The authors have declared that no competing interests exist.
Conceived and designed the experiments: FR AVS BSZ XSG. Performed the experiments: FR DH AS BA. Analyzed the data: FR DH AS BA AVS BSZ XS. Contributed reagents/materials/analysis tools: JGF MAB YK AF JYP PC VD VF FL SA. Wrote the paper: FR DH AS BA AVS BSZ XS.
Molecular signatures may become of use in clinical practice to assess the prognosis of breast cancers. However, although international consensus conferences sustain the use of these new markers in the near future, concerns remain about their degree of discordance and cost-effectiveness in different international settings. The present study aims to validate Ki67 as prognostic factor in a large cohort of early-stage (pT1–pT2, pN0) breast cancer patients.
456 patients treated in 1995–1996 were identified in the Institut Curie database. Ki67 (MIB1) was retrospectively assessed by immunohistochemistry for all cases. The prognostic value of this index was compared to that of histological grade (HG), Estrogen receptor (ER) and
All 456 patients were treated by lumpectomy plus axillary dissection and radiotherapy. 27 patients (5.9%) received systemic treatment. Tumors were classified as HG1 in 35%, HG2 in 42% and HG3 in 23% of cases. ER was expressed in 86% of the tumors,
We validate the prognosis value of the Ki67 rate in small size node negative breast cancer. We conclude that Ki67 is a potential cost-effective decision marker for adjuvant therapy in early-stage HG2, pT1–pT2, pN0, breast cancers.
Breast cancer prognostic factors are essential to identify patients at risk of distant metastasis development and to decide whether adjuvant treatments are needed. The most validated biological marker in non-metastatic breast cancer are tumor size, histological grade, mitotic index, Ki67 rate, axillary lymph node involvement, Estrogen Receptor (ER), Progesterone Receptor (PR) and
Our dataset consisted of 456 early-stage (pN0) breast cancer patients treated between 1995 and 1996 by breast conserving surgery with axillary lymph node dissection as primary treatment at the Institut Curie and identified through the Institut Curie prospective breast cancer database. The main inclusion criterion was the absence of pathologic axillary lymph node involvement. Patients who had received a neoadjuvant treatment (chemotherapy, hormonal therapy or radiotherapy) were excluded from the study.
The histological features (Histological Type, Elston Ellis Grade, Mitotic Index, Ki67 rate, Estrogen Receptor status, Progesterone Receptor status,
Mitotic Index was assessed on histological sections stained by Hematein, Eosin and Saffron. The criteria of Van Diest and al were used to define mitotic figures
Tissue sections were first digested in 0.1% trypsin and 0.1% calcium chloride in triphosphate buffer saline pH 7.6 for 5 minutes. Antigen retrieval was performed by incubating tissue sections for 20 minutes in citrate buffer 10 mM (ph 6.1) in a 850 W microwave oven. Tissue sections were then incubated for one hour with the anti-Ki67 monoclonal antibody (Clone MIB1, Dako A/S, Glostrup, Denmark) at 1/100 dilution. The revelation of the staining was performed using the Vectastain Elite ABC peroxydase mouse IgG kit (Vector Burlingame, CA, USA) and diamino-benzidine (Dako A/S) as chromogen. The semiquantitative assessment was performed by estimating at X200 magnification, the percentage of positive neoplastic nuclei within the area of highest positivity chosen after scanning the entire tumour surface at low power (x10 objective). All nuclei with homogeneous staining even with a light staining or only a nucleolar staining were interpreted as positive. A cut-off of >20% was used to define tumors with high KI67 rate.
