Interval Breast Cancers Veronica Irvin - PowerPoint Presentation

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Interval Breast Cancers

Veronica Irvin, PhD, MPHAssistant ProfessorCollege of Public Health and Human SciencesOregon State University

Sonali Jindal

, MDResearch Assistant ProfessorDepartment of Cell, Developmental & Cancer BiologyOregon Health Sciences University

Pepper Schedin

, PhD

Professor

Department of Cell, Developmental & Cancer Biology

Oregon Health Sciences University

Outline of Our Presentation

Our backgroundA Team building project between OHSU-OSU designed to understand efficacy of mammographic screening

Interval cancer definitionInterval cancer - what is knownWhy WHI?

Our proposed papers Future directionsQuestions & Discussion

Our background

Veronica IrvinResearch – benefits and harms of mammography screening

Secondary data analysis – Meta-analysis of quasi-experimental mammography studies

Population-level analysis using data from the California Health Interview Survey to assess number of screens, lumpectomies, and cancer detected Primary data collectionIn-depth interviews following mammogramsSonali JindalResearch- Stromal-epithelial interactions in normal and pathologic breast Role of immune cell microenvironment in early pre-invasive breast lesions including atypical hyperplasia/ in situ carcinomas Expertise in multiplex IHC & IF staining and quantitative image analysis using softwares like Image J, cell profiler, Aperio; RNAseq on FFPE tissue samples

Pepper Schedin

Research – develop breast cancer preventive and therapeutic strategies targeted to distinct “windows of mammary gland development” that confer hot spots of risk for breast cancer development and progression

Areas of expertise include:

Normal mammary gland biology and early stage disease

Comparative breast histology; humans and rodents

Young women's’ & postpartum

BrCa

Metastasis

Chemoprevention

Our background together–

Team-building grant between our 2 institutions Inter-disciplinary team:

16 faculty members

Public Health (2 members), BC Clinical Care & Breast Imaging (4 members), Prevention (4 members), Molecular & cell biology of BC (2 members), Early Detection & Imaging (4 members)Goal of team-building grant:

Evidence based consensus on breast cancer screening & prioritization of future research to improve screening efficacy

One of our identified gaps in the field of mammography screening:

mammography not only over diagnoses indolent cancers but under diagnoses life-threatening cancers including interval cancers.

Review of mammographic screening data revealed

Only 50 % of invasive cancers are detected on screeningThe other 50 % are a complicated mix:Too young for screening programLobular carcinoma that are not detected

Lack of compliance in screeningInterval cancers

MammogramMalmgren, BMC Cancer 2008.Yuan,European Journal of Cancer Care, 2015.Welch, Archives Internal Medicine 2011

Interval Breast Cancer – Definition and incidence

Interval breast cancers are cancers detected within the inter-interval screen, usually 12 – 24 months after a mammographic screening which had normal findings, but before the next routine screening.

Proportion of interval breast cancer vary by screening interval Houssami

& Hunter, 2017Interval breast cancers represent 17-30% of breast cancers & this proportion is higher with longer screening interval

Limited publications of US data

Pubmed search - Last 5 years - > 94464 papers on breast cancer -> 25 papers on interval cancer-> 2 from U.S. datasets

Current only 2 publications using U.S. data and data come from the Breast Cancer Surveillance Consortium

Rates of interval cancer and relationship between digital vs film mammogramDigital and film mammography had similar rates of screen-detected (4.47 vs. 4.42 per 1000 examinations) and interval cancers (0.73 vs. 0.79 per 1000 examinations) for digital versus film. Hendersen, 20152. Rates of interval cancers and relationship with breast density. Higher breast density plus Breast Cancer Screening Consortium 5-year risk model predictedo higher risk for interval cancer. Kerlikowske, 2015

Interval Breast Cancer

Data to date indicates that interval cancers are:More frequently Triple negative, ER negative, Her-2 positive Have increased tumor size Basal phenotype (CK5/6

+,Pcadherin+)

