formation.

The association between breast cancer risk factors and background parenchymal enhancement at dynamic contrast-enhanced breast MRI.

BACKGROUND: Background parenchymal enhancement (BPE) of normal tissue at breast magnetic resonance imaging is suggested to be an independent risk factor for breast cancer. Its association with established risk factors for breast cancer is not fully investigated. PURPOSE: To study the association between BPE and risk factors for breast cancer in a healthy, non-high-risk screening population. MATERIAL AND METHODS: We measured BPE and mammographic density and used data from self-reported questionnaires in 214 healthy women aged 43-74 years. We estimated odds ratios for the univariable association between BPE and risk factors. We then fitted an adjusted model using logistic regression to evaluate associations between BPE (high vs. low) and risk factors, including mammographic breast density. RESULTS: The majority of women had low BPE (84%). In a multivariable model, we found statistically significant associations between BPE and age (P = 0.002) and BMI (P = 0.03). We did find a significant association between systemic progesterone medication and BPE, but due to small numbers, the results should be interpreted with caution. The adjusted odds ratio for high BPE was 3.1 among women with density D (compared to B) and 2.1 for density C (compared to B). However, the association between high BPE and density was not statistically significant. We did not find statistically significant associations with any other risk factors. CONCLUSION: Our study confirmed the known association of BPE with age and BMI. Although our results show a higher likelihood for high BPE with increasing levels of mammographic density, the association was not statistically significant.

Mammographic Density Change and Risk of Breast Cancer.

BACKGROUND: We examined the association between annual mammographic density change (MDC) and breast cancer (BC) risk, and how annual MDC influences the association between baseline mammographic density (MD) and BC risk. METHODS: We used the Karolinska Mammography Project for Risk Prediction of Breast Cancer cohort of Swedish women (N = 43 810) aged 30-79 years with full access to BC risk factors and mammograms. MD was measured as dense area (cm2) and percent MD using the STRATUS method. We used the contralateral mammogram for women with BC and randomly selected a mammogram from either left or right breast for healthy women. We calculated relative area MDC between repeated examinations. Relative area MDC was categorized as decreased (>10% decrease per year), stable (no change), or increased (>10% increase per year). We used Cox proportional hazards regression to estimate the association of BC with MDC and interaction analysis to investigate how MDC modified the association between baseline MD and BC risk. All tests of statistical significance were two-sided. RESULTS: In all, 563 women were diagnosed with BC. Compared with women with a decreased MD over time, no statistically significant difference in BC risk was seen for women with either stable MD or increasing MD (hazard ratio = 1.01, 95% confidence interval = 0.82 to 1.23, P = .90; and hazard ratio = 0.98, 95% confidence interval = 0.80 to 1.22, P = .90, respectively). Categorizing baseline MD and subsequently adding MDC did not seem to influence the association between baseline MD and BC risk. CONCLUSIONS: Our results suggest that annual MDC does not influence BC risk. Furthermore, MDC does not seem to influence the association between baseline MD and BC risk.

Does three-dimensional functional infrared imaging improve breast cancer detection based on digital mammography in women with dense breasts?