After rehydration and antigenic retrieval in citrate buffer (10 mM, pH 6.1), the tissue sections were stained for estrogen receptor (ER, clone 6F11, Novocastra, 1/200), and progesterone receptor (PR, clone 1A6, Novocastra, 1/200). Revelation of staining was performed using the Vectastain Elite ABC peroxidase mouse IgG kit (Vector Burlingame, CA) and diaminobenzidine (Dako A/S, Glostrup, Denmark) as chromogen. Positive and negative controls were included in each slide run. Cases were considered positive for ER and PR according to standardized guidelines using a cut-off of ≥10% stained tumour nuclei
After rehydration and antigenic retrieval in citrate buffer (10 mM, pH 6.1), the tissue sections were stained for HER-2 (clone CB11, Novocastra, 1/1000). Revelation of staining was performed using the Vectastain Elite ABC peroxidase mouse IgG kit (Vector Burlingame, CA) and diaminobenzidine (Dako A/S, Glostrup, Denmark) as chromogen. Positive and negative controls were included in each slide run. The determination of HER2 overexpression was determined according to GEFPICS guidelines with FISH performed in all cases of HER2 2+ result
Statistical analyses were performed in both the whole population and in two restricted immune-phenotypic population defined as 1) ERpositive, HER2negative 2) ERpositive, HER2negative, Histological Grade 2.
Time to distant metastases and time to loco-regional recurrences were defined as the time from the breast cancer primary tumour diagnosis to the occurrence of the event. Time to death was defined as the time from the diagnosis of the metastases to the occurrence of the death. Survival analyses were performed using the Kaplan-Meier estimate of the survival function. Comparison between survival curves was performed using the logrank test. Hazard ratios were estimated using the Cox proportional hazard model. P-values were considered significant when below 0.05. Only variables with a significant p-value in univariate analyses were included in a multivariate ascending stepwise procedure using the Cox model.
The multivariate model performance was quantified with respect to discrimination (i.e., whether the relative ranking of individual predictions is in the correct order when compared to observation), quantified with the Concordance index (C-index) [Harrell et al Ref. 1, 1996] and its 95% confidence interval. The analyses were performed using R software (
The registration of patients of the Institut Curie (Paris and Saint-Cloud) in this cohort received a favorable agreement of the french National Committee on Computers and Liberties (CNIL, Commission nationale de l'informatique et des libertés). Patients gave informed written consent prior to be registered in the cohort. The study was approved by the breast cancer study group and the comity of clinical research study of the Institut Curie (Paris and Saint-Cloud).
A continuous retrospective series of 456 patients with pN0, pT1–pT2, invasive breast carcinoma, treated at the Institut Curie between 1995–1996 was identified using a prospective database (
456 pT1 pT2 pN0 invasive breast cancer patients | ||||||||
