scholarly journals Review: Radionuclide Molecular Imaging Targeting HER2 in Breast Cancer with a Focus on Molecular Probes into Clinical Trials and Small Peptides

Molecules ◽  
2021 ◽  
Vol 26 (21) ◽  
pp. 6482
Author(s):  
Shushan Ge ◽  
Jihui Li ◽  
Yu Yu ◽  
Zhengguo Chen ◽  
Yi Yang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Molecular Imaging ◽  
Imaging Techniques ◽  
Treatment Options ◽  
Growth Factor Receptor ◽  
Molecular Probes ◽  
Her2 Status ◽  
Developmental Trend ◽  
Her2 Positive ◽  
Monitor Treatment Response

As the most frequently occurring cancer worldwide, breast cancer (BC) is the leading cause of cancer-related death in women. The overexpression of HER2 (human epidermal growth factor receptor 2) is found in about 15% of BC patients, and it is often associated with a poor prognosis due to the effect on cell proliferation, migration, invasion, and survival. As a result of the heterogeneity of BC, molecular imaging with HER2 probes can non-invasively, in real time, and quantitatively reflect the expression status of HER2 in tumors. This will provide a new approach for patients to choose treatment options and monitor treatment response. Furthermore, radionuclide molecular imaging has the potential of repetitive measurements, and it can help solve the problem of heterogeneous expression and conversion of HER2 status during disease progression or treatment. Different imaging probes of targeting proteins, such as monoclonal antibodies, antibody fragments, nanobodies, and affibodies, are currently in preclinical and clinical development. Moreover, in recent years, HER2-specific peptides have been widely developed for molecular imaging techniques for HER2-positive cancers. This article summarized different types of molecular probes targeting HER2 used in current clinical applications and the developmental trend of some HER2-specific peptides.

scholarly journals Peptide Based Imaging Agents for HER2 Imaging in Oncology

2020 ◽  
Vol 19 ◽  
pp. 153601212096025 ◽  
Author(s):  
Maxwell Ducharme ◽  
Suzanne E. Lapi
Keyword(s):  
Breast Cancer ◽  
Pet Imaging ◽  
Imaging Techniques ◽  
Treatment Options ◽  
Growth Factor Receptor ◽  
Her2 Status ◽  
Cancer Type ◽  
Her2 Positive ◽  
Positron Emission ◽  
Imaging Probes

Breast cancer continues to be the most lethal cancer type in women and one of the most diagnosed. Understanding Breast cancer receptor status is one of the most vital processes for determining treatment options. One type of breast cancer, human epidermal growth factor receptor 2 (HER2) positive, has approved receptor-based therapies including trastuzumab and pertuzumab that can significantly increase the likelihood of survival. Current methods to determine HER2 status include biopsies with immunohistochemical staining and/or fluorescence in situ hybridization. However, positron emission tomography (PET) imaging techniques using 89Zr-trastuzumab or 89Zr-pertuzumab are currently in clinical trials for a non-invasive, full body diagnostic approach. Although the antibodies have strong specificity to the HER2 positive lesions, challenges involving long post-injection time for imaging due to the blood circulation of the antibodies and matching of long-live isotopes leading to increased dose to the patient leave opportunities for alternative PET imaging probes. Peptides have been shown to allow for shorter injection-to-imaging time and can be used with shorter lived isotopes. HER2 specific peptides under development will help improve the diagnosis and potentially therapy options for HER2 positive breast cancer. Peptides showing specificity for HER2 could start widespread development of molecular imaging techniques for HER2 positive cancers.

scholarly journals Loss of Human Epidermal Growth Factor Receptor 2 (HER2) Expression in Metastatic Sites of HER2-Overexpressing Primary Breast Tumors

2012 ◽  
Vol 30 (6) ◽  
pp. 593-599 ◽  
Author(s):  
Naoki Niikura ◽  
Jun Liu ◽  
Naoki Hayashi ◽  
Elizabeth A. Mittendorf ◽  
Yun Gong ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Growth Factor Receptor ◽  
Breast Tumors ◽  
Her2 Status ◽  
Her2 Positive ◽  
Metastatic Tumors ◽  
Epidermal Growth

