|Ahead of print
Impact of St. Gallen surrogate classification for intrinsic breast cancer sub-types on disease features, recurrence, and survival in South Indian patients
Beena Kunheri1, Rhaina V Raj2, DK Vijaykumar3, K Pavithran4
1 Department of Radiation Oncology, Amrita Institute of Medical Sciences, Amrita Viswa Vidyapeetham, Kochi, Kerala, India
2 Department of Amrita School of Medicine, Amrita Institute of Medical Sciences, Amrita Viswa Vidyapeetham, Kochi, Kerala, India
3 Department of Gynaecological Oncology, Amrita Institute of Medical Sciences, Amrita Viswa Vidyapeetham, Kochi, Kerala, India
4 Department of Medical Oncology, Amrita Institute of Medical Sciences, Amrita University (Deemed), Kochi, Kerala, India
Department of Radiation Oncology, Amrita Institute of Medical Sciences, Amrita Viswa Vidyapeetham, Kochi, Kerala
Source of Support: None, Conflict of Interest: None
BACKGROUND: Breast cancer is a heterogeneous group of disease, and recently, intrinsic sub-typing on the basis of gene expression profiling is found to be a predictor of breast cancer clinical course. The St. Gallen has released surrogate classification for breast cancer sub-types depending on immunohistochemistry (IHC) markers.
AIM: The aim of our study was to analyze the distribution of sub-types using IHC surrogate markers in our patient population and to assess the clinico-pathological factors in different sub-types.
MATERIALS AND METHODS: A total of 635 non-metastatic patients who underwent radical intend treatment from January 2011 to December 2013 were included for this retrospective analysis. A statistical analysis was done by Windows SPSS version 20. The Chi-square test was used to examine the correlations of these sub-types with clinico-pathological parameters. The Kaplan-Meier method estimates were used for survival analysis.
RESULTS: The median follow-up was 42.77 months (5 months to 112 months). Luminal B was the predominant group. Disease free survival (DFS) at 5 years was 95% in luminal A, 78% in luminal B HER-2 negative, 80% in luminal B HER-2 positive, 72% in triple negative, and 79% in HER-2/neu non-luminal. Tumor size, Ki67, T stage, N stage, and grade were significantly associated with DFS in all biological type with a P value of less than 0.05.
CONCLUSION: Surrogate classification was successfully applied in our patient cohort. Luminal B and triple negative sub-groups were more prevalent in our patients, and this finding is at variance with published international data. Biological sub-type also emerged as an important predictor of survival.
Keywords: Biological subtype, breast cancer, immunohistochemistry markers, St. Gallen
|How to cite this URL:|
Kunheri B, Raj RV, Vijaykumar D K, Pavithran K. Impact of St. Gallen surrogate classification for intrinsic breast cancer sub-types on disease features, recurrence, and survival in South Indian patients. Indian J Cancer [Epub ahead of print] [cited 2020 Jan 17]. Available from: http://www.indianjcancer.com/preprintarticle.asp?id=275393
| » Introduction|| |
Breast cancer is the most common cause of cancer in females across the world and second most common among Indian women. There is a rural-urban divide, and in urban India, recently breast cancer has become the most common cancer among females. India is rapidly stepping toward industrialization and urbanization resulting in change of lifestyle factors, possibly contributing to a gradual increase in the incidence of breast cancer in the country.,
Breast cancer is a spectrum of disease with varied clinical behavior and outcome. On the basis of gene expression profile mainly 5 intrinsic sub-types have been defined.
The St. Gallen international expert consensus on the primary therapy of early breast cancer defined a surrogate to distinguish luminal A-like breast cancer from luminal B-like, HER-2/neu, and triple negative disease, from a combination of estrogen receptor (ER), progesterone receptor (PR), Ki67%, and HER-2/neu immunohistochemical (IHC) profile, without a requirement of molecular diagnosis, which required ultra-specialized laboratories and is expensive. It was for predictive goals but not for prognostic purposes. Previous studies have shown that tumor presentation and clinical course vary among molecular sub-types.,,,, The clinical significance of this classification in terms of outcome, disease-free interval, and recurrence pattern remains unclear in our population. Around the world, breast cancer has an increasing incidence, but limited resources are available to treat it. Many of the less developed countries have low health expenditure per capita that renders the use of expensive laboratory tests and treatments inaccessible to the majority of patients worldwide. This surrogate classification is of great use because IHC is affordable, fast, and does not require an ultra-specialized laboratory facility. Moreover, in early luminal A tumors, chemotherapy can be avoided, thus, allowing the effective utilization of health resources.
| » Aims and Objectives|| |
To analyze the distribution of intrinsic breast cancer molecular sub-types using St. Gallen surrogate markers in our patients and to compare with published literature.
