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[from Menopause - Hormones and Cancer Proceedings]
edited by M. Neves -e-Castro and B.G. Wren 2002
[MHC CH 7 p55-66]

    Outline and Commentary on the 2002 Proceedings
    by Timothy D. Bilash MD, MS, OBGYN

    June 2003

    B.G. Wren [MHC CH 7]
    Sydney Menopause Centre
    Royal Hospital for Women
    New South Wales

  1. "The breast is capable of producing its own estrogen, independent of circulating blood levels of estradiol. It is known that breast [fat] cells are capable of converting steroid precursors into estradiol at levels many times greater than is found in circulating blood and that this local activity is probably the major source of hormones responsible for the promotion and growth of breast cancers ."

  2. "It is also acknowledged that sex hormones are not responsible for initiating the ocogenic mutations that cause breast cancer , but they do have a marked influence on the rate of mitotic activity echibited by normal and malignant cells."

  3. "The fact that women continue to seek a satisfactory preparation to relieve their estrogen deficiency-related distress is a clear indication that these alternative agents are not capable of controlling those menopausal problems."

  4. "The previously held belief that exogenous administration of hormones is contraindicated for post menopausal women with breast cancer may not always be so."

  5. Why Estrogen and Progesterone don't cause Breast Cancer

    1. Other epidemiological results show anomalies

      1. If estrogen were an initiating cause of breast cancer, would expect that postmenopausal women who cease to produce estrogen would have a declining incidence of tumors. The opposite is found.
        1. Women over the age of 70 years are ten times more likely to have breast cancer diagnosis than women under the age of 40.
        2. Beral and the Collaborative Group on Hormonal Factors in Breast Cancer have shown that the incidence increases in direct proportion to age, and in a reanalysis of 51 major studies showed a 1.023 per year of use increase.

      2. If estrogen or progesterone were the initiating cause of breast cancer, would expect that the high levels of estrogen and progesterone in pregnancy would increase the risk of recurrence or new tumors. No increased risk is seen, or a reduction in recurrence risk or even death is observed.

      3. SUPPORT HRT (decreased breast cancer risk)

        1. Some randomized studies show no increased recurrence or death when estrogen with continuous progestogen is given after diagnosis and treatment of breast cancer.
        2. NHANESI (Lando and coleagues) showed that women using HRT (mainly unopposed estrogen) for as long as 22 years had a RR = 0.9 (1-3 years), RR = 0.5 (3-9 years), RR = 0.9 (10 or more years). [cohort study]
        3. Schairer and co-workers reported a non- statistical 10% reduction in breast cancer risk with unopposed continuous progestins for 5 or more years. (see below for sequential estrogen-progestin) [cohort study]
        4. Ross and co-workers noted that continuous progestin given to postmenopausal women was not associated with an increased risk with a history of breast cancer. (see below for premenopausal) [retrospective cohort study]
        5. Plu-Bureau and associates found a 50% reduction in the risk of developing breast cancer when given unopposed progestogen for up to 10 years.
        6. Nachtigall and associates and Gambrell and associates showed a reduced risk of breast cancer with sequential progestogen.
        7. Ewertz in Denmark showed a non-significant reduction in breast cancer risk with use of progestogen.

      4. OPPOSE HRT (increased breast cancer risk)

        1. Persson and co-workers (1997) showed a 2-fold increase in breast cancer for women who were taking HRT. The risk was increased with the addition of progestin. This was not statistically significant however. [retrospective case-control]
        2. Colditz and colleagues and Goldstein and colleagues showed evidence from the epidemiological Nurses Health Study that suggested that estrogen increases the risk of breast cancer, with sequential progestin increasing the risk. [epidemiologic study]
        3. Ewertz in Denmark showed a slightly increased risk of breast cancer with the use of estrogen. (see above for progestin).
        4. Schairer and co-workers showed an increase of 20-30% on breast cancer with sequential estrogen-progesterone over 5 years or more. (see above for progestins) [cohort study]
        5. Ross and co-workers concluded a 10% increase in breast cancer risk for each 5 years of sequential estrogen-progestin use in premenopausal with a history of breast cancer. (see above for post menopausal). [retrospective cohort study]

