導入
“Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death in females worldwide.”
世界全体では乳癌は女性におけるがんの発生件数、がん死亡件数の原因第１位である。
★日本の疫学を追加せよ。
“There has been a decline in breast cancer mortality rates in the United States and elsewhere in the western world, attributable to the increased use of screening mammography and advances in adjuvant therapies.”
米国やその他の西洋諸国では乳がんの死亡率は低下傾向にある。これはマンモグラフィ検診や補助療法の進歩によると考えられている。
★日本の疫学を追加せよ。
“The majority of breast cancer recurrences occur within the first five years of diagnosis, particularly with hormone receptor-negative or human epidermal growth factor receptor 2 (HER2)-positive disease. However, some recurrences occur much later, particularly in the setting of hormone receptor-positive, HER2-negative tumors, which tend to behave more indolently[5]. This was shown in a study of 2838 patients with stage Ⅰ/Ⅱ or Ⅲ breast cancer who had not recurred with five yeasr of completing initial therapy; recurrence risks in the subsequent 5 and 10 years were still 11 and 19 percent, respectively [6].”
乳がんの再発の大半は診断後５年以内に起こる、特にホルモン受容体陰性あるいはHER-2陽性例ではそうである。しかし一部の症例ではこれよりはるかに後で再発を来すことがある、特にホルモン受容体陽性例やHER2陰性例ではそうである（これらの症例は緩徐な進行を示すため）。初期治療完了後の5年以内に再発を来さなかったStageⅠ/Ⅱ or Ⅲ 乳癌患者2838人の研究でこの結果が示された。即ち続く5年、10年の再発率はそれぞれ11、19%であった。
★BCTの後治療をまとめよ
★BCTの長期経過観察のデータをまとめよ
“in breast tumor recurrence”, “contralateral breast events”
治療
手術
DCISの場合
→乳房温存手術の適応
→切除組織に浸潤がなければ腋窩リンパ節評価は省略される。
→3cm以上にひろがるの病変、微小浸潤あり→センチネルリンパ節生検を実施する。
早期浸潤がん（臨床的腋窩リンパ節転移なし）
→乳房温存手術＋センチネルリンパ節生検
センチネルリンパ節生検で３個以上のリンパ節陽性
→腋窩リンパ節廓清を実施
PMRTの適応
乳房切除後、腫瘤径大(> 5cm)＆断端陽性＆リンパ節陽性
ホルモン療法（アジュバント療法）
閉経前と閉経後で治療方針が異なる。
閉経前：
+ タモキシフェン
+ 卵巣抑制（アブレーション） AIあるいはタモキシフェンを伴う
+ 再発高リスク群→卵巣抑制＋エキセメスタン(exemestane)もあり
閉経後：
+ AI５年
+ タモキシフェン or AI ２～３年→その他の薬剤の連続３～２年（合計５年法）
+ タモキシフェン 10年
+ タモキシフェン 5年→AI 5年（計10年)
化学療法（術後療法として）
適応：ホルモン陰性例、ホルモン陽性だが再発高リスク例
+ ホルモン陽性例患者では、分子生物学的検査によるリスク評価が可能である
リンパ節陽性例ではタキサン、アンスラサイクリンを含むレジメンが頻用される
+ Anti-HER2治療
標準ケモに追加で使用する
適応：HER2陽性、浸潤乳がん、リンパ節転移陽性あるいはリンパ節転移陰性例のうち中～高リスクのもの
再発形式
局所再発(locoregional reccurence)あるいは遠隔転移(metastatic disease)
局所再発
”For women treated for early breast cancer, the recurrence rate ranges from 4 to 7 percent with mastectomy or BCT, respectively[9].”
早期乳癌治療後の再発率：乳房切除術後 4%、BCT後 7%。
遠隔転移
“Although approximately 15 to 40 percent of recurrences involve the chest wall and axillary or supraclavicular lymph nodes, breast cancer has the potential to metastatsize to almost every organ in the body.”
再発の15~40%は領域再発。
“The most common sites of metastases are bone, liver, and lung. Approximately 50 to 75 percent of patients who relapse distantly do so in a single organ; the remainder will develop diffuse metastatic disease. Less than 5 percent of patients will manifest central nervous system (CNS) involvement as the first site of metastatic disease. ”
遠隔転移好発部位は、骨、肝、肺。50-75%の患者で遠隔転移は1臓器。
★論文では初発再発部位と出現時期を整理することになるか。再発時の転移臓器数をまとめるのも一法か。
２次原発乳がん (second primary breast cancer) 対側乳癌
この領域のデータはコンフリクトしており、明確な結論に達していない。
“For women without an inherited predisposition to breast cancer (ie, a BRCA1 or BRCA2 mutation), the risk of a second breast cancer is between 0.5 and 1.0 percent per year [12,13]. For women with a known genetic predisposition, the risk is much higher. The lifetime risk of second primary breast cancers may be as high as 65 percent for BRCA1 mutation carriers and 50 percent for BRCA2 carriers [14].”
