1. Chemoprevention of cancer Dr Manal Kahwaji Cancer fighting day Feb 2, 2016

2. Cancers could be prevented? Breast cancer Colorectal cancer Cervical cancer

3. Risk Assessment

4. Gail model

5. Gail Model on NCI website 5 year and lifetime estimates by race Validated for populations; but modest discriminatory value for the individual discriminatory value for the individual. Rockhill et al. J Natl Cancer Inst 93:358, 2001. http://www.cancer.gov/bcrisktool/

6. Risk factors not included in Gail model Age of diagnosis for family members 2nd degree relatives Alcohol intake Diabetes Physical activity Lactation history Use of HRT Height Weight Hormone level Bone mineral density Mammographic density

7. Prevention: Lifestyle Diet Exercise Alcohol Obesity

8. Reducing the risk of breast cancer 1.Early childbirth, breast feed 2.Exercise 3-7 hours / week 3.Maintain normal body weight 4.Minimize alcohol 5.Avoid long term HT, especially progestins 6.Low fat diet? Estimated 30-80% reduction in risk

9. Hormones and Chemoprevention

10. Breast Cancer Prevention Trial (BCPT) 13,388 women age > 35 – Estimated 5 year risk ≥ 1.66% 20 mg tamoxifen vs. placebo Stopped after average of 4 yrs; median follow-up: 55 months Fisher, JNCI, 1998

11. Tamoxifen reduced risk at all ages Age (years) Placebo Tamoxifen Fisher, et al. JNCI 1998;90:1371 Rate per 1,000 0 2 4 6 8 ≤49 50 - 59 ≥ 60

12. Tamoxifen in very high risk women 13 10.1 9.9 6.8 5.7 1.4 5.1 3.4 051015 LCIS Atypical hyperplasia ≥2 relatives All women Rate per 1,000 Fisher JNCI 1998; 90:1371 Placebo Tamoxifen

14. SERMs reduced the risk of ER+ but not ER- cancer

15. STAR Trial: Key outcomes per 1000 woman-years 19,747 women randomized, 5 year f/u Postmenopausal, average risk 4.0% OutcomeTam 20 mgRalox 60 mg Invasive BC4.34.4 Uterine Ca2.01.2 *DVT/PE3.72.6 Osteop. Fx2.72.5 CVD event4.44.6 *Cataracts12.39.7 * P < 0.05 Vogel, JAMA, 2006

16. Adverse Events From Prevention Trials of Tamoxifen & Raloxifene DVT/PE:1.9 (1.4-2.6) Endometrial cancer2.4 (1.5-4.0)  risk fatal stroke  risk cataracts  risk hot flashes ** Majority of adverse events in women ≥ 50 years Fisher JNCI,1998; Cuzick Lancet, 2003; Barrett-Conner, NEJM, 2006.

17. Comparison of 2 SERMs TamoxifenRaloxifene FDA Approvalbreast ca rx & prev. osteoporosis & breast ca prev. Populationpre and postpost-menopause Adverse and Side Effects DVT, hot flashes, cateracts, uterine ca DVT, hot flashes, flu-like syndrome, edema Duration rec5 yrs or lessStudied x 8 yrs

18. Tamoxifen and raloxifene FDA approved for prevention in high risk women: a 5-year risk >1.66% “American Cancer Society advises MRI for high risk women.” - March 28, 2007 Defined as 20-25% lifetime risk.

19. Aromatase inhibitors: the future? Block conversion of T to E ATAC: Treatment trial n=9366, 8 years – Anastrazole vs. Tamoxifen – 40% reduction in contralateral cancer – Less endometrial cancer, VTE, stroke – More fractures and musculoskeletal pain Letrozole after tamoxifen –37% reduction in contralateral cancer ATAC, Lancet Onc, 2008; Goss, JNCI, 2005. Ingle Annal Onc 2008.

20. Summary points Lifestyle – Exercise, weight loss or maintenance – Minimize alcohol – Avoid/stop HT – Low fat diet? Consider tamoxifen or raloxifene for high risk women Assess familial risk – Consider prophylactic surgery for BRCA carriers

21. Aspirin and cancer

22. Large meta-analysis 25000 people Aspirin 75 mg or more daily vs placebo for at least 4 years To evaluate cardiovascular disease and cancer incidence (Lancet 2011;377:31)

24. Aspirin to prevent CRC A study of Aspirin to prevent CRC A study of 14 000 patients who had taken part in aspirin RCTs for 20 years: Aspirin reduced the incidence of colon cancer (HR 0.76; CI 0.6–0.96). It had no effect on rectal cancers. Aspirin reduced mortality from colon cancer (HR 0.65; CI 0.48–0.88). 75mg was sufficient. NNT = 57 (57 people have to take aspirin for 5y to prevent 1 death from colon cancer). (Lancet 2010;376:1741, editorial 1713)

25. Aspirin after diagnosis of colorectal cancer 1279 men and women diagnosed with stage I, II or III colorectal cancer They determined aspirin use by questionnaire Follow-up was for >10y: (JAMA 2009;302:649)

26. Aspirin after diagnosis of colorectal cancer Patients who took aspirin regularly after diagnosis were less likely to die from cancer or any cause. No reduction in risk was seen in those who took aspirin prior to diagnosis. 10 year cancer survival was 74% for those who took aspirin vs. 69% for those who didn't. NNT = 20 (20 people diagnosed with colorectal cancer have to take aspirin for 1 extra to survive 10 years). Patients with overexpression of COX-2 in their tumours had the greatest benefits. (JAMA 2009;302:649)

27. Can aspirin reduce cancer metastases? Two meta-analyses discussed whether aspirin reduces long-term cancer mortality is by reducing distant metastases: Aspirin reduced the risk of distant metastatic spread It did not affect local or regional spread The benefit was greatest in GI cancers (Lancet 2012;379:1591 and Lancet DOI:10.1016/S1470-2045(12)70112-2).

28. Summary Aspirin reduces the incidence of cancer and cancer-related death, even 20y after stopping A reduced incidence may be seen as soon as 3y and reduced mortality at 5y 75mg is a sufficient dose and those under 55y appear to have no benefit Compared to the benefits, the harms are small..

29. Summary Aspirin is particularly effective at reducing incidence and mortality from colorectal cancer when used as primary prevention It also increases survival from colorectal cancer when used as secondary prevention A mutation of PIK3CA in colorectal cancer tumours may be a marker for individuals who would particularly benefit from aspirin therapy.

30. Summary A Lancet editorial suggests we should offer aspirin to those at high risk of colon cancer or those who have colon cancer after a personalised risk assessment They do not yet recommend population level use as primary or secondary prevention but more evidence is emerging.