    2. EXPLANATION for these findings***

      1. Bi-phasic response for progestin (Musgrove and co-workers 1991)

        1. short term progestogen application increases breast cell mitosis
        2. continous progestogen application decreases breast cell mitosis through an inhibition of phosphorylation of retinoblastoma protein

      2. Mechanisms of Progestin on Breast Cancer***

        1. estradiol dehydrogenase and estrone sulfotransferase are induced by progestin, transforming active estradiol into inactive estrone sulfate
        2. matures alveolar breast cells which dont proliferate
        3. reduces estradiol receptors which inhibits cell mitosis
        4. reduces production of proto-oncogenes c-myc and c-fos, known to accelerate mallignant breast cell mitosis
        5. reduces production of cathepsin D, a potent breast cancer growth factor
        6. increases apoptosis and death of breast cells
        7. "Continous progestogen use (wth or without estrogen) has been shown to reduce the rate of breast cell mitosis, and this is likely to reduce the risk of breast cancer."
        8. "Druckman has shown that not only is there variation in the cellular response to different concentrations of progestogen, but some progestogens appear to have a potent inhibitory response while others have none."

      1. Estrogen effects on Breast Cancer***

        1. it is often forgotten that estrogen has been used to treat women with breast cancer with equal results to tamoxifen
        2. women with pregnancy after breast cancer also have good or better long-term survival
        3. many processes for growth and death in breast cells affected
          1. mitosis
          2. angiogenesis
          3. cell differentiation
          4. quiescence
          5. repair
          6. apoptosis
        4. estrogens and progestins affect these cell signals
          1. cyclins
          2. cyclin-dependent kinases
          3. inhibitor proteins
          4. growth factors

    3. "The older concept, held by many physicians, that hormones are universally contraindicated for women with breast cancer, can now no longer be substantiated."

      1. "If oncogenic mutations occur following sporadic translocation of genetic material during mitosis, then it is reasonable to conclude that any increase in cell division will result in an increased rate of cancer."
      2. "Unopposed estrogen with or without sequential progestogens will increase the rate of breast cell mitosis; there is now clinical and epidemiological evidence that this increased mitotic rate is associated with an increased rate of cancer." Note however that this is an assumption.

  6. Study results from Royal Hospital for Women Study, Sydney Australia (Wren)

    1. There is no evidence for increased breast cancer recurrence when continuous estrogen plus progestogen is given to symptomatic breast cancer patients in the Royal Hospital Study for over 25 years (population-based study starting in 1968)

      1. E+P decreases breast cancer reccurence and death [see table 2 p59]
        1. OR = 0.4 for risk of recurrence
        2. OR = 0.6 for risk of recurrence on HRT (0-5) years after diagnosis
        3. OR = 0.3 for risk of recurrence on HRT (>5) years on HRT after diagnosis
        4. OR = 0.1 for risk of death
      2. no significant difference in new breast cancers for combined E+P HRT
      3. women who began HRT within 5 years of treatment and continued therapy for many years had a significant reduction in the risk of recurrence or death.
      4. no advantage to delay beginning HRT till after 5years, with recurrence rates identical to the women who began HRT in the first 5 years.
      5. HRT decreases breast cancer recurrence even when delayed [see table 3 pg60]

    2. tamoxifen + estrogen,
      tamoxifen + progestogen,
      tamoxifen + estrogen + progestogen all had lower rates of recurrence [see table 5 p61]
      the best results were found when a progestogen and estrogen were added to tamoxifen, the same reduction seen for estrogen plus progestin alone (OR = 0.4)

