Abstract
Breast cancer has emerged as a major health problem among women in India. There are few Indian studies which have looked at prevalence of molecular subtypes of breast cancer in Indian population. The primary objective of our study was to find out the prevalence of various molecular subtypes in operated cases of breast cancer patients presenting to us. Three hundred sixty patients who were operated in our department were analysed. Clinicopathological features of all cases were recorded. Classification into various molecular subtypes was done using St. Gallen 2013 criteria. Luminal B HER2 negative was the predominant molecular subtype in our study population constituting 30.3% of patients. The percentage of aggressive subtypes, viz. triple negative breast cancer and HER2 enriched, were 21.7% and 11.4% respectively. Only 19.4% of patients in our study population had tumour size ≤ 2 cm with nodes being positive in 56.9% of our patients at presentation. Data from our study and other studies published from India show that the two most aggressive subtypes of, viz. triple negative breast cancer and HER2 enriched, may be more prevalent in our population as compared to western population.
Keywords: Breast cancer, Molecular subtypes, India
Breast cancer at present is the leading cancer in Indian female population [1]. The total number of new cases of breast cancer stood at 162,468 as per GLOBOCAN 2018[1]. The age standardized incidence rate (per 100,000 population) of breast cancer in Indian population (24.7) is less than the global rate of 46.3 and well below the rate (84.9) observed in the USA but mortality related to it in the Indian population is very high [1–3]. In India, there were 87,090 deaths related to breast cancer, approximately half of newly diagnosed cases of breast cancer [1]. This is in sharp contrast to the USA, which had 234,087 new cases and 41,904 deaths [3]. The most common reason postulated for this is that approximately 1–8% of patients in India present in stage I; where as in the USA, this number is 60–70% [4].
It is now a well-established fact that breast cancer is a heterogenous and a complex disease. In spite of availability of well-established predictive markers, the response to treatment is not uniform in breast cancer patients [5, 6]. To answer this diverse behaviour, an attempt was made by Perou and Sorlie to move from traditional histopathology to molecular classification [7]. Using microarray-based gene expression analysis, they classified breast cancer into various intrinsic molecular subtypes [7]. But this technique has its limitation of being expensive and having limited availability. Keeping the above limitations in mind, St. Gallen panel recommended the use of surrogate markers in the form of more readily available and routinely done immunohistochemical (IHC) tests for the expression of oestrogen receptors, progesterone receptors and IHC or florescence in situ hybridization test (FISH) for epidermal growth receptor-2 (HER2/neu) receptors. As a surrogate to proliferative genes, IHC measurement of proliferative activity using Ki-67 index is recommended [8, 9]. The various molecular subtypes so obtained have been shown to have prognostic value. Luminal A subtype has the best prognosis, while triple negative breast cancer (TNBC) has the worst prognosis among the various molecular subtypes [10, 11].There are limited Indian studies which have attempted to find the prevalence of molecular subtypes in Indian population [6, 12–14].
Material and Methods
Breast cancer patients who were operated from January 2017 to April 2020 were considered for this study. The primary objective of our study was to estimate the prevalence of various molecular subtypes in operable breast cancer and correlate it with clinic-pathological features. Patients who had recurrent or metastatic disease at presentation and male patients with breast cancer were excluded. We operated 375 patients during this period out of which complete information about pathology and markers was available in 360 patients. Information on demographic profile and post-operative pathological parameters, viz. histology, tumour size, grade, lymph-vascular space invasion, lymph node status and perinodal extension, was obtained from histopathological reports. Immunohistochemistry (IHC) details for the expression of oestrogen receptor, progesterone receptor, HER2/neu receptor and Ki-67 were collected. IHC was done in post-operative specimen in 283 (78.6%) patients and in core needle biopsy specimen in 77 (21.4%) patients. IHC was done on 4-µ-thick sections using Ventana Benchmark GX automated platform for oestrogen receptor (Dako, monoclonal), progesterone receptor (Dako, monoclonal), HER2 neu (Dako, polyclonal) and Ki-67 (Dako, monoclonal). The slides were analysed by two pathologists independently. Specimen processed before 2018 (59 patients) were done manually; the rest all were automated. The expression for oestrogen and progesterone receptors was taken as positive if ≥ 1% of cells were immunoreactive. Allred score was calculated for oestrogen and progesterone receptors, and the percentage of progesterone positivity was noted. The expression of HER2 receptor was taken as negative if the score was zero or 1 + , equivocal if the score was 2 + and positive if the score was 3 + . Equivocal score was further confirmed by using FISH. Ki-67 being a continuous variable was expressed as percentage. The patients were classified into various molecular subtypes using St. Gallen 2013 criteria (Table 1).