BRCA陰性の場合、２次乳癌の罹患確率は0.5~1%/年である。
“Limited data suggest a slight execess of contralateral breast cancers following breast or chest wall radiation therapy(RT) [15-17].” As an example, in data from an Early Breast Cancer Trialists’ Collaborative Group meta-analysis, the annual odds ratio for contralateral breast cancer for irradiated compared with nonirradiated women was 1.18 (p=0.002) [15]. This result was statistically significant for women 50 years of age and older (1.25 p=0.002) but not for younger women (1.09, p=0.30). On the other hand, other data suggest that the risk may by higher wigh younder age at treatment [16-19].”
RTにより対側乳癌がわずかに上昇するとのデータあり。50歳以上でのみ増加するというデータと若年者で増加するというデータがあり、コンフリクトを生じている。
“A Dutch report suggests that postmastectomy radiotherapy using direct electron fields leads to a significantly lower radiation exposure to the contralateral breast than poslumpectomy RT using photons with tangenital fields [17]. The joint effects of pustlumpectomy RT and strong family history for breast cancer in this series were associated with a higher risk for a secondary breast tumor than expected when individual risks were summed (hazard ratio 3.52). However, a nested case-control study by the investigators from the Women’s Environmental Cancer and Radiation Epidemiology (WECARE) Study Collaborative group, which included patients with known BRCA1/BRCA2 mutations, did not find a significant increase in contralateral breast cancers in carries irradiate for breast cancer [19]. A similar finding was reoprted in a separate study of breast cancer patients who were carriers of deleterious BRCA mutations despite the use of tangenital fields in the majority of patients[20]. Clearly, data are conflicting and further study is needed.”
オランダの報告では電子線PMRTの方が乳房部分切除＋X戦傷者より被曝量が少ない。この報告ではRTにより対側乳癌が著しく増えていた。一方でBRCA陽性例を含むWECARE研究ではRTによる対側乳癌の増加は検出されなかった。検出できなかったとするその他の研究もある。
“A substantial number of second primary breast cancers occur after five years, necessitating long-term surveillance for all women with a history of breast cancer [21,22]. This is especially true for hormone receptor-positve breast cancers. As an example, in National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-04, which evaluated mastectomy with and without RT, 50 percent of all contralateral breast cancers were detected after five years of follow-up [23].”
対側乳がんの50%は治療終了から5年後以降に出現する。特にホルモン陽性乳がんでの対側乳がんの出現時期は遅い。
２次発がん
“There is an increased risk for second cancers associated with breast cancer treatment, whether RT, chemotherapy, or tamoxifen [38-40].”
“Second cancers that have been associated with breast cancer treatment include esophageal, lung, uterine, and ovarian cancers as well as melanoma, soft tissue sarcoma (notably angiosarcoma), acute myeloid leukemia, and myelodysplastic syndromes [38,39].”
乳癌治療後に増える二次がんは、食道、肺、子宮、卵巣、メラノーマ、ザルコーマ、AML、MDS。
“While patients treated with adjuvant RT are at risk for radiation-induced solid tumors and myeloid neoplasms, these are rare late complications [38,41-43].”
RT後の２次発がんは稀である。
“Preliminary resutls of Early Breast Cancer Trialists’ Collaborative Group (EBCTCT) meta-analysis of rials including over 40,000 women randomly assigned to radiation or not reported that radiation was associated with an increase in overall second cancer incidence (RR 1.23, 95% CI 1.12-1.36), and increased rates, specifically of [44]:
+ Contralateral breast cancer (881 versus 673 cases; RR 1.20, 95% CI 1.08-1.33)
+ Esophageal cancer (RR 2.42, 95% CI 1.19-4.92), mainly in trials including irradiation of the internal mammary chain nodes and supraclavicular fossa where the esophagus was not shielded from radiation field,
+ Leukemia (RR 1.71, 95% CI 1.05-2.79), and
+ Lung cancer incidence in the second decade following RT (RR 2.10, 95% CI 1,48-2.98). The risk was increased primarily in women who smoked prior to and after their diagnosis of breast cancer.
”
“Absolute risk of developing a secondary malignancy because of radiation is small. In a cohort study of 58,000 patients treated for invasive breast cancer, although the 10-year risk of a second nonbreast primary cancer relative to the general population was elevated (RR 1.22, 95% CI 1.17-1.27), this translated into approximately 13 cancers per 1000 women [38].”
RTによる２次発がんの増加は 10年で1000人あたり13人と推測されている。
“The risk of a secondary malignancy after RT varies on the time that has elapsed since treatment was completed. As an example, secondary leukemias (usually myeloid) tend to occur within five to seven years; solid tumors, including esophageal cancer, usually present at 10 years after radiation[45-47]. However, radiation-induced angiosarcoma typically presents with a latency period of five to eight years.”
晩期有害事象
今回論文対象外の予定なので省略した
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