PURPOSE: We aimed to estimate the incremental cancer detection rate achieved by adding three-dimensional functional infrared imaging (3DIRI) to digital mammography in women with dense breasts. MATERIALS AND METHODS: In this prospective study conducted between December 2014 and April 2016, 1727 women (median age 56) with percentage volumetric breast density > 6% were recruited at routine screening mammography to undergo additional 3DIRI. The 3DIRI findings were classified as negative or positive. Women with a negative mammography but positive 3DIRI were referred to dynamic contrast-enhanced MRI, whereas all other women underwent routine follow-up based on the mammography finding. Diagnosis of breast cancer was verified by histopathologic examination. The number of women diagnosed with a malignancy formed the basis of our statistical analysis. RESULTS: Mammography detected 7 cancers in 7 women. Of 1692 women with negative mammography, 222 women (13%) had a positive 3DIRI of which 219 underwent MRI. An additional 6 cancers were identified in 5 women, increasing the diagnostic yield from 7 of 1727 (0.41%) to 12 of 1727 (0.69%). The incremental cancer detection rate associated with using 3DIRI to select women for MRI was 5 of 222 (22.5 additional cancers per 1000). CONCLUSION: The use of 3DIRI to select women for an additional MRI can result in the detection of additional cancers in women with dense breasts, but at the expense of additional false positives and considerably lower positive predictive value of the combined examinations. Additional studies are necessary to evaluate the role of 3DIRI as an adjunct to mammography. KEY POINTS: • Use of three-dimensional functional infrared imaging to select women for an MRI in addition to screening mammography has the potential to improve breast cancer detection in women with dense breasts.

Localized mammographic density is associated with interval cancer and large breast cancer: a nested case-control study.

BACKGROUND: High mammographic density is associated with breast cancer and with delayed detection. We have examined whether localized density, at the site of the subsequent cancer, is independently associated with being diagnosed with a large-sized or interval breast cancer. METHODS: Within a prospective cohort of 63,130 women, we examined 891 women who were diagnosed with incident breast cancer. For 386 women, retrospective localized density assessment was possible. The main outcomes were interval cancer vs. screen-detected cancer and large (> 2 cm) vs. small cancer. In negative screening mammograms, overall and localized density were classified reflecting the BI-RADS standard. Density concordance probabilities were estimated through multinomial regression. The associations between localized density and the two outcomes were modeled through logistic regression, adjusted for overall density, age, body mass index, and other characteristics. RESULTS: The probabilities of concordant localized density were 0.35, 0.60, 0.38, and 0.32 for overall categories "A," "B," "C," and "D." Overall density was associated with large cancer, comparing density category D to A with OR 4.6 (95%CI 1.8-11.6) and with interval cancer OR 31.5 (95%CI 10.9-92) among all women. Localized density was associated with large cancer at diagnosis with OR 11.8 (95%CI 2.7-51.8) among all women and associated with first-year interval cancer with OR 6.4 (0.7 to 58.7) with a significant linear trend p = 0.027. CONCLUSIONS: Overall density often misrepresents localized density at the site where cancer subsequently arises. High localized density is associated with interval cancer and with large cancer. Our findings support the continued effort to develop and examine computer-based measures of localized density for use in personalized breast cancer screening.

Comparison of handheld ultrasound and automated breast ultrasound in women recalled after mammography screening.

Background Automated breast volume scanner (ABVS) is an ultrasound (US) device with a wide scanner that sweeps over a large area of the breast and the acquired transverse images are sent to a workstation for reconstruction and review. Whether ABVS is as reliable as handheld US is, however, still not established. Purpose To compare the sensitivity and specificity of ABVS to handheld breast US for detection of breast cancer, in the situation of recall after mammography screening. Material and Methods A total of 113 women, five with bilateral suspicious findings, undergoing handheld breast US due to a suspicious mammographic finding in screening, underwent additional ABVS. The methods were assessed for each breast and each detected lesion separately and classified into two categories: breasts with mammographic suspicion of malignancy and breasts with a negative mammogram. Results Twenty-six cancers were found in 25 women. In the category of breasts with a suspicious mammographic finding (n = 118), the sensitivity of both handheld US and ABVS was 88% (22/25). The specificity of handheld US was 93.5% (87/93) and ABVS was 89.2% (83/93). In the category of breasts with a negative mammography (n = 103), the sensitivity of handheld US and ABVS was 100% (1/1). The specificity of handheld US was 100% (102/102) and ABVS was 94.1% (96/102). Conclusion ABVS can potentially replace handheld US in the investigation of women recalled from mammography screening due to a suspicious finding. Due to the small size of our study population, further investigation with larger study populations is necessary before the implementation of such practice.