Predictors of recurrence in hormone receptor positive breast cancer treated with adjuvant endocrine therapy

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1 Predictors of recurrence in hormone receptor positive breast cancer treated with adjuvant endocrine therapy ANZBCTG ASM Hilary Martin Medical Oncologist Fiona Stanley Hospital

2 Overview Background mammographic breast density Study preliminary results

3 Hormone receptor positive breast cancer recurrence ATAC 1 SOFT 2 5 year DFS Overall disease free survival (median f/u) 86.3% anastrazole 83.8% tamoxifen 86.6% tamoxifen+ovarian sup 84.7% tamoxifen 72% anastrazole 68% tamoxifen (120 months) ~1/3 have further breast cancer related event at median 10yr f/u 1 Cuzick J et al Lancet Oncol. 2010; 11(12): Francis P et al N Engl J Med 2015;372:

4 Factors associated with recurrence Established prognostic factors utilised to decide adjuvant therapy nodal status tumour size grade

5 Adjuvant recurrence prediction

6 Oncotype Dx

7 Current treatment paradigm hormone receptor positive breast cancer High risk: chemotherapy + endocrine therapy Endocrine therapy High risk premenopausal Ovarian suppression + exemestane 5yrs or 10 yrs tamoxifen low risk premenopausal 5 yrs tamoxifen 5 years aromatase inhibitor post menopausal Switch for those pre/perimenopausal at time of cancer diagnosis who become postmenopausal

8 Are there biomarkers which can be measured or assessed during endocrine therapy which can predict endocrine response that be utilised to tailor therapy?

Mammographic breast density and cancer Density determined by composition of breast tissue components fat, epithelium and stroma 1976 first association report association 1 Relative risk

9 Mammographic breast density and cancer Density determined by composition of breast tissue components fat, epithelium and stroma 1976 first association report association 1 Relative risk of breast cancer increases with increasing mammographic breast density (general population) 2 1 Wolfe JN Am J Roentgenol 1976;126: Boyd et al J Natl Cancer Inst ;87(9):670-5

10 Mammographic density breast cancer and breast cancer recurrence N Recurrence rates high vs low density Comparator Cil T et al 1 335* 21% vs 5% HR %CI , p= % vs 0% p < >50% density vs <25% dense >50% density vs <25% density no radiotherapy Eriksson L et al 2 1,774 HR 1.92, p=0.039 local recurrence >25% density vs <25% density adjusted for other prognosticators * Patients had undergone breast conserving surgery ~30% of population did not receive adjuvant radiotherapy 1. Cil T et al Cancer 2009 Dec 15;115(24): Eriksson L et al Breast Cancer Res 2013; 15(4):R56

11 Determinants of mammographic breast density Genetic factors Dietary factors high glycaemic load, high intake of total and rapidly absorbed carbohydrates associated with higher breast density 1 Age (inverse relationship between age and breast density) subset of older women with dense breasts 36% women in 70s had dense breasts, 74% women aged had dense breasts 2 Weight lower % density in patients with higher BMI (p for trend=0.0001) 3 HRT combination CEE/progestin 4 1. Masala G et al PLoS One (8):e Checka CM et al Am J Roentgenol (3):W Irwin ML et al JCO (9): Greeendale GA et al J Natl Cancer Inst (1):30-37

12 Mean breast density at entry to the study and 95% confidence intervals, by age group Jack Cuzick et al. JNCI J Natl Cancer Inst 2004;96:

13 Mammographic breast density and age Checka CM et al The relationship of mammographic density and age:implications for breast cancer screening Am J Roentgenol 2012 Mar;198(3):W292-5

14 1) Can mammographic breast density be reduced through intervention 2) Will reduction in breast density result in reduced risk of breast cancer development or recurrence?