Purpose We evaluated whether patients with human epidermal growth factor receptor 2 (HER2) –positive primary breast tumors had metastatic tumors that were HER2 positive (concordant) or HER2 negative (discordant). We then evaluated whether treatment with trastuzumab or chemotherapy before biopsy of the metastasis had any effect on the rate of HER2 discordance. We also compared the overall survival durations of patients with HER2-concordant and -discordant tumors. Patients and Methods We retrospectively identified all patients who initially had been diagnosed with HER2-positive (immunohistochemistry 3+ and/or fluorescent in situ hybridization positive) primary breast cancer between 1997 and 2008 at MD Anderson Cancer Center who also had metastatic tumor biopsy results available for review. Results We included 182 patients who met our criteria. Forty-three (24%) of the 182 patients with HER2-positive primary tumors had HER2-negative metastatic tumors. The HER2 discordance rates differed significantly on the basis of whether patients received chemotherapy (P = .022) but not on the basis of whether patients received trastuzumab (P = .296). Patients with discordant HER2 status had shorter overall survival than did patients with concordant HER2 status (hazard ratio [HR], 0.43; P = .003). A survival difference remained among the 67 patients who received trastuzumab (HR, 0.56; P = .083) and 101 patients who did not (HR, 0.53; P = .033) before their metastasis biopsies. Conclusion We confirmed that loss of HER2-positive status in metastatic tumors can occur in patients with primary HER2-positive breast cancer. Our data strongly support the need for biopsies of metastatic lesions to accurately determine patient prognosis and appropriate use of targeted therapy.

Metastatic breast cancer: A regional audit of HER2 testing and trastuzumab access

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6097-6097
Author(s):  
P. Scullin ◽  
A. T. Drake ◽  
V. M. Coyle ◽  
J. J. McAleer
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Single Agent ◽  
Growth Factor Receptor ◽  
Metastatic Breast ◽  
Her2 Status ◽  
Her2 Receptor ◽  
Her2 Positive ◽  
Her2 Testing ◽  
Number Of Patients

6097 Background: Clinical trials have clearly established that patients receiving taxane-based chemotherapy for metastatic breast cancer (MBC) should be treated with trastuzumab if their tumour is shown to overexpress the human epidermal growth factor receptor 2 (HER2) receptor. This is based on median survival gains for patients with HER2 positive tumours treated with trastuzumab plus taxane chemotherapy compared to taxane alone. Methods: Patients commencing chemotherapy for MBC in Northern Ireland in 2004 were identified from pharmacy records. Their case notes were retrospectively reviewed to determine whether patients in routine clinical practice had HER2 testing and trastuzumab treatment if indicated. Results: One hundred and fifty six patients commenced chemotherapy, of whom 145(93%) had HER2 testing. In 69(44%) patients the HER2 result was already available at the time of this relapse. In the remaining 76(49%) patients the result became available in a median of 41.5 (range 0–368) days. Of those tested, 48 patients (33%) were HER2 positive (immuno-histochemistry 3+ or fluorescence in situ hybridization positive). Thirty eight of these patients were treated with trastuzumab, either as a single agent or in combination with chemotherapy. There were valid reasons for trastuzumab omission in 7 of 10 patients not given trastuzumab (4 given first line anthracycline-based regimen, 1 had cardiac dysfunction, 1 had extensive lung metastastes and 1 was unfit for treatment). The data were examined for variations in chemotherapy and trastuzumab use across the 4 health boards which comprise the region. The number of patients commencing chemotherapy ranged from 6.9 to 11.4 patients per 100,000 population indicating a significantly different utilisation (p<0.001). Conclusions: In our region 145 of 156 patients who received chemotherapy for MBC were tested for overexpression of the HER2 receptor (93%). Of those patients who were eligible to receive trastuzumab 31 out of 34 (91%) received trastuzumab. There were inequalities in the region regarding chemotherapy for MBC and the time required to obtain a HER2 result averaged 41.5 days. Testing of HER2 status at time of original diagnosis would streamline management of metastatic disease. No significant financial relationships to disclose.

