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A tumor specific antibody to aid breast cancer screening in women with dense breast tissue.

ABSTRACT: Screening for breast cancer has predominantly been done using mammography. Unfortunately, mammograms miss 50% cancers in women with dense breast tissue. Multi-modal screenings offer the best chance of enhancing breast cancer screening effectiveness. We evaluated the use of TAB004, an antibody that recognizes the tumor form of the glycoprotein MUC1 (tMUC1), to aid early detection of breast cancer. Our experimental approach was to follow tMUC1 from the tissue into circulation. We found that 95% of human breast cancer tissues across all subtypes stained positive for TAB004. In breast cancer cell lines, we showed that the amount of tMUC1 released from tumor cells is proportional to the cell's tMUC1 expression level. Finally, we showed that TAB004 can be used to assess circulating tMUC1 levels, which when monitored in the context of cancer immunoediting, can aid earlier diagnosis of breast cancer regardless of breast tissue density. In a blinded pilot study with banked serial samples, tMUC1 levels increased significantly up to 2 years before diagnosis. Inclusion of tMUC1 monitoring as part of a multi-modal screening strategy may lead to earlier stage diagnosis of women whose cancers are missed by mammography.

SUBMITTER: Roy LD

PROVIDER: S-EPMC5489651 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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A tumor specific antibody to aid breast cancer screening in women with dense breast tissue.

Roy Lopamudra Das LD Dillon Lloye M LM Zhou Ru R Moore Laura J LJ Livasy Chad C El-Khoury Joe M JM Puri Rahul R Mukherjee Pinku P

Genes & cancer 20170301 3-4

Screening for breast cancer has predominantly been done using mammography. Unfortunately, mammograms miss 50% cancers in women with dense breast tissue. Multi-modal screenings offer the best chance of enhancing breast cancer screening effectiveness. We evaluated the use of TAB004, an antibody that recognizes the tumor form of the glycoprotein MUC1 (tMUC1), to aid early detection of breast cancer. Our experimental approach was to follow tMUC1 from the tissue into circulation. We found that 95% of ...[more]

PMID: 28680538

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Project description:ImportanceImproved screening methods for women with dense breasts are needed because of their increased risk of breast cancer and of failed early diagnosis by screening mammography.ObjectiveTo compare the screening performance of abbreviated breast magnetic resonance imaging (MRI) and digital breast tomosynthesis (DBT) in women with dense breasts.Design, setting, and participantsCross-sectional study with longitudinal follow-up at 48 academic, community hospital, and private practice sites in the United States and Germany, conducted between December 2016 and November 2017 among average-risk women aged 40 to 75 years with heterogeneously dense or extremely dense breasts undergoing routine screening. Follow-up ascertainment of cancer diagnoses was complete through September 12, 2019.ExposuresAll women underwent screening by both DBT and abbreviated breast MRI, performed in randomized order and read independently to avoid interpretation bias.Main outcomes and measuresThe primary end point was the invasive cancer detection rate. Secondary outcomes included sensitivity, specificity, additional imaging recommendation rate, and positive predictive value (PPV) of biopsy, using invasive cancer and ductal carcinoma in situ (DCIS) to define a positive reference standard. All outcomes are reported at the participant level. Pathology of core or surgical biopsy was the reference standard for cancer detection rate and PPV; interval cancers reported until the next annual screen were included in the reference standard for sensitivity and specificity.ResultsAmong 1516 enrolled women, 1444 (median age, 54 [range, 40-75] years) completed both examinations and were included in the analysis. The reference standard was positive for invasive cancer with or without DCIS in 17 women and for DCIS alone in another 6. No interval cancers were observed during follow-up. Abbreviated breast MRI detected all 17 women with invasive cancer and 5 of 6 women with DCIS. Digital breast tomosynthesis detected 7 of 17 women with invasive cancer and 2 of 6 women with DCIS. The invasive cancer detection rate was 11.8 (95% CI, 7.4-18.8) per 1000 women for abbreviated breast MRI vs 4.8 (95% CI, 2.4-10.0) per 1000 women for DBT, a difference of 7 (95% CI, 2.2-11.6) per 1000 women (exact McNemar P = .002). For detection of invasive cancer and DCIS, sensitivity was 95.7% (95% CI, 79.0%-99.2%) with abbreviated breast MRI vs 39.1% (95% CI, 22.2%-59.2%) with DBT (P = .001) and specificity was 86.7% (95% CI, 84.8%-88.4%) vs 97.4% (95% CI, 96.5%-98.1%), respectively (P < .001). The additional imaging recommendation rate was 7.5% (95% CI, 6.2%-9.0%) with abbreviated breast MRI vs 10.1% (95% CI, 8.7%-11.8%) with DBT (P = .02) and the PPV was 19.6% (95% CI, 13.2%-28.2%) vs 31.0% (95% CI, 17.0%-49.7%), respectively (P = .15).Conclusions and relevanceAmong women with dense breasts undergoing screening, abbreviated breast MRI, compared with DBT, was associated with a significantly higher rate of invasive breast cancer detection. Further research is needed to better understand the relationship between screening methods and clinical outcome.Trial registrationClinicalTrials.gov Identifier: NCT02933489.