15 Mean breast density tamoxifen vs placebo Jack Cuzick et al. JNCI J Natl Cancer Inst 2004;96: patients breast cancer prevention trial (IBIS1) 1 Tamoxifen reduction in breast density most during the first 18 months of treatment 7.9% density reduction 95%CI=6.9% to 8.9% vs placebo group 3.5%, 95%CI % greatest net reduction <45yrs

16 Tamoxifen and breast cancer risk reduction - prevention Cuzick et al 1 nested case-control study using IBIS1 population 123 cases dx with breast cancer, 942 controls without breast cancer Tamoxifen arm Comparator 10% reduction breast density vs <10% reduction breast density Risk reduction 63% reduction (OR %CI , p=0.002) Placebo arm 10% reduction breast density vs <10% reduction breast density No significant risk reduction (OR %CI 0.72 to 1.77 p=0.6) 1 Cuzick J et al J Natl Cancer Inst 2011;103(9):

17 Mammographic density with tamoxifen Study Design Age range, y Outcome Korea 2012 (Kim et al) Korea 2013 (Ko et al) Sweden 2013 (Li et al) Northwest 2015 (Nyante et al) Hospital-based patient cohort Hospital-based patient cohort Patient cohort Case-control Loco-regional or distant recurrence Loco-regional, contralat or distant recurrence Breast cancer specific death Breast cancerspecific death events/case tamoxifen users Not reported Mammogram type Digital, craniocaudal view Digital, view not specified Film, mediolateral oblique view Film, craniocaudal view Density measurement method Computerassisted thresholding (Cumulus) Visual assessment Fullyautomated thresholding Computerassisted thresholding (Cumulus) Main density measure Absolute change in percent density Change in BI- RADS category Relative change in dense area Absolute change in percent density Main association with outcome tamoxifen users <5% reduction vs 5% reduction HR = 1.52 (95% CI = 0.92 to 2.51) reduction in BI-RADS category (continuous) HR = 0.35 (95% CI = 0.17 to 0.68) >20% reduction vs 10% increase HR = 0.50 (95% CI = 0.27 to 0.93) >8.7% reduction vs <- 0.5% reduction OR = 0.44 (95% CI = 0.22 to 0.88) Adapted from Nyante et al table 4 Nyante SJ et al J Natl Cancer Inst 2015;107(30)

Adjuvant tamoxifen and mammographic breast density change Recurrence-free survival curves according to mammographic density reduction a total recurrence b systemic recurrence c locoregional

18 Adjuvant tamoxifen and mammographic breast density change Recurrence-free survival curves according to mammographic density reduction a total recurrence b systemic recurrence c locoregional recurrence patients adjuvant tamoxifen MDR positive (fall in mammographic breast density) or MDR (mammographic breast density reduction) negative (no fall in breast density) those with MDR after average of 19 months adjuvant tamoxifen - 65% lower risk of recurrence - 87% reduction locoregional - 52% reduction in systemic recurrence 1 Ko et al Breast Cancer Res Treat 2013 Dec;142(3):559-67

19 Adjuvant endocrine therapy, mammographic breast density 1,066 patient % aromatase inhibitor at time of mammogram 83.6% tamoxifen Kim J et al Breast Cancer Res 2012;14(4):R102

20 Predicted survival functions from delayed-entry Cox proportional hazards regression models (A) women not treated with tamoxifen and (B) women treated with tamoxifen 474 patients who received tamoxifen, 500 without Baseline mammogram prior to start hormone treatment next at least 6 months post baseline Tamoxifen arm:relative density reduction of >20% reduced risk of death as a result of breast cancer of 50% (HR 0.50;95% CI 0.27 to 0.93) compared to with stable mammographic breast density Jingmei Li et al. JCO 2013;31:

21 Aromatase inhibitor studies Study Population Eligibilty Intervention N Mean absolute change Vachon, 2007 Fabian, 2007 Mousa, 2008 Cigler, 2010 Postmenopausal cases from NCIC MA17 Postmenopausal women High risk postmenopausal women Postmenopausal cases and non-cases Prior TAM use Taking hormone replacement therapy Taking hormone replacement therapy Letrozole Placebo (p=0.58) Average duration therapy 12 months Letrozole months Letrozole None > 25% density Letrozole Placebo (p=0.04) (p=0.61) (p=0.61) Median 24 months 12 months 24 months Adapted table 1 Vachon CM et al Clin Cancer Res 2013;19(8):

