TMIST A Breast Cancer Screening Trial November 10, 2016 ECOG-ACRIN Fall Group Meeting Orlando, FL

Should Tomosynthesis replace digital mammography for breast cancer screening?

We have not had a breast cancer screening trial since the 1980s We have not had a breast cancer screening trial since the 1980s. Do our newer tools In the context of improved therapy find IMPORTANT cancers?

In order to reduce mortality, an effective screening test should REDUCE the number of advanced breast cancers in the population screened, over time.

How is TM currently used in North America? 23% of available mammography systems. Many systems are being used in the same centers where DM is also being used – patients assigned somewhat randomly to the next available machine. Most systems require both TM images PLUS DM images. Synthetic 2D images are possible with many systems, but are not widely utilized. Cost for machines is higher for TM than DM. Time to interpret is ~ 2X for TM.

Literature on TM+DM vs DM Diagnostic accuracy (AUC) trends better for TM+DM vs. DM. Screening recall rates trend lower for TM+DM vs DM. Cancer detection rate trends higher for TM+DM vs DM. Lesion Characterization trends better for TM+DM vs. DM. Average glandular dose is significantly higher for TM+DM vs. DM (~2X)

What we don’t know How do Tomosynthesis and Digital Mammography compare in reducing advanced breast cancer in the population being screened? How does Tomosynthesis affect breast cancer mortality compared with DM? What is the rate of overdiagnosis?

What we don’t know Do ALL Tomosynthesis systems perform at the same diagnostic accuracy, sensitivity and specificity in the North American population? Should all DM systems be replaced by TM or would some women be equally well served by DM?

TMIST Primary Aim Compare the number of advanced cancers detected using TM vs. DM With advanced or aggressive cancers defined as- 1) All invasive cancers over 2.0 cm. in size. 2) All invasive tumors that are over 1 cm. in size and which have prognostic markers that suggest aggressive behavior, (ie triple negative or her2+). 3) All tumors that have positive nodes or metastases at the time of diagnosis.

TMIST Study Design Study Type: Randomized Clinical Trial. Patient Population: Asymptomatic women presenting for screening mammography, ages 45-74. No prior breast cancer, implants. Can’t be pregnant or lactating. Number of Women: 164,946 women (82,473 per arm) Randomization Assignments: Breast Tomosynthesis (TM) or Digital Mammography (DM).

TMIST Study Design Frequency of Screening- Annual for Premenopausal women Annual for Postmenopausal women ages 45-70 who either have dense breasts, OR are on hormone therapy OR have a family history of breast cancer. Annual for Postmenopausal women over age 70 who either have dense breasts or are on hormone therapy. Biennial for all other postmenopausal women.

Definitions Postmenopausal- No periods for 12 months or longer. Menopausal status identified at study entry. Dense breasts: Two densest BIRADS categories. If baseline mammogram, assigned after mammogram read by the study radiologist. Positive Family History: First degree relative (mother/father, sister/brother, daughter/son) with breast cancer.

Trial Methods Annual screening will take place at entry and 1, 2,3 and 4 years after entry. (5 screens) Biennial screening will take place at entry and 2 and 4 years after entry (3 screens). Truth on breast cancer status will be determined by biopsies and follow-up information. Total numbers of advanced cancers will be compared 4.5 years after randomization in both study populations (TM vs DM).

Secondary Study Aims Patient-Centered Aims To compare the recall and biopsy rates due to abnormal screening examinations for TM versus DM To compare quality of life (QOL) and patient preferences for breast cancer screening regimens among women receiving TM versus DM To assess treatment decision making among women diagnosed with breast cancer

Secondary Study Aims Imaging Aims To compare diagnostic accuracy of TM versus DM To compare interval cancer rates.

Secondary Study Aims Biological Aims To determine correlates of TM/DM findings, pathology and genetic analysis, and other patient characteristics with long-term patient outcomes, including interval cancer rate. To ascertain potential biomarkers for aggressive tumors and/or poor outcomes via blood DNA/RNA/protein analysis. To assess and compare the characteristics (e.g. stage, grade, cell subtype) of cancers detected from screening by TM and DM.

Study Timeline Funding decision was made on 10/11/2016! We hope to gain protocol and central IRB approval and activate the study some time mid-2017. 2172 women have enrolled at 3 sites in Canada to date. (Under funding from the Canadian Breast Cancer Foundation) as of 10/14/2016. We will plan to start accrual at ~90 sites shortly after IRB approval - ~April 2017.

What is the time line for the study after activation? Open all sites for accrual by October 2017. Accrue all 164,946 women over 30 months (April 2017-September 2019). Image women for 4 years after randomization, so that the final round of imaging will take place between September 2022-August 2023. Follow-on the women accrued annually up until 4.5 years after randomization through 8 years after study activation. So, follow-up information will take place from the present (for patients already enrolled in Canada) through early 2024.

TMIST QUESTIONS? TMIST@ecog-acrin.org