女性荷爾蒙療法與乳癌發生風險之相關性研究：台灣健保資料庫之分析

Abstract

研究目的： 由於荷爾蒙療法對於潮熱及陰道乾澀的療效顯著，因此，美國在1960年代以後女性使用此療法極為盛行，但由於其用藥安全的疑慮，美國國家衛生研究院自從在1993年開始，陸續進行許多大規模的研究之後，到目前為止，使用雌激素合併黃體素對於乳癌的風險已被確定，但單純使用雌激素對於乳癌的風險仍然不明。在此同時，許多研究諸如英國MWS也已看到雌激素合併黃體素或是單純使用雌激素具有相當的風險，因此本研究希望能透過健保資料庫進一步釐清兩種荷爾蒙使用方式對於乳癌風險的差別。 本研究藉由健保資料庫描述雌激素的醫療利用情形，計算各類雌激素製劑的使用型態，進而評估與乳癌發生風險的相關性。 研究方法： 本研究主要以全民健康保險研究資料庫中1997-2008共12年的100萬健保抽樣歸人檔之婦女所有就醫記錄檔為母群體，經過扣除非女性498,838人，未滿20歲193,511人，超過79歲2,242，1998年以前曾發生癌症，或是乳癌前曾發生過其他癌症的1,926人，以及曾使用過乳癌用藥的850人，我們得到305,633人，再扣掉曾使用中藥的239,910人，最後，我們得到未曾使用中藥而曾使用荷爾蒙的25,671人為研究組，而未使用中藥也未使用荷爾蒙的40,052人為對照組，共計65,723位女性。然後我們以乳癌的發生為結果，分別計算不同女性荷爾蒙使用狀況下的風險比，以Cox model作回歸分析。 結果與討論： 相對於未使用中藥與女性荷爾蒙兩者的女性，停用荷爾蒙越久，其發生乳癌的風險就越低，在最後一年並用雌激素與黃體素者風險最高，風險比8.71(95%CI, 5.50-13.82)，而僅使用雌激素的風險則較低，風險比為2.04(95%CI, 1.37-3.06)。停經後的女性仍有相類似的情況，最後一年並用雌激素與黃體素者的風險比為54.05 (95%CI, 28.94-100.93)，而僅使用雌激素的風險比為3.01(95%CI, 1.32-6.87)。 結論： 本研究顯示，在1997到2008年的健保資料庫中，乳癌的發生風險，合併雌激素與黃體素處方有較僅使用雌激素製劑處方的婦女較高的風險，本研究顯示在55至79歲婦女使用僅含雌激素處方，仍有乳癌發生風險較高的安全疑慮。

Aim: Proven benefits of hormone replacement therapy (HRT) include relief of vasomotor symptoms and vaginal atrophy and prevention and treatment of osteoporosis. Therefore, HRT given as either unopposed estrogen replacement therapy (ERT) or estrogen plus progestin gained widespread popularity in the United States since 1960s. The Women's Health Initiative (WHI) trial of estrogen plus progestin vs. placebo was stopped early, after a mean 5.6 years of follow-up, because the overall health risks of hormone therapy exceeded its benefits. The Women’s Health Initiative Estrogen-Alone trial comparing conjugated equine estrogens with placebo was stopped early because of an increased stroke incidence and no reduction in risk of coronary heart disease. Preliminary results suggesting possible reduction in breast cancers which are not consistent with the findings of some observational studies warranted more detailed analysis. Because female hormones are reimbursed under the National Health Insurance program in Taiwan, it is possible to access and analyze nationwide data for these drugs. The purposes of this study were to estimate the effect of hormone replacement therapies (HRT) on the risk of incidence of breast cancer in women in Taiwan. Method: We used the 1,000,000 random sampling from the National Health Insurance Research Database (NHIRD) during 1997-2008 in our study. After excluded male, aged fewer than 20 and above 80, women who had cancer or had breast cancer medication previously, we had totally 305,633 women. In order to avoid the effect of Chinese herbal product, we also excluded 239,910 women who ever used it. At last, we recruited 65,723 who used estrogen alone, progesterone alone, estrogen plus progesterone and women used neither hormone nor Chinese herbal products were recruited into our study. The risk of hormone utilization was estimated by Cox model.

Results & Discussion: Among 2,798 women who have used solely estrogen plus progestin during study period, 45 newly breast cancer were diagnosed after taking estrogen plus progestin. Comparing to 76 newly diagnosed breast cancers among 5,156 women who have used unopposed estrogen during the same study period, significant higher estimated hazard rate of estrogen plus progestin users was found in present study. Women used combination of estrogen and progesterone in the last year were under the higher risk (HR: 8.71, 95%CI, 5.50-13.82) than estrogen-only (HR: 2.04, 95%CI, 1.37-3.06). Of all breast cancer women among estrogen plus progestin users, 23 (51%) of them were diagnosed at age between 55 and 79 years. Further analyses found that the significant association between the current use of estrogen plus progestin and the risk of breast cancer incidence among women aged between either 20 to 79 years or 55 to 79 years who were less likely to use oral pills. The data also demonstrated that discontinued exposure to estrogen plus progestin for half a year will significant decrease the risk of breast cancer among both women of reproductive age and 55 to 79 years of age, and the trend for lower risk was observed for women discontinuing exposure for longer period. This observation suggests a role for cumulative exposure of estrogen plus progestin on breast cancer risk. The positive association between ERT use and the increase of breast cancer occurrence was also found. In addition, the trends across categories of usage status appeared to be the longer discontinued ERT use before breast cancer was diagnosed are significant associated with the lower risk of breast cancer, indicating a positive relationship exists between excessive exposure of unopposed estrogen and breast cancer. The results of present study strongly support an added impact of progestin on the breast cancer risk associated with ERT. Various type of HRT were prescribed either following the updated guidelines on the use of HRT or after careful clinical judgment based on well informed about the potential benefit and perceived risks of HRT by well-trained qualified physicians resulting in the clinical performance that women use combined estrogen-progestin had significant higher breast cancer incidence than those use unopposed estrogen. Conclusions: This study provides strong evidence that the addition of a progestin to HRT enhances markedly the risk of breast cancer relative to estrogen use alone in Taiwan. These findings have important implications for the risk–benefit equation for HRT in women using estrogen plus progestin.