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 Beatson, GT (1896). On the treatment of inoperable cases of carcinoma of the mamma. Suggestions for a new method of treatment with illustrative cases. Lancet, 2, 104-7.

Clemons, M., & Goss, P. (2001). Estrogen and the risk of breast cancer. N engl J med, 344(4), 276-285.

“Estrogen receptors/SERMS,” (n.d.). In National cancer institute. Retrieved from http://www.cancer.gov/cancertopics/understandingcancer/estrogenreceptors/AllPages

“Facts for life tamoxifen,” (2010). In Susan g. komen for the cure. Retrieved from http://ww5.komen.org/uploadedfiles/content_binaries/806-326a.pdf

“Facts for life aromatase inhibitors” (2010). In Susan g. komen for the cure. Retrieved from http://ww5.komen.org/uploadedFiles/Content_Binaries/806-03910.pdf

Fisher, B., Costantino, J. P., Wickerham, D. L., Redmond, C. K., Kavanah, M., Cronin, W. M., ... & Volmark, N. (1998). Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. Journal of the National Cancer Institute, 90(18), 1371-1388.

Goss, P. E., & Strasser-Weippl, K. (2004). Aromatase inhibitors for chemoprevention. Best Practice & Research Clinical Endocrinology & Metabolism, 18(1), 113-130.

Howell, A., & Dowsett, M. (1997). Recent advances in endocrine therapy of breast cancer. BMJ, 315(7112), 863-866.

Johnston, S. R., & Dowsett, M. (2003). Aromatase inhibitors for breast cancer: lessons from the laboratory. Nature Reviews Cancer, 3(11), 821-831.

Jordan, V. C. (1988). The development of tamoxifen for breast cancer therapy: a tribute to the late Arthur L. Walpole. Breast cancer research and treatment, 11(3), 197-209.

Jordan, V. C., & Morrow, M. (1999). Tamoxifen, raloxifene, and the prevention of breast cancer. Endocrine reviews, 20(3), 253-278.

Lacassagne, A. (1936). Hormonal pathogenesis of adenocarcinoma of the breast. The American Journal of Cancer, 27(2), 217-228.

Mouridsen, H., Gershanovich, M., Sun, Y., Pérez-Carrión, R., Boni, C., Monnier, A., ... & Dugan, M. (2001). Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group. Journal of Clinical Oncology, 19(10), 2596-2606.

Nabholtz, J. M., Buzdar, A., Pollak, M., Harwin, W., Burton, G., Mangalik, A., ... & Von Euler, M. (2000). Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial. Journal of Clinical Oncology,18(22), 3758-3767.

Ramaswamy, B., Lu, Y., Teng, K. Y., Nuovo, G., Li, X., Shapiro, C. L., & Majumder, S. (2012). Hedgehog signaling is a novel therapeutic target in tamoxifen resistant breast cancer aberrantly activated by PI3K/AKT pathway. Cancer Research.

Smith, I. E., & Dowsett, M. (2003). Aromatase inhibitors in breast cancer. New England Journal of Medicine, 348(24), 2431-2442.

Stockwell, S. (2008). Classics in oncology: George thomas beatson md (1848‐1933). CA: A Cancer Journal for Clinicians, 33(2), 105-107.

History

1896: George Beatson

  • Bilateral oophorectomy  breast cancer remission
  • “Father of endocrine ablation in cancer management”

1936: Antoine Lacassagne

  • Estrogen directly contributes to cancer
  • Estrogen antagonist to treat breast cancer

1962: Jensen and Jacobson

  • Estrogen receptor

1962: Tamoxifen discovered

  • Initially proposed as a contraceptive
  • Arthur Walpole encouraged antiestrogen application

1970s: First aromatase inhibitor (aminoglutethimide) used to treat advanced breast cancer

  • Initially developed as anticonvulsant
  • Redeveloped to inhibit steroid hormone synthesis

Background: Estrogen

  • Female characteristics
  • Sexual reproduction
  • Produced and secreted by ovaries
  • Converted from androgens by enzyme aromatase

Targets

  • Breast and uterus
  • Act by binding to estrogen receptors (ERs)
  • In breast and uterus  cell proliferation

Breast Cancer

  • More than 2/3 of breast cancers are estrogen receptor positive
  • Lifetime cumulative estrogen exposure
  • Depriving estrogenic signaling: main form of hormonal therapy

References

Tamoxifen vs. Aromatase Inhibitors

Questions??

Erin Ong

BSCI338G

Tamoxifen

Clinical Trials

  • Nolvadex®
  • Estrogen analog
  • Competitive antagonist
  • Partial agonist effects
  • Administered orally
  • “Gold standard”

Aromatase Inhibitors

National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 Study (1998)

  • Does tamoxifen prevent invasive breast cancer in women at increased risk?
  • Over 13,000 participants randomly assigned to receive 20 mg tamoxifen or placebo daily for 5 years
  • Anastrazole (Arimidex®), exemestane (Aromasin®), letrozole (Femara®)
  • Inhibits aromatase
  • For postmenopausal, estrogen-receptor positive patients
  • Administered orally after surgery or radiation therapy

Results

Johnston & Dowsett, Nature Reviews Cancer, 3: 821-831, 2003

Fisher et al., Journal of the National Cancer Institute, 90:1377-1388, 1998

International Letrozole Breast Cancer Group

Clinical Trials

Fisher et al., Journal of the National Cancer Institute, 90:1377-1388, 1998

Side effects

Length of Treatment

North American Multicenter Randomized Trial (2000)

  • Tamoxifen vs. Anastrazole
  • 353 postmenopausal, ER+ women diagnosed with breast cancer
  • Randomly assigned anastrazole pill + tamoxifen placebo or anastrazole placebo + tamoxifen pill for first line of therapy
  • 5 years
  • Resistance
  • Hedgehog (Hhg) pathway
  • P13/AKT pathway
  • Vismodegib

Time to progression medians: for letrozole 41 weeks (9.4 months); for tamoxifen median TTP was 26 weeks (6.0 months).

Naboltz et al., Journal of Clinical Oncology, 18:3758-3767, 2000

Mouridson et al., Journal of Clinical Oncology, 19:2596-2606, 2001

Cost

Side Effects

  • Increased risk of thromboembolism
  • Vaginal bleeding and discharge
  • Hot flashes
  • Cataracts

  • Can lower LDL cholesterol
  • Can prevent bone demineralization

Which one is better?

  • About $100 per month
  • Covered by insurance or offered with discount by AARP and other assistance programs
  • Cost
  • Resistance
  • Side effects
  • Research on aromatase inhibitors still limited
  • History of patient
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