Higher histologic gradeMore advanced diseasePoorer prognosis((Collett K et al. Cancer Epidemiol Biomarkers Prev, 2005; Domingo L et al. Breast Cancer Res 2014; Kalager, 2012; Weber et al. Breast Cancer Res Treat,2016; Meshkat B, et al. Breast 2015)(Domingo L et al. Breast Cancer Res 2014)

Problem

:Aggressive interval cancers are not being diagnosed by regular screening thus warranting the need for new methodology to detect these cancers before they become symptomaticObjective:Access WHI research expertise and database to

estimate incidence of interval cancers by age-strata and clinical characteristics for US women.To compare high-risk characteristics between women diagnosed with interval cancers and those diagnosed with screen-detected cancers.

Critical Gaps:Do survival differ in women with interval cancers – similar/different than women with screen detected breast cancersIs the biology of interval cancers different from the screen detected cancers

Do interval cancers present more as pure invasive cancer without in situ carcinoma in background?

Is the tumor microenvironment different in interval cancer vs. screen detected cancers?

Are specific mutations more frequent in interval cancers?

Do

Qol

differ in women with interval cancers – similar/different than women with screen detected breast cancers

What variables associate with interval cancers could be used to target early screening- age, race, demographic, insurance status, OCP use

Opportunities within the WHI consortia

WHI data collected annual data medical record and surveysLarge sample size of women age 50 – 79 (n=161,000)Variables needed to construct interval cancer variable are present

Our review of existing WHI publications

Relationship of ethnicity & breast cancer incidence & outcome (Chlebowski, JNCI, 2005)African American women had lower

bc risk than White women However, African American women more likely to have ER+, higher grade, poorly differentiated tumors and lower survival than White women

Health-related quality of life among breast cancer survivors (Paskett, Cancer, 2008)Lower HRQOL among African American women compared to White womenAlcohol and folate intake with breast cancer risk (Duffy, Breast Cancer Res Treat, 2005)Higher alcohol intake increased risk of breast cancerNo relationship with folateStressful life events and breast cancer risk (Michael, Health Psychol, 2009)No relationship determined between stressful events and breast cancerMammography screening dates. Simon, Breast Cancer Res Treat, 2014.Proposed paper by Marilyn Johnson-Kozlow to assess personal habits with breast cancer risk We did not locate any published or proposed WHI papers addressing interval breast cancer.

Proposed Milestones

Proposed paper # 1 – Incidence of interval cancers & associated factors

To estimate incidence of interval cancers by age-strata and clinical characteristics for women age 50+ in the U.S.To compare high-risk characteristics between women diagnosed with interval cancers and those diagnosed with screen-detected cancers. High-risk characteristics will include: family, personal medical history, reproductive history, physical measurements, tumor characteristics, personal habits, socio-demographics (including race/ethnicity)

Proposed paper # 2 - Survival and HRQOL estimatesTo compare survival estimates and health-related quality of life between women diagnosed with interval cancers and those diagnosed with screen-detected cancers

Proposed paper # 1 -

Incidence of interval cancersObjectivesTo estimate incidence of interval cancers by age-strata and clinical characteristics for women age 50+ in the U.S.

To compare high-risk characteristics between women diagnosed with interval cancers and those diagnosed with screen-detected cancers.Dependent Variable: Interval breast cancer (1) vs screen-detected (0)

We would need to construct interval breast cancer using date of breast caner diagnosis & had mammogram in past year. Independent variables: Tumor characteristics; Medical and family history of cancer; Reproductive history; Physical measurements – bmi, waist and hip circumference; Personal habits – smoking, alcohol, general exercise; Socio-demographics – age, race/ethnicity, Dataset: WHI Observational study; WHI I 1993 – 2005; Ext 1 2005 – 2009; Ext 2 2010- 2020Proposed analyses: Bivariate analyses t-test, anovas. Estimates of incidence per 1,000 exams. Cox proportional hazard model adjusted for covariates

