PATIENT CONSENT and REGISTRATION
病人同意書和註冊

TISSUE SUBMISSION - PROSIGNA (PAM50) ASSAY
組織提交 - prosigna (pam50) 分析

• Luminal A intrinsic subtype
  A 腔固有亞型
• Risk of Recurrence score $\le 60$$\le 60$<= 60\leq 60
  復發風險評分 $\le 60$$\le 60$<= 60\leq 60
• Sites notified of results to confirm randomisation
  通知各研究機構結果以確認隨機化
  

  

STRATIFICATION 策略

Centre 中心
Age (50-59, 60-69, $\ge 70$$\ge 70$>= 70\geq 70 years)
年齡（50-59、60-69、 $\ge 70$$\ge 70$>= 70\geq 70 歲）
ROR score ( $\le 40,41-60$$\le 40,41-60$<= 40,41-60\leq 40,41-60 )
ROR 得分 ( $\le 40,41-60$$\le 40,41-60$<= 40,41-60\leq 40,41-60 )
Minimum radial surgical margins for invasive carcinoma and associated DCIS ( $<1,\ge 1$$<1,\ge 1$< 1, >= 1<1, \geq 1 to $<2,\ge 2\mathrm{mm}$$<2,\ge 2\mathrm{mm}$< 2, >= 2mm<2, \geq 2 \mathrm{~mm} )
浸潤性癌及相關 DCIS 的最小徑向手術邊緣 ( $<1,\ge 1$$<1,\ge 1$< 1, >= 1<1, \geq 1 至 $<2,\ge 2\mathrm{mm}$$<2,\ge 2\mathrm{mm}$< 2, >= 2mm<2, \geq 2 \mathrm{~mm} )

Follow-up: 跟進：

• End of RT (Arm A) or 3 months after randomisation (Arm B)
  RT 結束 (A 組) 或隨機抽籤後 3 個月 (B 組)
• 6 and 12 months after randomisation (Arms A & B)
  隨機分組後 6 個月和 12 個月 (A、B 組)
• Annually to 10 years (Arms A & B)
  每年至 10 年 (武器 A 和 B)

4

STUDY DESIGN 研究設計

4.1 Registration 4.1 註冊

4.2 Confirmation of randomisation and stratification
4.2 確認隨機化和分層

• Age (50-59, 60-69, $\ge 70$$\ge 70$>= 70\geq 70 years);
  年齡（50-59、60-69、 $\ge 70$$\ge 70$>= 70\geq 70 歲）；
• Minimum radial surgical margin for invasive carcinoma and any associated DCIS (<1, $\ge 1$$\ge 1$>= 1\geq 1 to $<2,\ge 2\mathrm{mm}$$<2,\ge 2\mathrm{mm}$< 2, >= 2mm<2, \geq 2 \mathrm{~mm} );
  浸潤性癌及任何相關 DCIS 的最小徑向手術邊緣 (<1, $\ge 1$$\ge 1$>= 1\geq 1 至 $<2,\ge 2\mathrm{mm}$$<2,\ge 2\mathrm{mm}$< 2, >= 2mm<2, \geq 2 \mathrm{~mm} )；
• ROR score (0-40, 41-60); ROR 得分（0-40，41-60）；
• Centre. 中心。