N (%) | 10y LRRFI | p value | RR [95%CI] | 10y DDFI | p value | RR [95%CI] | ||
all | 456 (100) | 85 [81–88] | 85 [82–89] | |||||
Age (years) | >55 | 219 (48) | 89 [84–94] | 0.042* | 1 | 87 [82–92] | 0.27 | 1 |
>40 and ≤55 | 214 (47) | 83 [78–88] | 1.3 [0.8–2.1] | 85 [80–90] | 1.3 [0.8–2.1] | |||
≤40 | 23 (5) | 66 [49–90] | 2.6 [1.2–5.8] | 74 [58–94] | 1.9 [0.8–4.6] | |||
BMI | BMI 20–25 | 277 (61) | 83 [78–88] | 0.5285 | 1 | 83 [79–88] | 0.06 | 1 |
BMI<20 | 22 (5) | 91 [79–100] | 0.8 [0.3–2.3] | 95 [85–100] | 0.4 [0.1–1.8] | |||
BMI 25–30 | 86 (18) | 91 [85–98] | 0.7 [0.4–1.3] | 94 [89–99] | 0.5 [0.2–1.07] | |||
BMI>30 | 38 (8) | 87 [76–100] | 0.6 [0.2–1.5] | 76 [63–92] | 1.6 [0.8–3.2] | |||
Familial | No | 376 (83) | 86 [82–90] | 0.09 | 1 | 85 [82–89] | 0.84 | 1 |
Yes | 79 (17) | 80 [71–90] | 1.5 [0.9–2.6] | 86 [78–94] | 1.06 [0.6–1.9] | |||
Menopause | No HRT | 195 (43) | 89 [85–94] | 0.04* | 1 | 87 [82–93] | 0.26 | 1 |
HRT | 80 (17) | 84 [76–93] | 1.7 [0.9–3.2] | 84 [76–93] | 1.2 [0.6–2.4] | |||
Pre-menopausal | 181 (40) | 81 [75–87] | 1.9 [1.2–3.2] | 83 [78–89] | 1.5 [0.9–2.6] | |||
T | T1 | 345 (76) | 85 [82–89] | 0.26 | 1 | 86 [83–90] | 0.002* | 1 |
T2 | 111 (24) | 82 [74–89] | 1.3 [0.8–2.1] | 79 [72–88] | 2 [1.2–3.2] | |||
pT | pT1 | 344 (75) | 86 [82–90] | 0.39 | 1 | 86 [82–90] | 0.03* | 1 |
pT2 | 112 (25) | 82 [75–90] | 1.24 [0.7–2] | 81 [74–89] | 1.7 [1.1–2.8] | |||
Margin | <3 mm | 163 (36) | 79 [73–86] | 0.007* | 1 | 85 [79–91] | 0.55 | 1 |
≥3 mm | 293 (64) | 88 [84–92] | 0.5 [0.3–0.8] | 85 [81–90] | 0.8 [0.5–1.3] | |||
Type | Ductal | 346 (76) | 85 [81–89] | 0.25 | 1 | 85 [81–89] | 0.03* | 1 |
Lobular | 64 (14) | 84 [74–94] | 1.2 [0.7–2.2] | 80 [71–92] | 1.3 [0.7–2.3] | |||
Ductal Lobular | 13 (3) | 72 [49–100] | 1.7 [0.5–5.4] | 76 [55–100] | 2.2 [0.8–6.2] | |||
Other | 33 (7) | 92 [83–100] | 0.3 [0.08–1.4] | 100 [100–100] | 0 | |||
LVI | No | 385 (84) | 86 [82–90] | 0.10 | 1 | 87 [83–91] | 0.01* | 1 |
Yes | 71 (16) | 80 [71–91] | 1.5 [0.9–2.6] | 75 [66–87] | 1.9 [1.2–3.3] | |||
Mitotic index | I | 311 | 86 [82–90] | 0.75 | 1 | 90 [86–93] | 7e−5 | 1 |
II | 58 | 81 [71–93] | 1.2 [0.6–2.2] | 75 [64–88] | 2.5 [1.4–4.7] | |||
III | 87 | 84 [76–92] | 1.2 [0.7–2] | 76 [67–86] | 2.7 [1.6–4.6] | |||
EE Grade | I | 161 (35) | 89 [84–94] | 0.11 | 1 | 93 [89–97] | 2e−4 | 1 |
II | 192 (42) | 84 [78–90] | 1.4 [0.8–2.3] | 84 [78–90] | 2.4 [1.2–4.6] | |||
III | 103 (23) | 80 [72–89] | 1.8 [1.04–3.3] | 75 [67–84] | 4.4 [2.2–8.6] | |||
ER and HER2 | ER+ HER2− | 371 (81) | 86 [82–90] | 0.31 | 1 | 88 [84–91] | 6e−4 | 1 |
HER2+ | 23 (5) | 76 [59–97] | 1.6 [0.7–3.7] | 61 [44–85] | 3.4 [1.7–6.7] | |||
ER− HER2− | 62 (14) | 81 [71–92] | 1.4 [0.7–2.5] | 80 [70–91] | 1.6 [0.8–2.9] | |||
Ki67 | < = 20 | 274 (60) | 88 [84–92] | 0.08 | 1 | 92 [88–95] | <1e−6* | 1 |
>20 | 182 (40) | 79 [73–86] | 1.5 [0.9–2.3] | 74 [68–81] | 3 [1.8–4.8] |
BMI: body mass index, LN: lymph node, pT: histological size of the invasive carcinoma (pT1≤20 mm, pT2>20vmm), LVI: lympho-vascular involvement, EE: histological grade according to Ellis and Elston, ER: Estradiol Receptor, HER2: Human Epidermal Receptor type 2. LRFI: Loco-Regional Free Interval. DDFI: Distant Disease Free Interval.