To find how the St. Gallen surrogate classification of intrinsic breast cancer predicts the disease features, recurrence pattern, and disease free survival (DFS) in our population.
| » Materials and Methods|| |
Breast cancer patients treated at our center from January 2011 to December 2013 with radical intent were included for this retrospective analysis. Data collection was from our hospital medical records. From IHC parameters (ER, PR, HER-2/neu, and Ki67%), patients were classified into different biological groups. Data collection and analysis were done during the period, July 2017 to August 2017.
Patients without IHC details of ER, PR, HER-2/neu, and Ki67 were excluded from the study or
If HER-2+ on IHC and confirmation Fluorescent in situ hybridization(FISH) test was not available. Also, patients with distant metastatic disease at presentation and patients with the history of prior malignancies were excluded.
Classification of groups
Tumors were classified by IHC staining according to St. Gallen sub-types as follows:
- Luminal A: ER positive and/or PR positive, HER-2 negative, Ki67%=20%
- Luminal B HER-2 negative: ER positive and/or PR positive, HER-2 negative, Ki67%>20%
- Luminal B HER-2 positive: ER positive and/or PR positive, HER-2 positive
- HER-2/neu non-luminal: ER negative and/or PR- negative, HER-2 positive
- Triple negative: ER negative and/or PR negative, HER-2 negative.
ER/PR status was determined by IHC and considered ER+/PR+, if greater than 1% staining.
Tumors were considered HER-2 positive, if they scored 3+ by IHC. In case of scoring 2+, tumors were considered HER-2+, if FISH showed HER-2 gene amplification. If HER FISH was not available, those cases were not included for analysis.
The subject Ki67 (proliferation index)% cut-off value is a subject of debate.,, It is practically observed that generally our patients have a higher Ki67% values, even for grade 1–2 tumors. In addition, controversy exists as to cut-off values for Ki67% because of differences in IHC standardization protocols. In this analysis, we considered a Ki67 value of 20% as cut-off.
A total of 635 patients were available during this period with complete IHC details.
Disease features at presentation
Pathological T and N stage for patients undergoing upfront surgery, and clinical T and N stage for patients undergoing neo-adjuvant chemotherapy. American Joint Committee on Cancer staging 7th edition was used for T and N stage classification.
Disease free survival and recurrence sites
DFS was defined as the length of time between histological diagnosis and recurrence in either the ipsilateral breast, lymph nodes (nodal), bone or visceral (liver, lung, and central nervous system(CNS)), or death. Contralateral breast cancers were considered as new primaries not as recurrence.
It was defined as the length of time between histological diagnosis and death due to any cause.
Statistical analysis was done by Windows SPSS version 20. The Chi-square test was used to examine the correlations of breast cancer sub-types with clinico-pathological parameters. The Kaplan-Meier method estimates were used for survival analysis, and the log-rank test was used to compare the DFS between the sub-groups.
This is a retrospective analysis of biological sub-types of breast cancer in patients already treated with standard accepted modalities. The patient's identity was not revealed. The study was cleared by institutional review board and ethical committee.
| » Observations and Results|| |
A total of 635 non-metastatic patients who underwent radical intent treatment were included in the study. The biological classification was applied from IHC data. There were 151 luminal A (23.77%), 176 luminal B HER-2 negative (27.71%), 59 luminal B HER-2 positive (9.29%), 169 triple negative (26.61%), and 80 (12.59%) HER-2/neu non-luminal cases. The proliferation index (Ki67) cut-off was taken as up to 20. Luminal B tumors (luminal B HER positive and negative together) were most prevalent followed by triple negative. Different clinical parameters such as tumor size, Ki67 value, T stage, N stage, tumor grade, and recurrence pattern were looked into the variation between each sub-type [Table 1]. The median tumor size was not different between the sub-types. The median proliferation index (%) was 51 in triple negative, 42 in HER-2/neu non-luminal, 40 in luminal B HER-2 positive, 35 in luminal B HER-2 negative, and lowest in luminal A (12%). T stage was available for 630 patients T1 (142), T2 (366), T3 (101), and T4 (21). Nodal stages were available for 622 patients of which 260 (41.80%) N0, 218 (35.05%) N1, 56 (9.00%) N2, and 28 (4.50%) N3. Most tumours were grade 2. The distribution of T stage, N stage, and grade are as shown in [Table 1]. Out of 50 recurrences, 26 were in the triple negative group. Recurrence percentage was 1.98% (3 out of 151) in luminal A group, 6.81% (12 out of 176) in luminal B HER-2 negative, 8.47% (5 out of 59) in luminal B HER-2 positive, 15.38% (26 out of 169), and 5% (4 out of 80) in HER-2/neu non-luminal as shown in [Table 2] and [Table 3].
|Table 1: Univariate analysis of various prognostic factors on disease free survival|
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The median follow-up of our patient group was 42.77 months (range 5 months to 112 months).