22 Study Population Eligibilty Intervention N Mean absolute change Cigler, 2011 Prowell, 2011 Kim, 2012 Vachon 2013 Postmenopausal women Any visible density Postmenopausal cases DCIS or Stage I III cases < 6 months prior local therapy Premenopausal and Postmenopausal case Postmenopausal breast cancer cases matched to healthy controls ER positive>2 years endocrine Cases from AI trials Control screen Exemestane Placebo Anastrozole 50 Any aromatase inhibitor Exemestane or Anastrozole Controls (p=0.59) (p=0.96) (p=0.52) +2% (p=0.87) 16% (p=0.08) Av duration therapy 6 months 12 months 24 months 6 months 12 months % 13 months (p=0.73) 10 months

23 Aromatase inhibitor use and mammographic breast density change Kim et al: 175 women treated with AI MBD reduction at 13 months <5% 7 times greater risk recurrence at 68.8months f/u compared with reduction >5% (not statistically significant (95%CI: ) Kim J et al Breast Cancer Res 2012;14(4):R102

24 Mammographic breast density and aromatase inhibitors Aromatase expression is increased in tissue cores from dense regions compared to non-dense regions of healthy women 1 No clear association between these papers thus far?no correlation?longer follow-up mammogram time required or larger study cohort?different density measurement tool required eg MRI to detect smaller AI related change 1Vachon CM et al Breast Cancer Res Treat. 2011;125:243-52

25 Aims and objectives Aim: to investigate potential predictors of endocrine sensitivity in order to guide endocrine therapy Primary focus mammographic breast density change as predictor of breast cancer recurrence Other potential predictors to be investigated Treatment related toxicity BMI change Bone mineral density change Concomitant medications Tissue correlates with outcome and mammographic breast density

26 Study Methods Prospectively collected breast unit database Case note review 1942 patients (21 subsequently excluded as metastatic or DCIS only) single researcher 239 fields Compliance Toxicity and management concomitant medications Chemotherapy induced menopause return of menstrual function (not present in Korean study) Electronic records systems Bone mineral density from hospital system

27 Mammograms Mammograms from breastscreen WA and hospital system digital and film Baseline (at time of diagnosis) and subsequent mammograms contralateral CC view Film scanned to enable reading via Cumulus Single reader Dr Jennifer Stone

28 Measurement mammographic breast density: Cumulus technique Thresholding technique Manually select level of brightness to define as dense Outline of breast defined % dense area calculated

29 Tissue Tissue microarrays normal tissue and cancer Planned analysis potential predictors of endocrine resistance and markers associated with mammographic breast density Endocrine sensitivity/resistance: estrogen receptor coactivators: SRC 1 estrogen receptor corepressor:ncor1 2 estrogen receptor co-regulators: protein kinase RNA-activated Activator (PACT) Transactivating Region Binding protein TARBP and DICER associated with endocrine resistance/sensitivity 3 Markers mammographic breast density:matrix metalloproteinases (MMP) 1, 3, 9, 12, estrogen receptor alpha and beta 4 1 Osborne CK et al J Natl Cancer Inst 203;95: Girault I et al Clin Cancer Res 2003; 9: Redfern et al Proc Natl Acad Sci USA 2013;110 : Maskarinec G et al2010 Gesundheitswesen 2010;72:286

30 Results: Demographics Age at diagnosis >80 Premenopausal Perimenopausal Postmenopausal Unknown BMI < Unknown Received chemotherapy Received radiotherapy N (%) 13 (0.7%) 83 (1%) 314 (16%) 555 (29%) 574 (30%) 259 (13%) 118 (6%) 419 (22%) 147 (8%) 1327 (69%) 25 (1%) 627 (33%) 570 (30%) 499 (26%) 90 (4%) 135 (7%) 640 (33%) 1210 (63%)