4.3 Randomisation 4.3 隨機化

5 ELIGILIBILITY 5 資格

5.1 Inclusion criteria 5.1 納入標準

5.1.1 Registration 5.1.1 註冊

1. Female patients aged $\ge 50$$\ge 50$>= 50\geq 50 years of any menopausal status.
   年齡 $\ge 50$$\ge 50$>= 50\geq 50 歲、任何更年期狀態的女性病患。
2. Primary invasive carcinoma characteristics as assessed by conventional histopathology:
   以傳統組織病理學評估的原發性浸潤性癌症特徵：
   a) Unifocal histologically confirmed invasive breast carcinoma;
   a) 經組織學證實的單灶浸潤性乳癌；
   b) Maximum microscopic size of invasive carcinoma $\le 2\mathrm{cm}$$\le 2\mathrm{cm}$<= 2cm\leq 2 \mathrm{~cm};
   b) 侵襲性癌症的最大顯微尺寸 $\le 2\mathrm{cm}$$\le 2\mathrm{cm}$<= 2cm\leq 2 \mathrm{~cm} ；
   c) Grade 1 or 2 histology;
   c) 1 級或 2 級組織學；
   d) ER and PR positive in $\ge 10\mathrm{\%}$$\ge 10\mathrm{\%}$>= 10%\geq 10 \% of tumour cells in either the core biopsy or therapeutic surgical resection specimen of the primary breast carcinoma;
   d) 在原發性乳癌的核心活檢或治療性手術切除標本中， $\ge 10\mathrm{\%}$$\ge 10\mathrm{\%}$>= 10%\geq 10 \% 腫瘤細胞的 ER 和 PR 陽性；
   e) HER2 negative on IHC (score 0 or $1+$$1+$1+1+ ) or in situ hybridisation as per established national or international guidelines. Equivocal IHC score (2+) must be assessed by in situ hybridisation to confirm negative HER2 status.
   e) 根據既定的國家或國際指引，IHC（分數 0 或 $1+$$1+$1+1+ ）或原位雜交測定 HER2 陰性。IHC 評分不確定 (2+) 者必須進行原位雜交評估，以確認 HER2 陰性狀態。
3. Primary tumour must be resected by breast conserving surgery with microscopically negative margins for invasive carcinoma and any associated DCIS (no cancer cells adjacent to any inked edge/surface of specimen) or re-excision showing no residual disease (refer Section 9.1).
   原發性腫瘤必須以保乳手術切除，且顯微鏡下浸潤性癌和任何相關的 DCIS 邊緣為陰性（標本的任何墨色邊緣/表面附近沒有癌細胞），或再次切除顯示沒有殘留疾病（參閱第 9.1 節）。
4. Histologically confirmed negative nodal status determined by sentinel node biopsy or axillary dissection.
   經由前哨結點活檢或腋窩解剖確定組織學證實為陰性結點狀態。
   Note: Patients with pNO (i+) disease are eligible for study participation (malignant cells in regional lymph node(s) no greater than 0.2 mm in maximum dimension detected by hematoxylin-eosin (H&E) or IHC, including isolated tumour cells).
   註： 患有 pNO (i+) 疾病的患者有資格參與研究 (經由蘇木紅-伊索因 (H&E) 或 IHC 檢測到最大尺寸不超過 0.2 mm 的區域淋巴結中的惡性細胞，包括孤立的腫瘤細胞)。
5. No evidence of distant metastasis.
   無遠端轉移跡象。

5.1.2 Randomisation 5.1.2 隨機化

1. Primary tumour characteristics as assessed by Prosigna (PAM50) Assay:
   由 Prosigna (PAM50) 分析評估的原發性腫瘤特徵：
   a) Luminal $A$$A$AA intrinsic subtype; and
   a) Luminal $A$$A$AA 內在亞型；以及
   b) ROR score $\le 60$$\le 60$<= 60\leq 60. b) ROR 得分 $\le 60$$\le 60$<= 60\leq 60 。

5.2 Exclusion criteria 5.2 排除標準

1. Primary tumour characteristics:
   原發性腫瘤特徵：
   a) Presence of multifocal or multicentric invasive carcinoma or associated multifocal or multicentric DCIS;
   a) 存在多灶性或多中心浸潤性癌，或伴有多灶性或多中心 DCIS；
   Note: 請注意：

• Multifocal disease is defined as two or more invasive carcinoma or associated DCIS that are grossly or macroscopically distinct, with a minimum intervening distance of 5 mm .
  多灶性疾病的定義為兩個或兩個以上的浸潤性癌或伴隨的 DCIS，其大體上或顯微鏡下有明顯的區別，最小間隔距離為 5 mm。
• Individual macroscopic tumours that are joined microscopically by contiguous uniform tumour cell density may indicate a single tumour.
  顯微鏡下由連續均勻的腫瘤細胞密度連接起來的單個大腫瘤可能顯示為單一腫瘤。
• Where small, microscopic satellite foci of invasive tumour or associated DCIS are identified in close proximity to the primary tumour, the pathologist should determine if the additional foci are considered a component of the primary tumour or distinctly separate lesions constituting multifocal disease.
  如果在原發腫瘤附近發現微小的浸潤性腫瘤衛星病灶或相關的 DCIS，病理學家應確定這些額外的病灶是否被視為原發腫瘤的組成部分，或是構成多發性疾病的明顯獨立病灶。
  b) Evidence of clinical or pathologic T4 disease (extension to the chest wall, oedema or ulceration of skin, satellite skin nodules, inflammatory carcinoma);
  b) 有臨床或病理 T4 疾病的證據 (擴展至胸壁、皮膚水腫或潰瘍、衛星皮膚結節、發炎性癌)；
  c) Invasive component of the primary tumour is present as microinvasive carcinoma ( $\le 1\mathrm{mm}$$\le 1\mathrm{mm}$<= 1mm\leq 1 \mathrm{~mm} in maximum dimension) only;
  c) 原發性腫瘤的浸潤性成分僅呈現為微浸潤性癌症（ $\le 1\mathrm{mm}$$\le 1\mathrm{mm}$<= 1mm\leq 1 \mathrm{~mm} 最大尺寸）；
  d) Grade 3 histology; d) 3 級組織學；
  e) Presence of lymphovascular invasion.
  e) 存在淋巴管侵犯。