ER positive and HER2 negative tumors constituted a subgroup of 371 (81.4%) cases (
371 ER positive HER2 negative, pN0 invasive breast cancer patients | ||||||||
N (%) | 10y LRRFI | p | RR [95%CI] | 10y DDFI | p | RR [95%CI] | ||
all | 371 | 86 [82–90] | 88 [84–91] | |||||
Age (years) | >55 | 190 (51) | 90 [85–95] | 0.009* | 1 | 88 [83–93] | 0.69 | 1 |
>40 and ≤55 | 167 (45) | 85 [79–91] | 1.2 [0.7–2] | 88 [82–93] | 1.3 [0.7–2.2] | |||
≤40 | 14 (4) | 57 [36–90] | 3.7 [1.5–9] | 85 [68–100] | 1.1 [0.2–4.5] | |||
BMI | 20–25 | 233 (63) | 83 [78–89] | 0.5 | 1 | 86 [84–92] | 0.03* | 1 |
<20 | 20 (5) | 90 [77–100] | 0.9 [0.3–2.7] | 94 [80–97] | 0.6 [0.1–2.4] | |||
25–30 | 67 (18) | 95 [90–100] | 0.6 [0.3–1.2] | 97 [92–100] | 0.4 [0.1–1] | |||
>30 | 27 (7) | 87 [74–100] | 0.7 [0.2–2.7] | 78 [84–94] | 2 [0.9–4.6] | |||
Familial | No | 302 (82) | 87 [82–91] | 0.52 | 1 | 88 [81–93] | 1 | 1 |
Yes | 68 (18) | 85 [76–94] | 1.2 [0.6–2.2] | 88 [90–100] | 1 [0.4–2.1] | |||
Menopause | No HRT | 171 (46) | 91 [86–96] | 0.1 | 1 | 89 [72–97] | 0.4 | 1 |
HRT | 66 (18) | 85 [76–95] | 1.7 [0.8–3.4] | 87 [90–98] | 1.2 [0.5–2.6] | |||
Pre-menopausal | 134 (36) | 81 [75–89] | 1.8 [1.04–3.3] | 87 [77–89] | 1.5 [0.8–2.8] | |||
T | T1 | 289 (78) | 87 [83–92] | 0.07 | 1 | 89 [86–93] | 0.0002* | 1 |
T2 | 82 (22) | 81 [73–91] | 1.6 [0.9–2.8] | 80 [72–89] | 2.8 [1.6–4.9] | |||
pT | pT1 | 289 (78) | 88 [83–92] | 0.11 | 1 | 89 [85–93] | 0.001* | 1 |
pT2 | 82 (22) | 81 [73–91] | 1.6 [0.9–2.7] | 82 [73–91] | 2.5 [1.4–4.4] | |||
Margin | <3 mm | 124 (33) | 82 [75–89] | 0.03* | 1 | 87 [80–93] | 0.35 | 1 |
≥3 mm | 247 (67) | 88 [84–93] | 0.6 [0.3–0.9] | 88 [83–92] | 0.7 [0.4–1.3] | |||
Type | Ductal | 275 (74) | 87 [83–91] | 0.26 | 1 | 88 [83–92] | 0.17 | 1 |
Lobular | 60 (16) | 84 [75–95] | 1.4 [0.7–2.6] | 81 [70–92] | 1.4 [0.7–2.7] | |||
Ductal Lobular | 11 (3) | 69 [45–100] | 2.2 [0.7–7.1] | 90 [73–100] | 1.4 [0.3–7.9] | |||
Other | 25 (7) | 90 [78–100] | 0.5 [0.1–2.1] | 100 [100–100] | 0 | |||
LVI | No | 319 (86) | 86 [82–90] | 0.59 | 1 | 89 [85–92] | 0.04* | 1 |
Yes | 52 (14) | 85 [76–96] | 1.2 [0.6–2.3] | 79 [68–92] | 2 [1.1–3.8] | |||