31 Results:tumour characteristics Grade unknown Nodal status N0 N1 (1-3 nodes) N2 (4-9 nodes) N3 (>9 nodes) Unknown T stage T1 2cm T2 >2, 5cm T3 >5cm Missing N(%) 548 (29%) 1065 (55%) 288 (15%) 19 (1%) 1214 (63%) 498 (25%) 132 (6.8%) 70 (3.6%) 7 (0.3%) 1183 (62%) 620 (32%) 99 (5%) 18 (1%) Known HER2+ve 163 (8.4%)

32 HRT exposure 1234 (64%) no exposure 345 (18%) taking at time of diagnosis 273 (14%) exposure in past

33 Hormonal treatment - initial

34 Initial endocrine therapy 600 (31%) were continuing on initially prescribed endocrine therapy at last review 370 (19%) had ceased initial endocrine treatment due to completion of planned therapy

35 Switch 794 (41%) had been exposed to greater than 1 form of antioestrogen therapy 145 planned switch from tam to letrozole 178 planned switch to anastrazole 50 planned switch to examestane 421 (22%) ceased first hormonal therapy secondary to toxicity

36 Recurrence data median f/u 64 months 241 (12.5%) further breast cancer Local recurrence:47 (2%) Regional:21 (1%) contralateral cancer 50 (2%) distant metastatic disease 171 (9%)

37 DFS by BMI at baseline Univariate anaylsis comparing BMI <25 with BMI >=25: Odds of recurrence 1.6 times higher if BMI >=25 (p=0.003) (95%CI ) DFS by BMI base line Lower or greater than BMI analysis time BMIbi = 0 BMIbi = 1

38 Recurrence by first line endocrine treatment Aromatase inhibitor Tamoxifen HR 0.36 p= %CI

39 Mammographic density data 4301 mammograms for 689 patients in this dataset currently read 506 patients had both a baseline and mammogram after between 11-24months endocrine treatment All had been adherent to endocrine therapy (self reported) 24months Entire cohort -6.0% Mean % density change Recurrence -5.9 (N=64) p non-significant recurrence vs no recurrence Mean % density change no recurrence -6.1 (N=441)

40 Mammographic breast density % change by menopausal status Menopausal status N Mean Range Premenopausal % -4.2 to 9% Perimenopausal % -3.6 to 1.9% Postmenopausal % -4.0 to 4.8%

41 Mammographic breast density change by endocrine therapy N Mean 95%CI mean Tamoxifen to -5.2% Letrozole to -4.3% Anastrazole to -3.0%

42 Kaplan Meier DFS curve reduction in breast density vs no reduction Percentage breast density change: MDR+ve (blue) vs MDR-ve (red) entire cohort No statistically significant difference Separation curves at ~8yrs similar to separation of Li et al

43 Post-menopausal at time of DFS curves

44 Change in mammographic breast density pda unique rank of ( datetest ) by umn Percentage dense area mammographic breast density over time tamoxifen vs aromatase inhibitor lower 0 1 lb/ub

45 Baseline percentage dense area and survival Overall survival better in those with higher baseline breast density HR p= %CI higher baseline density associated with younger age

46 Further analysis mammographic breast density Completion of dataset reading Multivariate analysis required Adjustment for film vs digital mammogram density area change assessment tamoxifen, aromatase inhibitor, and at months treatment Density change at switch Density change at completion of endocrine therapy and during follow-up

47 Summary Interim data analysis thus far Mammographic density shows promise in those treated with tamoxifen in earlier studies aromatase inhibition less clear Clinical relevance with aromatase inhibitor in postmenopausal/tamoxifen in premenopausal Bone mineral density data further investigation of trend found with expanded data set Ongoing research into predictors to guide endocrine therapy required

48 Acknowledgements A/Prof Andrew Redfern Dr Jennifer Stone Dr Andrew Davidson Jill Tinnings Francis Yap & Kimberley Chung Breast screen WA Liz Wylie, Jan Tresham Bruce Latham, Jennet Harvey, Wendy Erber, Katie Meehan, Bob Mirzai TRF funding for study

49 Thank you Questions?

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