2. Contra-indication or unwillingness to have adjuvant endocrine therapy after breast cancer surgery.
   乳癌手術後不適合或不願意接受輔助內分泌治療。
3. Planned to receive adjuvant chemotherapy or biologic anti-cancer therapy (i.e. any adjuvant systemic therapy for breast cancer other than endocrine therapy) after breast cancer surgery.
   計劃在乳癌手術後接受輔助化療或生物抗癌治療 (即除內分泌治療外的任何乳癌輔助全身治療)。
   Note: Any therapy (including bone-directed therapy) unrelated to breast cancer is permitted at the discretion of treating clinicians.
   註： 任何與乳癌無關的治療 (包括骨導向治療) 均可由主治醫師酌情決定。
4. Treated with neoadjuvant endocrine therapy, chemotherapy or biologic anti-cancer therapy prior to breast cancer surgery.
   在乳癌手術前接受新輔助內分泌治療、化療或生物抗癌治療。
   Note: Any therapy (including bone-directed therapy) unrelated to breast cancer is permitted at the discretion of treating clinicians.
   註： 任何與乳癌無關的治療 (包括骨導向治療) 均可由主治醫師酌情決定。
5. Prior breast or thoracic RT for any condition.
   曾因任何情況接受乳房或胸部 RT。
6. Pre-operative breast imaging evidence of invasive carcinoma or DCIS aside from the primary carcinoma resected by breast conserving surgery.
   除保乳手術切除的原發性癌外，術前乳房影像證據顯示有浸潤性癌或 DCIS。
7. Concurrent invasive breast carcinoma or DCIS in contralateral breast diagnosed prior to randomisation.
   隨機分組之前診斷出對側乳房同時存在浸潤性乳癌或 DCIS。
   Note: Concurrent diagnosis of lobular carcinoma in situ in contralateral breast is not an exclusion criterion.
   註： 同時診斷對側乳房有原位小葉癌並非排除標準。
8. Prior diagnosis of invasive breast carcinoma or DCIS in either breast irrespective of disease free interval.
   任何一邊乳房曾診斷為浸潤性乳癌或 DCIS，不論無病間隔時間。
   Note: Prior diagnosis of lobular carcinoma in situ in either breast is not an exclusion criterion.
   註： 事先診斷出任一乳房有原位小葉癌並非排除標準。
9. A diagnosis of non-breast malignancy $<5$$<5$< 5<5 years prior to randomisation with the following exceptions:
   隨機抽樣前 $<5$$<5$< 5<5 年診斷為非乳房惡性腫瘤，但下列情況除外：
   a) Patients who are diagnosed with carcinoma in situ of cervix, endometrium or colon; melanoma in situ; and non-metastatic basal or squamous cell carcinoma of the skin at any time prior to randomisation are not excluded from study participation.
   a) 不排除在隨機化前任何時間診斷出子宮頸、子宮內膜或結腸原位癌、原位黑色素瘤，以及非轉移性皮膚基底或鱗狀細胞癌的患者參與研究。
   b) Patients who are diagnosed with other non-breast malignancy $\ge 5$$\ge 5$>= 5\geq 5 years prior to randomisation and without evidence of disease recurrence are not excluded from study participation.
   b) 隨機抽樣前 $\ge 5$$\ge 5$>= 5\geq 5 年診斷出患有其他非乳房惡性腫瘤，且無疾病復發證據的患者，不排除參與研究。
10. Significant comorbidity precluding definitive RT for breast cancer (e.g. cardiovascular or pulmonary disease, scleroderma, systemic lupus erythematosus).
    患有重大併發症，無法接受乳癌的確診 RT (例如心血管或肺部疾病、硬皮病、系統性紅斑狼瘡)。
11. Life expectancy <10 years.
    預期壽命 <10 年。
12. Known pathogenic mutation of BRCA1, BRCA2 or TP53, or a mutation in another breast cancer predisposition gene.
    已知的 BRCA1、BRCA2 或 TP53 致病基因突變，或其他乳癌易感基因突變。
13. Pregnant or lactating patients.
    懷孕或哺乳的病患。
14. Inability to be registered to the study $\le 8$$\le 8$<= 8\leq 8 weeks after the last surgical procedure for breast cancer.
    在上一次乳癌手術後 $\le 8$$\le 8$<= 8\leq 8 週無法註冊參加研究。
    15)14)Inability to commence RT no later than 12 weeks from the last surgical procedure for breast cancer if the patient is randomised to receive RT.
    15)14)Inability to commence RT no later than 12 weeks from the last surgical procedure for breast cancer if the patient is randomised to receive RT。
    16)15)Inability to provide informed consent.
    16)15)無法提供知情同意。
    17)16)Psychiatric, addictive, or any other disorder that precludes compliance with protocol requirements.
    17)16)精神疾病、上癮或任何其他障礙，導致無法遵守方案要求。
    18)17)Inaccessibility for follow-up.