Mitotic index | I | 285 (77) | 87 [82–91] | 0.93 | 1 | 90 [85–94] | 0.005* | 1 |
II | 48 (13) | 82 [71–95] | 1.1 [0.5–2.3] | 81 [69–93] | 3.1 [1.1–4.3] | |||
III | 38 (10) | 88 [78–100] | 1.1 [0.4–2.5] | 83 [71–96] | 2.8 [1.4–5.8] | |||
EE Grade | I | 153 (41) | 88 [83–94] | 0.22 | 1 | 94 [89–97] | 0.003* | 1 |
II | 169 (46) | 85 [79–91] | 1.5 [0.5–4.2] | 83 [76–89] | 2.5 [1.2–5.1] | |||
III | 49 (13) | 83 [72–95] | 1.7 [0.6–5.3] | 87 [77–97] | 3.8 [1.6–8.8] | |||
Ki67 | < = 20 | 248 (67) | 88 [83–92] | 0.3 | 1 | 91 [88–95] | 0.0003* | 1 |
>20 | 63 (45) | 82 [75–90] | 1.3 [0.8–2.5] | 79 [71–87] | 2.6 [1.5–4.6] |
BMI: body mass index, LN: lymph node, pT: histological size of the invasive carcinoma (pT1≤20 mm, pT2>20 mm), LVI: lympho-vascular involvement, EE: histological grade according to Ellis and Elston, ER: Estradiol Receptor, HER2: Human Epidermal Receptor type 2. LRFI: Loco-Regional Free Interval. DDFI: Distant Disease Free Interval.
169 ER positive HER2 negative, Histological Grade II, pN0 invasive breast cancer patients | ||||||||
N (%) | 10y LRRFI | p | RR [95%CI] | 10y DDFI | p | RR [95%CI] | ||
all | 169 | 85 [79–90] | 82 [76–89] | |||||
Age (years) | >55 | 88 (52) | 86 [79–94] | 0.2 | 1 | 83 [75–91] | 0.3 | 1 |
>40 and ≤55 | 74 (44) | 86 [77–94] | 1 [0.5–2.2] | 80 [70–91] | 1.4 [0.7–2.9] | |||
≤40 | 7 (4) | 57 [30–100] | 2.8 [0.8–9.9] | 0 | 0 | |||
BMI | 20–25 | 109 (65) | 83 [76–91] | 0.8 | 1 | 79 [72–88] | 0.02* | 1 |
<20 | 8 (5) | 73 [47–100] | 1.5 [0.3–6.3] | 83 [58–100] | 0.5 [0.1–4] | |||
25–30 | 29 (17) | 92 [81–100] | 0.8 [0.3–2.2] | 0 | 0 | |||
>30 | 12 (7) | 90 [73–100] | 0.5 [0.06–3.5] | 70 [46–100] | 2 [0.7–6] | |||
Familial | No | 140 (83) | 84 [78–91] | 0.7 | 1 | 83 [76–90] | 0.4 | 1 |
Yes | 28 (16) | 87 [74–100] | 1.2 [0.5–2.9] | 83 [69–99] | 1.4 [0.6–3.5] | |||
Menopause | No HRT | 76 (45) | 87 [79–96] | 0.1 | 1 | 85 [77–94] | 0.3 | 1 |
HRT | 34 (20) | 90 [80–100] | 1.6 [0.6–4.5] | 77 [63–93] | 2 [0.8–5.4] | |||
Pre-menopausal | 59 (35) | 79 [68–90] | 2.3 [1–5.2] | 82 [72–93] | 1.6 [0.6–3.8] | |||
T | T1 | 127 (75) | 84 [77–91] | 0.5 | 1 | 84 [78–91] | 0.04* | 1 |