scholarly journals Outcomes by Tumor Subtype and Treatment Pattern in Women With Small, Node-Negative Breast Cancer: A Multi-Institutional Study

2014 ◽  
Vol 32 (20) ◽  
pp. 2142-2150 ◽  
Author(s):  
Ines Vaz-Luis ◽  
Rebecca A. Ottesen ◽  
Melissa E. Hughes ◽  
Rizvan Mamet ◽  
Harold J. Burstein ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cohort Study ◽  
Growth Factor Receptor ◽  
Her2 Status ◽  
Survival Outcomes ◽  
Breast Cancers ◽  
Tumor Subtype ◽  
Her2 Positive ◽  
Distant Relapse ◽  
Node Negative Breast Cancer

Purpose Treatment decisions for patients with T1a,bN0M0 breast cancer are challenging. We studied the time trends in use of adjuvant chemotherapy and survival outcomes among these patients. Patients and Methods This was a prospective cohort study within the National Comprehensive Cancer Network Database that included 4,113 women with T1a,bN0M0 breast cancer treated between 2000 and 2009. Tumors were grouped by size (T1a, T1b), biologic subtype defined by hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status, and receipt of chemotherapy with or without trastuzumab. Results Median follow-up time was 5.5 years. Eight percent of patients with HR-positive/HER2-negative tumors were treated with chemotherapy. Fifty-two percent of those with HER2-positive or HR-negative/HER2-negative breast cancers received chemotherapy, with an increase over the last decade. Survival outcomes diverged by subtype and size, but the 5-year distant relapse-free survival (DRFS) did not exceed 10% in any subgroup. The 5-year DRFS for patients with T1a tumors untreated with chemotherapy ranged from 93% to 98% (n = 49 to 972), and for patients with T1b tumors, it ranged from 90% to 96% (n = 17 to 2,005). Patients with HR-positive/HER2-negative disease had the best DRFS estimates, and patients with HR-negative/HER2-negative tumors had the lowest. In this observational, nonrandomized cohort study, the 5-year DRFS for treated patients with T1a tumors was 100% for all subgroups (n = 12 to 33), and for patients with T1b tumors, it ranged from 94% to 96% (n = 88 to 241). Conclusion Women with T1a,b tumors have an excellent prognosis without chemotherapy. Size and tumor subtype may identify patients in whom the rate of recurrence justifies consideration of chemotherapy. These patients represent an optimal group for evaluating less toxic adjuvant regimens to maintain efficacy while minimizing short- and long-term risks.

Comparison of Breast Cancer Recurrence and Outcome Patterns Between Patients Treated From 1986 to 1992 and From 2004 to 2008

2015 ◽  
Vol 33 (1) ◽  
pp. 65-73 ◽  
Author(s):  
Rachel J.D. Cossetti ◽  
Scott K. Tyldesley ◽  
Caroline H. Speers ◽  
Yvonne Zheng ◽  
Karen A. Gelmon
Keyword(s):  
Breast Cancer ◽  
Hazard Rate ◽  
Growth Factor Receptor ◽  
Cancer Recurrence ◽  
Disease Recurrence ◽  
Her2 Status ◽  
Study Cohort ◽  
Her2 Positive ◽  
Cancer Agency ◽  
Er Positive