Project description:BackgroundMammographic screening alone will miss a certain fraction of malignancies, as evidenced by retrospective reviews of mammograms following a subsequent screening. Mammographic breast density is a marker for increased breast cancer risk and is associated with a higher risk of interval breast cancer, i.e. cancer detected between screening tests. The purpose of this review is to estimate risks and benefits of supplemental breast ultrasound in women with negative mammographic screening with dense breast tissue.MethodsA systematic search and review of studies involving mammography and breast ultrasound for screening of breast cancer was conducted. The search was performed for the period 1/2000-8/2008 within the data source of PubMed, DARE, and Cochrane databases. Inclusion and exclusion criteria were determined prospectively, and the Oxford evidence classification system for diagnostic studies was used for evidence level. The parameters biopsy rate, positive predictive value (PPV) for biopsy, cancer yield for breast ultrasound alone, and carcinoma detection rate by breast density were extracted or constructed.ResultsThe systematic search identified no randomized controlled trials or systematic reviews, six cohort studies of intermediate level of evidence (3b) were found. Only two of the studies included adequate follow-up of subjects with negative or benign findings. Supplemental breast ultrasound after negative mammographic screening permitted diagnosis of primarily invasive carcinomas in 0.32% of women in breast density type categories 2-4 of the American College of Radiology (ACR); mean tumor size for those identified was 9.9 mm, 90% with negative lymph node status. Most detected cancers occurred in mammographically dense breast ACR types 3 and 4. Biopsy rates were in the range 2.3%-4.7%, with PPV of 8.4-13.7% for those biopsied due to positive ultrasound, or about one third of the PPV of biopsies due to mammography.LimitationsThe study populations included wide age ranges, and the application to women age 50-69 years as proposed for mammographic screening could result in less striking benefit. Further validation studies should employ a uniform assessment system such as BI-RADS and report not only PPV, but also negative predictive value, sensitivity and specificity.ConclusionSupplemental breast ultrasound in the population of women with mammographically dense breast tissue (ACR 3 and 4) permits detection of small, otherwise occult, breast cancers. Potential adverse impacts for women in this intermediate risk group are associated with an increased biopsy rate.

Project description:PurposeOne major risk factor for breast cancer is high mammographic density. It has been estimated that dense breast tissue contributes to ~ 30% of all breast cancer. Prevention targeting dense breast tissue has the potential to improve breast cancer mortality and morbidity. Anti-estrogens, which may be associated with severe side-effects, can be used for prevention of breast cancer in women with high risk of the disease per se. However, no preventive therapy targeting dense breasts is currently available. Inflammation is a hallmark of cancer. Although the biological mechanisms involved in the increased risk of cancer in dense breasts is not yet fully understood, high mammographic density has been associated with increased inflammation. We investigated whether low-dose acetylsalicylic acid (ASA) affects local breast tissue inflammation and/or structural and dynamic changes in dense breasts.MethodsPostmenopausal women with mammographic dense breasts on their regular mammography screen were identified. A total of 53 women were randomized to receive ASA 160 mg/day or no treatment for 6 months. Magnetic resonance imaging (MRI) was performed before and after 6 months for a sophisticated and continuous measure breast density by calculating lean tissue fraction (LTF). Additionally, dynamic quantifications including tissue perfusion were performed. Microdialysis for sampling of proteins in vivo from breasts and abdominal subcutaneous fat, as a measure of systemic effects, before and after 6 months were performed. A panel of 92 inflammatory proteins were quantified in the microdialysates using proximity extension assay.ResultsAfter correction for false discovery rate, 20 of the 92 inflammatory proteins were significantly decreased in breast tissue after ASA treatment, whereas no systemic effects were detected. In the no-treatment group, protein levels were unaffected. Breast density, measured by LTF on MRI, were unaffected in both groups. ASA significantly decreased the perfusion rate. The perfusion rate correlated positively with local breast tissue concentration of VEGF.ConclusionsASA may shape the local breast tissue microenvironment into an anti-tumorigenic state. Trials investigating the effects of low-dose ASA and risk of primary breast cancer among postmenopausal women with maintained high mammographic density are warranted. Trial registration EudraCT: 2017-000317-22.

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A tumor specific antibody to aid breast cancer screening in women with dense breast tissue.

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A tumor specific antibody to aid breast cancer screening in women with dense breast tissue.

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