High ki67 expression in small invasive breast cancer-More aggressive treatment? Literature review and TMUH result 在一公分以下的早期小型乳癌 Ki67高表現是否需要更積極的治療? 文獻回顧及北醫經驗 臺北醫學大學附設醫院 乳房外科 洪進昇 醫師

Small Cancer Small size is not a hall mark of low risk in rapidly proliferating tumors Time Low proliferation, apoptosis and genetic instability Large number of cells required to generate metastatic potential Time Reference Foulkes WD, Reis-Filho JS, Narod SA. Tumor size and survival in breast cancer—a reappraisal. Nat Rev Clin Oncol 2010; 7:348-53 Tumour cell High proliferation, apoptosis and genetic instability Apoptotic tumour cell Small number of cells required to generate metastatic potential Clone with metastatic potential Foulkes WD, et al. Nat Rev Clin Oncol 2010.

Recurrence-free survival (proportion) Time since diagnosis (months) The effect of HER2 status on survival of patients with small breast tumors HER2-positive p < 0.0001 Recurrence-free survival (proportion) Time since diagnosis (months) HER2-negative 0.0 0.2 0.4 0.6 0.8 1.0 12 24 36 48 60 MD Anderson series 965 patients with T1a/bN0 tumors who did not receive adjuvant systemic therapy HER2 status HER2+ HER2- n 98 867 5 yr RFS 77.1% 93.7% Patients with HER2-positive T1abN0M0 tumors have a significant risk of relapse and should be considered for systemic, anti-HER2, adjuvant therapy Gonzalez-Angulo AM, et al. J Clin Oncol 2009

Should we give adjuvant systemic therapy for T1a,b N0 M0 Breast Cancer ? According to EBCTCG studies, adjuvant chemo reduce risk of recurrence and improve survival in both LN (-), LN (+) and in both HR positive and negative Polychemo reduce annual recurrence 23% (37% for women < 40 years) 5 years of tamoxifen reduce recurrence by 41% For patients with T1a,bN0M0 breast cancer treated with local therapy alone, 10-year RFS is more than 90%. The absolute benefit of chemotherapy in terms of 10-year RFS would only be about 2.5%, benefit 4% for tamoxifen and additional 2% if chemotherapy was added. So, for patients with T1a,bN0M0 breast cancer, who might benefit from adjuvant chemotherapy ? J Clin Oncol. 2006 May 1;24(13):2113-22.

Ki-67 expression One of many possible proliferation markers we could be measuring Excellent IHC performance characteristics

Breast Cancer Subtyping by IHC + - >20% ≤13% + +/- +/- >13% - - + Based on a series of studies over the last decade, one of the more widely accepted and employed surrogates  6-marker immunopanel consisting of ER, PR, HER2, Ki67, CK5 or CK5/6, and EGFR. ER/HER2 already routine for predictive purposes (inclusion of PR more prognostic) Ki67 for differentiation of Lum A and B will be discussed in great detail later in this presentation. Ck5 and EGFR have demonstrated individual sensitivity, and even greater sensitivity when used as pair, for identification of basal-like breast cancer - - - +

Need adjuvant Chemotherapy! IHC4 score ER, PgR, HER2, and Ki67 that can segregate the luminal A and B and similar to that defined by a 50-gene expression profile Example: Breast cancer, 0.3 cm, T1aN0M0, stage IA ER 70%, PR 10%, Her-2 0+, Ki-67 20 % Need adjuvant Chemotherapy! IHC4 score = 46.403 Cheang MC, Chia SK, Voduc D, Gao D, Leung S, Snider J. Ki67 index, HER2 status, and prognosis of patients with luminal B breast cancer. J Natl Cancer Inst 2009; 101: 736¡V50

Material and Method

Inclusion criteria From 2011 to 2015 Breast cancer patients received treatment and follow-up in TMUH Small breast cancer: T1mi, T1a, T1b Ki67 data available Exclude: distant metastasis (+) while diagnosed

Results

Patients Ki-67 Expression (14%) p Low (N=53) High (N=51) Age   52.72 (+/- 11.176) 50.86 (+/- 10.216) 0.526 Breast Right 28 23 0.43 left 25 Histology IDC 45 38 0.469 others 8 13 Grade 1 24 12 0.045 2 17 26 3 7 Unknown 9 6 Tumor stage 1mi 0.506 1a 15 14 1b Lymph node No 51 50 0.144 Yes stage 1A 0.581 1B

  Ki-67 Expression (14%) Low (N=53) High (N=51) Operation method Partial 34 32 Simple 19 Chemotherapy No 47 43 0.544 Yes 6 11 Radiotherapy 22 25 0.442 31 26 Target therapy 53 41 4 ER + 37 0.037 - 14 PR 36 28 0.172 17 23 Her2 5 0.003 48 Recurrence 1 Distant metastasis Death Follow-up 614.53 ( 422.619) 535.65 ( 407.212) 0.464