T2 | 42 (25) | 86 [76–98] | 0.7 [0.3–1.8] | 76 [64–91] | 2 [1–4.5] | |||
pT | pT1 | 118 (70) | 85 [78–92] | 0.5 | 1 | 84 [77–92] | 0.12 | 1 |
pT2 | 42 (25) | 86 [76–98] | 0.7 [0.3–1.8] | 79 [67–93] | 1.8 [0.8–4] | |||
Margin | <3 mm | 54 (32) | 85 [75–96] | 0.5 | 1 | 78 [67–92] | 0.6 | 1 |
≥3 mm | 115 (68) | 84 [78–92] | 0.7 [0.3–1.6] | 84 [77–91] | 0.8 [0.4–1.7] | |||
Type | Ductal | 120 (71) | 85 [79–92] | 0.8 | 1 | 83 [76–91] | 0.5 | 1 |
Lobular | 38 (23) | 83 [71–98] | 1 [0.4–2.5] | 75 [61–91] | 1.3 [0.6–3] | |||
Ductal Lobular | 9 (5) | 73 [47–100] | 1.5 [0.3–6.6] | 0 | 0 | |||
Other | 2 (1) | 0 | 0 | 0 | 0 | |||
LVI | No | 138 (82) | 85 [79–92] | 0.4 | 1 | 84 [77–90] | 0.3 | 1 |
Yes | 31 (18) | 82 [69–98] | 1.4 [0.6–3.3] | 76 [60–95] | 1.5 [0.6–3.6] | |||
Mitotic index | I | 137 (81) | 85 [78–91] | 0.6 | 1 | 85 [79–92] | 0.2 | 1 |
II | 29 (17) | 83 [70–100] | 0.9 [0.3–2.3] | 73 [58–92] | 2 [0.8–4.5] | |||
III | 3 (2) | 0 | 0 | 66 [30–100] | 2.3 [0.3–17] | |||
Ki67 | < = 20 | 102 (60) | 85 [78–93] | 0.5 | 1 | 88 [81–95] | 0.07 | 1 |
>20 | 67 (40) | 84 [75–94] | 0.8 [0.4–1.7] | 75 [65–87] | 2 [0.9–4] |
BMI: body mass index, LN: lymph node, pT: histological size of the invasive carcinoma (pT1≤20 mm, pT2>20 mm), LVI: lympho-vascular involvement, ER: Estradiol Receptor, HER2: Human Epidermal Receptor type 2. LRFI: Loco-Regional Free Interval. DDFI: Distant Disease Free Interval.
The kernel density plots of the Mitotic Index (MI) in each grade categories showed a low mitotic index (≤20) for 100% of the HG1 tumors and for 96% of the HG2 tumors. Only HG3 tumors had a Mitotic Index higher than 20 in 80%. Ki67 distribution was a much more discriminatory factor with extreme values in HG1 (90% with Ki67≤20) and HG3 (85% with Ki67>20) tumors. In contrast, a wide spectrum of the Ki67 rate was observed in HG2 tumors: it was ≤20% in 59% of the cases and >20 in 41%. We identified a subgroup of 262 (57%) samples with a low MI (<20) and a low Ki67 rate (≤20), 112 (24%) samples with a low MI and a high Ki67 rate, 77 (15%) samples with high MI and a high Ki67 rate and 12 (3%) samples with high MI and low Ki67 rate.