Purpose To determine whether the patterns of relapse according to estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) status changed in the contemporary era. Patients and Methods Female patients referred to the British Columbia Cancer Agency with biopsy-proven stage I to III breast cancer (BC), diagnosed between 1986 and 1992 (cohort 1 [C1]) and between mid-2004 and 2008 (cohort 2 [C2]), and with known ER and HER2 status were eligible. Data were prospectively collected. C2 patients were matched to C1 patients for stage, grade, and ER and HER2 status. The primary end point was hazard rate of relapse (HRR) for BC by study cohort according to biomarker status. Secondary outcomes included HRR according to stage, grade, and age and hazard rate of death (HRD). Results After matching, 7,178 patients were included (3,589 patients in each cohort). BC subtype distribution was as following ER positive/HER2 negative, 70.8%; ER positive/HER2 positive, 6.9%; ER negative/HER2 positive, 6.6%; and ER negative/HER2 negative, 15.8%. For the overall population, the HRR approximately halved in all yearly intervals to year 9 in C2 compared with C1. Differences in HRR between cohorts were greater in the initial five intervals for HER2-positive and ER-negative/HER2-negative BC. The HRR decreased in C2 compared with C1 for all disease stages and grades. The HRD in C2 also decreased compared with C1, although to a lesser extent. Conclusion Although the pattern of relapse remains similar, there has been a significant improvement in BC relapse-free survival. Outcomes have improved for all BC subtypes, especially HER2-positive and ER-negative/HER2-negative BC, with the early spike in disease recurrence markedly decreased. These contemporary hazard rates are important for treatment decisions, patient discussions, and planning clinical trials of early BC.

scholarly journals Estrogen receptor, Progesterone receptor, and human epidermal growth factor receptor-2 status in breast cancer: A retrospective study of 5436 women from a regional cancer center in South India

2018 ◽  
Vol 07 (01) ◽  
pp. 07-10 ◽  
Author(s):  
Rekha Vijay Kumar ◽  
Dipti Panwar ◽  
Usha Amirtham ◽  
Chennagiri Srinivasmurthy Premalata ◽  
Champaka Gopal ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Epidermal Growth Factor Receptor ◽  
Retrospective Study ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Her2 Status ◽  
Her2 Positive ◽  
Epidermal Growth

Abstract Aim: The aim of the study was to analyze the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) status over 7 years in South Indian women with breast cancer. Further analysis of a subgroup was done to study clinically defined subtypes and the role of preanalytical factors in needle core biopsies (NCBs) and excised specimens. Materials and Methods: This was a retrospective study from January 2010 to December 2016. Patients diagnosed with invasive breast cancer and available immunohistochemistry (IHC) reports of ER, PR, and HER2 status were analyzed. The cases for the year 2016 were analyzed further to observe the impact of preanalytical factors on the IHC staining patterns and surrogate status. Results: A total of 5436 patients were included with a median age of 48 years. Among these, 65% were ≤ 55 years. The overall incidence of hormone receptor (HR)-positive patients was 48%; HER2 positive, 15%; and triple-negative breast cancer (TNBC), 37%. The incidence of HR positive, HER2 positive, and TNBC were 45%, 16%, and 39% and 53%, 13%, and 34% in patients <56 years and over 55 years, respectively (P < 0.001). There was an increase in HR positivity and decrease in TNBCs over time. There was no significant difference in the staining patterns in NCBs and excised specimens. Conclusion: With time, there is an increase in hormone-positive tumors which may be attributed to better IHC techniques and tissue handling. There was no statistical difference in the patterns of ER, PR, and HER2 immunostaining in core biopsy and excised specimens.

scholarly journals Local and Central Evaluation of HER2 Positivity and Clinical Outcome in Advanced Gastric and Gastroesophageal Cancer—Results from the AGMT GASTRIC-5 Registry

2020 ◽  
Vol 9 (4) ◽  
pp. 935
Author(s):  
Florian Huemer ◽  
Lukas Weiss ◽  
Peter Regitnig ◽  
Thomas Winder ◽  
Bernd Hartmann ◽  
...  
Keyword(s):  
Treatment Options ◽  
Gastroesophageal Junction ◽  
Growth Factor Receptor ◽  
Her2 Status ◽  
Individual Treatment ◽  
Her2 Positive ◽  
Her2 Testing ◽  
Negative Results ◽  
First Line Therapy ◽  
Her2 Positivity