DFS at 5 years was 95% in luminal A, 78% in luminal B HER-2 negative, 80% in luminal B HER-2 positive, 72% in triple negative, and 7 9% in HER-2/neu non-luminal.
Overall survival at 5 years was 98% in luminal A, 92% in luminal B HER-2 negative, 90% in luminal B HER-2 positive, 88% in triple negative, and 95% in HER-2/neu non-luminal. Overall survival of according to biological subtype shown in [Figure 1].
Tumor size, Ki67, T stage, N stage, and grade were significantly associated with DFS in all biological type with a P value of less than 0.05 [Table 1].
| » Discussion|| |
Breast cancer is a heterogeneous group of disease with varying natural history and survival. To identify the intrinsic breast cancer sub-types, the full proof method is gene expression profiling. Because of the non-availability and expense, this cannot be used in routine clinical practice. The IHC expression of hormonal receptors, HER-2/neu, and Ki67 values can categorize breast cancer analogous to molecular profiling. The St. Gallen expert consensus on primary therapy of breast cancer released surrogate classification for breast cancer sub-types to guide adjuvant treatment decision-making.
In the present study, our aim was to analyze the distribution of breast cancer sub-types in our population and to assess the clinico-pathological factors in different sub-types. We also analyzed the pattern of recurrence and survival in these sub-types.
There are several limitations in this study. There are inherent limitations in classifying breast cancer sub-types by IHC surrogates. Since this was a retrospective study clinico-pathological factors were not available for all the patients, and long-term follow-up was also not present for all the patients. Another limitation is the use of Ki67 because there is a controversy existing as to cut-off values for Ki67% because of the differences in IHC standardization protocols.
One of the strengths to this study was that all HER-2/neu samples that scored 2+ were further analyzed by FISH to confirm or exclude HER-2/neu over-expression. IHC for hormonal receptors, HER-2/neu, and Ki67 was routinely done in our patients, and hence, we could classify our patients to different biological subtypes.
The distribution of biological sub-type in our cohort was luminal A 23.7%, luminal B HER-2 negative 27.71%, luminal B HER-2 positive 9.29%, triple negative 26.61%, and HER-2/neu non-luminal (12.59%), indicating that in our group luminal B was predominant followed by triple negative and luminal A. Ines Vasconcelos et al. from Berlin breast center has reported around 60% of luminal A in their population followed by luminal B.
When clinico-pathological factors were considered, advanced T and N stage was predominant in triple negative followed by luminal B group. Higher tumor grade and proliferation index were also seen in triple negative. T stage, N stage, Ki67, and grade were predictors of DFS in all sub-groups with significant P value.
Another goal of the present study was to evaluate the pattern of recurrence and outcome of the major breast cancer sub-types. Our data are consistent with previous studies showing that luminal B tumors had a higher recurrence than their luminal A counterpart.,
Our study showed a highest recurrence for triple negative (30% local and 70% systemic), which translated into a shorter DFS. HER-2/neu non-luminal has high DFS and low recurrence than luminal B, which is not the case with most of the published literature.,, This could probably be because of less number patients in that group and treatment with anti-HER-2/neu agents.,
We were able to successfully apply IHC based surrogate classification in our patient cohort. Luminal B and triple negative sub-groups are more prevalent in our patients, and this finding is at variance with published international data. Biological sub-type also emerged as an important predictor of survival.
| » Conclusion|| |
St. Gallen surrogate classification according to IHC can be successfully implemented for breast cancer intrinsic sub-typing in centers with standardized IHC facility. On the basis of sub-typing, treatment can be tailored thus allowing meaningful utilization of resources. Early luminal A type of tumors chemotherapy can be avoided thus saving the cost and reducing morbidity. This classification also has a strong predictive value for survival.
| » Summary|| |
The gene expression profiling of breast cancers identifies distinct molecular sub-types with prognostic implications. In this study, we were able to do the sub-typing by IHC surrogates proposed by St. Gallen. The gene expression profiling requires specialized laboratory and specialists and is expensive. Most states in India have a low level of per capita health expenditure. Hence, the classification of breast cancer depending on gene profiling is not cost-effective in our situation, and the classification using IHC markers might be more practical and puts less strain on resources. We found a significant difference among sub-types when comparing clinical parameters, recurrence, and survival. Luminal tumors with better prognosis are comparatively less in our population compared to international cohorts calling for further research in India-specific situation.
Dr. Vijay Kumar, MD, DM, Department of Medical Oncology, Amrita Institute of Medical Sciences for helping with the statistical analysis.
Financial support and sponsorship
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]