Univariate analyses (
Loco Regional Recurrence Free Interval. Multivariate analysis | |||||||
456 pN0 | 371 ER+ HER2− pN0 | ||||||
N (%) | RR | p | N (%) | RR | p | ||
Surgical margin | <3 mm | 163 (36) | 1 | 0.006* | 124 (33) | 1 | 0.048* |
≥3 mm | 293 (64) | 0.5 [0.3–0.8] | 247 (67) | 0.6 [0.3–0.9] | |||
Menopause | No HRT | 195 (43) | 1 | 0.03* | |||
HRT | 80 (17) | 1.6 [0.8–3.1] | |||||
Pre-menopausal | 181 (40) | 1.9 [1.2–3.2] | |||||
Age (years) | >55 | 190 (51) | 1 | 0.06 | |||
>40 & < = 55 | 167 (45) | 1.3 [0.7–2.2] | |||||
< = 40 | 14 (4) | 3.4 [1.4–8.2] |
Univariate analyses (
We designed a multivariate ascending stepwise procedure using the Cox model to determine the probability of distant metastasis. In the whole population, Ki67 rate and histological grade remained significant variables (
Distant Metastasis Free Interval. Multivariate analysis | ||||||||||
456 pN0 | 371 ER+HER2− pN0 | 169 ER+HER2− HG2 pN0 | ||||||||
N (%) | RR | p | N (%) | RR | p | N (%) | RR | p | ||
Ki67 | < = 20 | 274 (60) | 1 | 0.01* | 248 (67) | 6e−4 | 102 (60) | 1 | 0.04* | |
>20 | 182 (40) | 2 [1.1–3.6] | 123 (33) | 2.6 [1.5–4.6] | 67 (40) | 2.2 [1.01–4.8] | ||||
EE | I | 161 (35) | 1 | 0.06 | ||||||
II | 192 (42) | 1.8 [0.9–3.7] | ||||||||
III | 103 (23) | 2.6 [1.1–5.8] |
Ki67 rate (%). EE Grade: Histological Grade as defined by Elston Ellis
Development of distant relapse was observed in 73 patients (16%). Median delay from metastasis diagnosis to death was 36 months [1–144]. 19 patients (26%) had metastasis in bone only as first diagnostic of secondary tumor location. Other sites were lung, liver, brain, lymph node, bowel and skin. Primary tumors features (lympho-vascular invasion, histological grade, hormone receptor status), time lapse between primary tumor and first metastasis and first metastasis location (bone versus other locations) were all correlated to the time-lapse from first metastatic event to death from breast cancer (
Overall Survival Analysis from Metastasis Event to Death. | |||||||
N (%) | 36 months OS | Univariate Analysis | Multivariate Analysis | ||||
RR | p | RR | p | ||||
All | 73 | 54 [44–68] | |||||
LVI | No | 54 (74) | 58 [46–73] | 1 | 0.05* | 1 | 0.016* |
Yes | 19 (26) | 46 [27–76] | 1.7 |
2.1 [1.2–3.8] | |||
EE Grade | I | 12 (16) | 82 [63–100] | 1 | 0.03* | ||
II | 32 (44) | 58 [42–79] | 1.8 [0.8–4.2] | ||||
III | 29 (40) | 9 [24–62] | 2.8 [1.2–6.3] | ||||
ER | Positive | 56 (77) | 63 [50–77] | 1 | 0.04* | ||
Negative | 17 (23) | 29 [14–61] | 1.8 [1–3.4] | ||||
PR | Positive | 50 (69) | 69 [56–84] | 1 | 0.005* | ||
Negative | 23 (31) | 26 |
2.1 [1.2–3.7] | ||||
HR | ER+ or PR+ | 57 (78) | 63 [51–78] | 1 | 0.03* | 1 | 0.03* |
ER− & PR− | 16 (22) | 25 [10–58] | 2 [1.1–3.7] | 2.2 [1.1–4.1] | |||
ER/HER2 | ER+ HER2− | 50 (68) | 64 [51–80] | 1 | 0.07 | ||
HER2+ | 10 (14) | 50 [27–93] | 1.5 [0.6–3.3] | ||||
ER− HER2− | 13 (18) | 23 [8–62] | 2 [1.1–4.2] | ||||
Delay (months) | <24 | 8 (11) | 25 [7–83] | 1 | 0.002* | 1 | 0.005* |
> = 24 | 65 (89) | 58 [47–72] | 0.3 [0.1–0.7] | 0.3 [0.1–0.6] | |||
First Metastasis Location | Bone Only | 19 (26) | 73 [56–93] | 1 | 0.02* | ||
Other | 54 (74) | 39 [27–56] | 1.8 [1.1–3.2] |
73 metastatic breast cancer patients. LVI: lympho-vascular involvement, EE Grade: Histological Grade as defined by Elston Ellis. ER: Estrogen Receptor, PR: Progesteron Receptor, HER2: Human Epidermal Receptor type 2, Delay: Delay from primary tumour diagnosis to first metastatic event.