Patients received chemotherapy   Chemotherapy Age =< 45 6 > 45 15 Grade 1 4 2 8 3 unknown Histology IDC 14 others Tumor Micoinvasive 1a 1b 12 Lymph node Yes No   Chemotherapy ER + 11 - 6 PR 8 9 ER or PR Her2 TNBC 3 Luminal B1 Her2+ Ki-67 0-18% 7 19-29% 2 >=30%

Discussion

Definition of “small” and “low-risk” breast cancer T1 mic: Microinvasion ≤0.1 cm into surrounding tissue T1a : Tumour >0.1 cm and ≤0.5 cm in greatest dimension T1b : Tumour >0.5 cm and ≤1 cm in greatest dimension Sobin L, et al, TNM classification of malignant tumours. 7th ed. Chichester: Wiley-Blackwell, 2010. p.181-93; “Low-risk”: node negative AND all of the following features:1 pT≤2cm Grade 1 Absence of extensive peritumoural vascular invasion Oestrogen receptor and/or progesterone receptor expressed HER2 neither overexpressed nor amplified Aged ≥35 years References Goldhirsch A, Wood WC, Gelber RD, et al. Progress and promise: highlights of the international expert consensus on the primary therapy of early breast cancer 2007. Ann Oncol 2007; 18:1133-44. Sobin L, Gospodarowicz M, Wittekind C. Breast tumours. In: UICC International Union Against Cancer - TNM classification of malignant tumours. 7th ed. Chichester: Wiley-Blackwell, 2010. p.181-93. Goldhirsch A, et al. Ann Oncol 2007; 18:1133-44.;

1,894 patients ,stage I-II BC enrolled in NEMESI 402 (21.2%) were pT1a-pT1b. Adjuvant chemotherapy was delivered in 127/402 (31.59%). Younger age, grading G3, high proliferative index, ER-negative and HER2-positive status were significantly associated with the decision Adjuvant chemotherapy was administered in 88.4% triple-negative 73.46% HER2-positive Adjuvant trastuzumab was delivered in 30/49 HER2-positive BC (61.2%) Gori et al. BMC Cancer 2012, 12:158

Prognostic role Predictive role Ki-67 expression in Relapse-free survival Breast cancer-free survival Predictive role Can Ki67 serve as a tool to identify patients who especially benefit from chemotherapy or endocrine therapy? Can Ki67 identify patients who benefit from a particular chemotherapy agent? Can Ki67 predict a benefit of a specific endocrine treatment?

Ki67 Index, HER2 Status, and Prognosis of Patients With Luminal B Breast Cancer J Natl Cancer Inst 2009; 101: 736¡V50

The 10-year breast cancer-specific survival luminal A, luminal B, and luminal/HER2+ was 92% (95% CI 90–94), 79% (74–85), and 78% (67–90), respectively (p<0·001). Hazard ratio comparing luminal A and B subtypes 1·5 for relapse-free survival 1·8 for breast cancer-specific survival

J Clin Oncol. 2017 Jan 3 Z1031A and Z1031B Post-menopausal women, stage II or II breast cancer AI neoadjuvant treatment Z1031B repeat biopsy after 4 wks AI neoadjuvant treatment If Ki-67<10, continue 12 to 14 wks AI if ki-67>10, neoadjuvant chemotherapy Ki67-based Preoperative Endocrine Prognostic index (PEPI score)

PEPI = 0 disease, the relapse risk over 5 years was only 3 PEPI = 0 disease, the relapse risk over 5 years was only 3.6% without chemotherapy, supporting the study of adjuvant endocrine monotherapy in this group. Chemotherapy efficacy was lower than expected in ER-positive tumors exhibiting AI-resistant proliferation. The optimal therapy for these patients should be further investigated.

IBCSG VIII and IX J Natl Cancer Inst 2008;100: 207 ¡V 212

IBCSG VIII and IX A high Ki-67 labeling index was associated with other factors that predict poor prognosis and worse disease-free survival Did not predict the relative efficacy of chemoendocrine therapy compared with endocrine therapy alone. Ki-67 labeling index was an independent prognostic factor but was not predictive of better response to adjuvant chemotherapy in these studies. J Natl Cancer Inst 2008;100: 207 ¡V 212

Limitation Short Follow up time Limited case number Ki67 routinely check since 2013 Limited case number The measurement of Ki67 is not usually consisted

Conclusion High expression of ki-67 combined with younger age, grading G3, ER-negative and HER2-positive are unfavorable factors Ki-67 has the role in predict breast cancer prognosis, especially in Lumina B patients Ki-67 was not predictive of better response to adjuvant chemotherapy in these studies Not enough evidence of chemotherapy delivery in small, high ki-67 breast cancer

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