Trastuzumab in combination with a platinum and fluorouracil is the treatment of choice for patients with advanced human epidermal growth factor receptor 2 (HER2) positive gastric cancer and gastroesophageal junction (GEJ) cancer. Pathological assessment of the HER2 status in gastric/GEJ cancer, however, still remains difficult. However, it is a crucial prerequisite for optimal treatment. The GASTRIC-5 registry was designed as an observational, multi-center research initiative comparing local and central HER2 testing. HER2 status was assessed by immunohistochemistry (IHC) and in equivocal cases (IHC score 2+) by additional in-situ hybridization. Between May 2011 and August 2018, tumor samples of 183 patients were tested in local and central pathology laboratories, respectively. Central testing revealed HER2 positivity in 38 samples (21%). Discordant HER2 results were found in 12% (22 out of 183) with locally HER2 positive/centrally HER2 negative results (9%, 17 out of 183), exceeding locally HER2 negative/centrally HER2 positive results (3%, 5 out of 183). Centrally confirmed HER2 positive patients receiving trastuzumab-based palliative first-line therapy showed a longer median overall survival compared to centrally HER2 positive patients not receiving trastuzumab (17.7 months (95% CI: 10,870–24,530) vs. 6.9 months (95% CI: 3.980–9.820), p = 0.016). The findings of the GASTRIC-5 registry corroborate the challenge of HER2 testing in gastric/GEJ cancer and highlight the necessity for central quality control to optimize individual treatment options. Centrally HER2 positive patients not receiving trastuzumab had the worst outcome in a Western real-world gastric/GEJ cancer cohort.

scholarly journals Study of Receptor Status in Carcinoma Breast Patient

2018 ◽  
Vol 16 (2) ◽  
pp. 48-50 ◽  
Author(s):  
Shakera Ahmed ◽  
Khondker AK Azad
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Treatment Options ◽  
Growth Factor Receptor ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Receptor Status ◽  
Background Estimation ◽  
Epidermal Growth ◽  
The Cost

Background: Estimation of Estrogen Receptor (ER) Progesterone Receptor (PR) and Human Epidermal Growth Factor Receptor 2 (HER2) is mandatory for choosing treatment options and prognosis of breast cancer patients. This estimation can be done by Immunohistochemistry (IHC) and Fluoroscence In Situ Hybridization (FISH) test. As the tests are expensive many of our patients can’t afford to do it. But if we practice doing the test routinely the cost will be reduced and our patients will be benefited. So we underwent a primitive study on receptor status in breast cancer patients. Our goal was to encourage the surgeons to advice receptor status routinely and treat the patients accordingly as patients prognosis will be much more better if they are treated according to their receptor status.Methods: This was a retrospective observational study of 74 breast cancer patients in a private clinic. In this study we have shown their receptor status by IHC and the data were analyzed.Results: Among the 74 patients 32 were ER +ve PR +ve, 11 were ER +ve PR -ve, 02 were ER –ve PR +ve, 29 were ER -ve PR -ve. ER &/or PR positive patients will be more responsive to hormone therapy. 28 patients were HER2 +ve, 34 patients were HER2 –ve and 9 were equivocal. HER2 positive patients will be benefited from targeted therapy. Among the patients 11 were triple negative that means they have worst prognosis.Conclusion: As knowing the receptor status in breast cancer help us as a predictive, prognostic and therapeutic indicator, we must advice it routinely and take steps to make it cheaper and easily available.Chatt Maa Shi Hosp Med Coll J; Vol.16 (2); July 2017; Page 48-50

Evaluation of clinical significance of basal-like subtype of breast cancer identified by immunohistochemistry

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 21107-21107
Author(s):  
L. B. Cassol ◽  
M. Graudenz ◽  
A. Zelmanowicz ◽  
A. Cancela ◽  
C. Coral ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Molecular Subtypes ◽  
Treatment Options ◽  
Growth Factor Receptor ◽  
Immunohistochemical Analysis ◽  
Her2 Positive ◽  
Prognostic Evaluation ◽  
Egfr Expression ◽  
Number Of Patients ◽  
Epidermal Growth