Proposed paper # 2 –

Survival and quality of lifeObjectivesTo compare survival estimates and health-related quality of life between women diagnosed with interval cancers and those diagnosed with screen-detected cancers

Dependent Variables: Survival and Health-Related Qualify of Life (Rand-36)

Independent variable: Interval vs Screen-detected tumorCo-variates: tumor characteristics; medical history of cancer; Socio-demographics – age, race/ethnicity, Dataset: WHI Observational study; WHI I 1993 – 2005; Ext 1 2005 – 2009; Ext 2 2010- 2020Proposed analyses: Survival estimates using Kaplan Meier curves and multivariable Cox proportional hazard models. Multivariate linear regression for health-related quality of life.

Future collaborations with Use of Tissue samples from WHI

RNA sequencing

heatmap

obtained from FFPE breast cancer cases. Gene signature separated by ER status.

Potential use of FFPE tumor tissue

Multiplex Staining in single showing basic panel and lymphoid panel for multiple biomarkers. This novel technique

allows sequential staining and quantification of 12 biomarkers on single FFPE tissue section

Limitations

Specific date of mammogram unknownDistinguishing between true interval cancer and a false negative mammographic screen diagnosis

Lack of information on breast density which may contribute to missed diagnosisWomen between 40-50 years not included in study

If you are interested in partnering with us or have suggestions for research, please contact us at:

Veronica IrvinVeronica.Irvin@oregonstate.edu541-737-1074

Pepper SchedinSchedin@ohsu.edu503-494-4931

Sonali JindalJindal@ohsu.edu503-494-2977

Questions & Discussion

References

Chlebowski et al. Ethnicity and Breast Cancer: Factors Influencing Differences in Incidence and Outcome. J Natl Cancer Inst (2005) 97 (6): 439-448. Collett et al. A Basal Epithelial Phenotype Is More Frequent in Interval Breast Cancers Compared with Screen Detected Tumors. 2005. 14(5): 1108.

 Duffy et al. Alcohol and folate intake and breast cancer risk in the WHI Observational Study. Breast Cancer Res Treat. 2009 August ; 116(3): 551–562. 

Henderson et al. Breast cancer characteristics associated with digital versus screen-film mammography for screen-detected and interval cancers. JR Am J Roentgenol. 2015. 205(3): 676–684.  Houssami & Hunter. The epidemiology, radiology and biological characteristics of interval breast cancers in population mammography screening. Breast Cancer. 2017. 3:12

References

Kalager et al. Prognosis in women with interval breast cancer: population based observational cohort study.  2012;345:e7536.  Kerlikowske et al. Identifying Women with Dense Breasts at High Risk of Interval Cancers. Ann Intern Med. 2015; 162(10): 673-681.

 Malmgren et al. Increase in mammography detected breast cancer over time at a community based regional cancer center: a longitudinal cohort study 1990–2005. BMC Cancer. 2008; 8:131. Meshkkat

et al. A comparison of clinical-pathological characteristics between symptomatic and interval breast cancer. Breast. 2015. 24(3):278-82.  Michael et al. Influence of stressors on breast cancer incidence in the Women’s Health Initiative. Health Psychol. 2009 March ; 28(2): 137–146.

Refences

Paskett et al. Breast Cancer Survivors’ Health-related Quality of Life: Racial Differences and Comparisons to Non-cancer Controls. Cancer . 2008 December 1; 113(11): 3222–3230. Simon et al. Mammography Interval and Breast Cancer Mortality in Women over the age of 75. Breast Cancer Res Treat. 2014.148(1): 187–195.

  Welch HG, Frankel BA. Likelihood that a woman with screen-detected breast cancer has had her "life saved" by that screening. Arch Intern Med. 2011;171:2043-6. Welch HG,

Passow HJ. Quantifying the Benefits and Harms of Screening Mammography. JAMA Intern Med. 2014;174:448-54. Yuan et al. Using administrative data to estimate time to breast cancer diagnosis and percent of screen-detected breast cancers – a validations study in Alberta, Canada. European J Cancer Care. 2015. ;24(3):367-75.