    3. study characteristics
      1. retrospective (historical) cohort study
      2. after treatment for breast cancer, cohorts of 442 women elected to take HRT, 1222 women elected not to take
      3. continuous dosing
      4. most started within 5 years after treatment, 28% >5 years after treatment
      5. most were self-referred (symptomatic)
      6. majority of women who took unopposed hi dose progestogen did so for menopausal symptoms after developing metastases
        1. usually offered Provera 200-400mg or megesterol acetate 40-60 mg daily (high dose)
        2. initially offered a moderate dose of Provera 50mg or Northisterone acetate 5mg, but regimen has varied
        3. Provera dose ranging from 5 to100mg and norestisterone ranging from 1 to 5 mg
        4. 46 of 52 using unopposed estrogen were using a vaginal topical application, thought to have little effect on breast activity
        5. Premarin/conjugated estrogen 0.3mg or 0.625 mg, Ogen/estrone sulfate 1.25mg, estradiol valerate 2mg, or 17B-estradiol 1-2 mg was added for continued symptoms
        6. HRT users were average 4 years younger, with slightly smaller tumors, and more stage I, and more exposed to HRT prior to study

  7. Steps to inhibit estrogenic activity have yielded the best results to date in terms of prolongation of life.
    1. all these regimens have resulted in a 30-40% improvement in survival time
      1. ovarian ablation
      2. anti-estrogens (tamoxifen)
      3. specific estrogen receptor modulators/ SERMS (raloxifene)
      4. estrogen antagonists
      5. aromatase inhibitors
      6. progestogens

    2. Hormones are often given given after breast cancer treatment with positive results
      1. Tamoxifen (weak estrogen) has been used for partial remission of breast cancer in up to 40% of women
      2. Progestins and SERMS reduce tumor growth

    3. Short term vs long term benefits?
      1. Tamoxifen >5 years increases risks
      2. progestins appear to have long term and possible short term benefits

  8. Summary about this study on continuous hormone dosing:***

    "The clinical use of progestogen, particularly medroxy progesterone acetate (MPA), has been promoted for over 40 years to treat women with secondary spread of breast cancer. While the dosage of MPA has of necessity been high (400-2000mg) the inhibitory effect has been as effective as that of tamoxifen, and is probably mediated by the same internal cell-cycle control mechanisms which influence cell division in vitro. The theraputic applications of
    continuous progestin therapy has been shown to reduce the risk of new breast cancers and to inhibit the progress of breast cancer that has spread outside the breast.

    However, in spite of the excellent effect that progestogens (MPA, megestrol acetate, norethisterone, dydrogesterone) have on reducing breast cell mitosis and inhibiting breast cancer growth, a large number of women using progestogen continue to remain distressed by estrogen deficiency symptoms and thus require the addition of estrogen to control their problems (Table 6). In the present study we found that about one-quarter of those women who had breast cancer elected to take estrogen with continuous progestogen to relieve symptoms of estrogen deficiency.

    Following a review of this self-selected group of women, it would appear that those who chose to use this form of HRT were not disadvantaged by the therapy. There was no increase in either recurrence or deaths among women on HRT. In fact, women receiving combined estrogen-progestogen had a lower risk of recurrence or of death than women not on HRT, presenting a similar profile to those women who became pregnant following breast cancer. There was no advantage to women who delayed using HRT till after 5 years following their treatment for breast cancer, with recurrence rates identical to those of women beginning HRT in the first 5 years.

    However, for women who began HRT within 5 years of treatment for breast cancer, and continued the therapy for many years after,
    there was a significant reduction in the risk of recurrence or death. It appears from these figures that, once therapy has been inititated and the longer it is maintained, the less is the risk of recurrence.

    The risk of developing a new cancer while on continuous combined estrogen and progestogen was not increased
    above the risk found among women who did not use HRT, suggesting that continuous combined HRT is not responsible for initiating the development of breast cancer.

    The main advantage for those women taking combined therapy lay in the fact that their distressing estrogen deficiency symptoms had been relieved without compromising their suvival outcome.
    This population-based comparative study suggests that estrogen and progestogen administered continuously to women with a history of breast cancer does not have an adverse outcome. From our results, it would appear that the use of continous progestogen in a hormonal regimen conveys a degree of protection from breast cancer development and growth that is not evident with unopposed estrogen or with sequential progestogen and estrogen."

    [ISLT] continuous combined hormonal regimen may be better for symptomatic patients (high estrogen status). It is possible that asymptomatic (postmenopausal) patients may do better with cyclic therapy (low estrogen status, low receptor status).

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