21107 Background: At present time, prognostic evaluation of initial breast cancer is mostly based on patients’ clinical and tumoral histological features. Recently, molecular subtypes of invasive breast cancer were recognized through DNA microarray profiling studies. This new classification can potentially improve the prognostic evaluation but this technology is still not widely available. The possibility of identifying the molecular subtypes through simpler and cheaper methods is promising. The identification of basal-like breast cancer (BLBC) is particularly important because it has a poor outcome and fewer treatment options available. Additionally, Epidermal Growth Factor Receptor (EGFR) expression seems to be more frequent in this subtype. Methods: A retrospective cohort of 112 consecutive patients with pathologic stage I or II primary breast carcinomas, treated in the same institution between 1995 and 2000, was studied. Histological and clinical features as well as clinical outcome and survival were reviewed. Immunohistochemical analysis was carried out in representative blocks of tumors with antibodies against Estrogen Receptor (ER), Human Epidermal Growth Receptor - type 2 (HER2), CK5/6 and EGFR. The primary endpoint was to determine the prevalence of BLBC (ER and HER2-negative and CK 5/6 and/or EGFR-positive) in this population. Results: 13 of 112 tumors (11,6 %) were BLBC. Their mean age was 49 years; 77 % were stage II and 100 % were invasive ductal carcinomas. There was no prognostic difference between BLBC and the subtypes luminal (ER-positive and HER2-negative); HER2-overexpressing (HER2-positive) and undetermined (four markers negative) relating to disease-free and overall survival. This is probably related to limited number of patients in this study and good prognosis of initial-stage patients. 11 of 112 cases (10%) were positive for EGFR. EGFR-positive tumors tended to be ER- negative (23 % vs 5 %; p=0,01). Conclusions: Our results suggest that it is possible to identify BLBC by immunohistochemical analysis of ER, HER2, CK 5/6 and EGFR. Besides, EGFR expression seems to be more frequent in ER-negative tumors, which suggest EGFR-targeted drugs may benefit this population. No significant financial relationships to disclose.

Ki67 as Proliferative Marker in Patients with Early Breast Cancer and Its Association with Clinicopathological Factors

Oncology ◽  
2021 ◽  
pp. 1-10
Author(s):  
Amelie de Gregorio ◽  
Thomas Wolfram Paul Friedl ◽  
Eva Hering ◽  
Peter Widschwendter ◽  
Nikolaus de Gregorio ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Early Breast Cancer ◽  
Tumor Biology ◽  
Growth Factor Receptor ◽  
University Hospital ◽  
Proliferation Index ◽  
Her2 Status ◽  
Clinicopathological Factors ◽  
Her2 Positive ◽  
Proliferative Marker

<b><i>Introduction:</i></b> Ki67 as a proliferative marker has prognostic and therapeutic relevance in early breast cancer (EBC). However, standard cutoffs for distinguishing low and high Ki67 do not exist. <b><i>Material and Methods:</i></b> Data from all patients treated at the University Hospital Ulm for EBC between January 2013 and December 2015 with documented results for internal Ki67 assessment of the primary (<i>n</i> = 917) tumor were retrospectively analyzed evaluating the associations between Ki67 and other clinicopathological factors. <b><i>Results:</i></b> 595 (64.9%) patients had a Ki67 &#x3c;20% and 322 (35.1%) a Ki67 ≥20%. The median Ki67 was 10% (range 1–90%). Median Ki67 values according to the hormone receptor (HR)/ human epidermal growth factor receptor 2 (HER2) subtypes were 10% for HR-positive/HER2 negative (HR+/HER2−) disease (<i>n</i> = 717), 20% for HR+/HER2+ (<i>n</i> = 76), 30% for HR−/HER2+ (<i>n</i> = 45), and 60% for HR−/HER2− (<i>n</i> = 75). 75.2% or 89.3% of all patients with HER2-positive or triple-negative disease had a Ki67 ≥20%, respectively. Using a multivariable logistic regression with Ki67 (&#x3c;20% vs. ≥20%) as binary dependent variable, younger age, positive nodal status, higher grading, histological nonspecific type carcinoma, negative HR status, and positive HER2 status were shown to be significantly associated with a higher proliferative index (Ki67 ≥20%). <b><i>Conclusion:</i></b> This analysis described Ki67 in different subtypes in EBC and its association with clinicopathological factors. According to more aggressive tumor biology, the respective subgroups also showed higher median Ki67 levels. However, definition of low and high proliferation index itself is difficult. It is essential to interpret Ki67 indices carefully with regard to the own institutional values and other clinicopathological factors.

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