This study aimed to analyze the Ki67 rate prognostic value in a large cohort of 456 consecutive early-stage (pT1–pT2), pN0 breast cancer patients. These patients were all treated by primary breast-conserving surgery followed by whole-breast radiotherapy. A few patients received either adjuvant chemotherapy (5.9%) or a 5-year adjuvant hormonal therapy (8.5%). The median follow-up length was 12 years.
In the whole population, the Ki67 rate (threshold 20%) was the most significant factor associated to the distant disease free interval, in univariate and in multivariate analyses, outperforming the values of both Mitotic Index and HG. Ki67 rate was the only significant variable in the subgroups of ER+ HER2− and of ER+ HER2− HG2 tumors. As the concordance between the HG and Ki67 rate was high for HG1 and HG3 tumors and as the prognostic value of the Ki67 was significant in the ER+ HER2− HG2 subgroup (37% of the cases), we conclude that the Ki67 is a cost-effective decision marker for the indication of adjuvant therapy in more than one third of early-stage, pT1–pT2, pN0, breast cancer patients.
Proliferation is a key determinant of both prognosis
Nottingham histological grade (HG) was the second independent prognostic factor for distant metastases in the whole subpopulation but this marker did not reach statistical significance in the subpopulation of luminal cancers. This confirms data showing that HG is a valuable prognostic factor
We built a nomogram based on Ki67 rate and HG to determine the 5 and 10 years probability of distant metastasis event. The maximum distant metastasis free probability [HG1, low Ki67 rate] was 96% and 92% at 5 and 10 years respectively. The minimum distant metastasis free probability was 84% and 70% at 5 and 10 years respectively.
In the whole series of 456 patients, we showed that young age, pre-menopausal status or hormone replacement therapy and non-clear surgical margins (less than 3 mm) were associated with an increased rate of loco-regional recurrences. Ki67 rate was not a factor associated to the loco-regional recurrence free interval. We built a multivariate model and corresponding nomogram based on menopause status and surgical margins to predict the 5 and 10 years loco-regional recurrence probability. The maximum loco-regional free probability [margin> = 3 mm, post-menopause status] was 95% and 92% at 5 and 10 years respectively. The minimum loco-regional free probability [margin<3 mm, pre-menopause status] was 85% and 72% at 5 and 10 years respectively. Many authors have already reported that young age, defined in either three classes or according to the menopause status, and a satisfactory surgical margin (3 mm) were major prognostic factors associated with loco-regional recurrence
Finally, we identified that hormonal receptor status, lympho vascular invasion, bone metastasis and the late discovery of the first metastases were significant variables correlated to the time lapse from a first metastatic event to death from breast cancer. We built a multivariate Cox model and corresponding nomogram based on time-lapse from primary tumour to first metastatic diagnosis, and two primary tumor features (lympho vascular invasion and hormone receptor status) to predict the 1, 5 and 10 years probabilities of death from breast cancer. The minimum death probability [time-lapse >24 months, no lympho vascular invasion, hormone receptor positive status] was 5%, 50% and 85% at 1, 5 and 10 years respectively. The maximum death probability [time-lapse <24 months, lympho vascular invasion, hormone receptor negative status] was 70% and 100% at 1 and 5 years respectively. Several groups have previously identified these factors. Chang et al
In conclusion, our study confirms the validity of the Ki67 proliferation marker to better evaluate the risk of distant metastases in early stage, pT1–pT2, pN0 breast cancers. Ki67 was not a relevant prognostic factor of loco-regional recurrence or of the time-lapse between the diagnosis of first metastasis and death. Since the concordance between the HG and Ki67 rate was high for HG1 and HG3 tumors and since the prognostic value regarding distant relapse of Ki67 rate was significant in the ER+ HER2− HG2 subgroup, we concluded that the Ki67 rate is a potential cost-effective prognostic proliferation marker in this later subgroup which represents 37% of early stage pN0 breast cancer patients. Three nomograms were built from this study to determine the probability of metastatic relapse, loco-regional recurrence and death from breast cancer at the time of first metastases diagnosis.
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