Table 1.
Schema for classification into molecular subtypes using St. Gallen 2013 criteria [8]
| Molecular subtype | Oestrogen receptor | Progesterone receptor | HER2/neu | Ki67 index |
|---|---|---|---|---|
| Luminal A | Positive | Positivity ≥ 20% | Negative | < 20% |
| Luminal B | ||||
| HER2 negative | Positive | Positivity < 20% | Negative | Any |
| Positive | Any | Negative | ≥ 20% | |
| HER2 positive | Positive | Any | Positive | Any |
| HER2 enriched | Negative | Negative | Positive | Any |
| Triple negative breast cancer (TNBC) | Negative | Negative | Negative | Any |
Statistical Analysis
Statistical analysis was performed using Statistical Product and Service solution, SPSS version 22 for Windows. Pearson chi-square was used for comparison of categorical data. Continuous data was expressed as mean, and analysis of variance test (ANOVA) was used to make comparison between groups. Independent t-test was used to make comparison of mean between two groups. P value < 0.05 was taken as significant.
Results
The mean age of patients in our study was 54.4 years with the majority of patients in age group between 41 and 70 years (76.1%). Infiltrating ductal carcinoma was the most common histology seen in 333 (92.5%) out of 360 patients. The mean tumour size was 3.7 cm with only 70 (19.4%) patients having tumour size of ≤ 2 cm. A total 9.7% (35) of all our patients received neoadjuvant chemotherapy, out of which 28 patients had locally advanced breast cancer and 7 patients were those who desired breast conservation surgery. Lymphovascular invasion was present in 86 (23.9%) of patients. Lymph nodes were positive in 205 (56.9%) patients with 86 (23.9%) patients having perinodal extension. The percentage of patients positive for oestrogen, progesterone and HER2 receptor was 66.9%, 56.7% and 28.6%, respectively (Table 2).
Table 2.
Demographic profile of entire cohort
| Entire cohort (n = 360) | |
|---|---|
| Mean age (years) (range) | 54.4 (24–82) |
| ≤ 40 years | 50 (13.9%) |
| 41–70 years | 274 (76.1%) |
| > 70 years | 36 (10%) |
| Clinical stage | |
| Early/operable breast cancer (OBC) | 319 (88.6%) |
| Locally advanced breast cancer (LABC) | 41 (11.4%) |
| Surgery | |
| Modified radical mastectomy | 308 (85.6%) |
| Breast conservation surgery | 49 (13.6%) |
| Bilateral modified radical mastectomy | 3 (0.8%) |
| Neoadjuvant chemotherapy | |
| Yes | 35 (9.7%) |
| No | 325 (90.3%) |
| Mean tumour size (centimetres) (median) | 3.7(0.8–10) (3 cm) |
| ≤ 2 cm | 70 (19.4%) |
| > 2 cm to ≤ 5 cm | 236 (65.6%) |
| > 5 cm | 54 (15%) |
| Histology | |
| Infiltrating duct carcinoma (IDC) | 333 (92.5%) |
| Invasive lobular carcinoma (ILC) | 19 (5.3%) |
| Other histology’s | 8 (2.2%) |
| Lymphovascular invasion | |
| Yes | 86 (23.9%) |
| No | 274 (76.1%) |
| Grade | |
| Grade I | 121 (33.6%) |
| Grade II | 129 (38.6%) |
| Grade III | 84 (23.3%) |
| Unavailable | 26 (7.2%) |
| Lymph node status | |
| Negative | 155 (43.1%) |
| Positive | 205 (56.9%) |
| 1–3 nodes positive | 86 (23.9%) |
| 4–9 nodes positive | 62 (17.2%) |
| > 9 nodes positive | 57 (15.8%) |
| Perinodal extension | |
| Yes | 86 (23.9%) |
| No | 274 (76.1%) |
| Oestrogen receptor positive | |
| Yes | 241 (66.9%) |
| No | 119 (33.1%) |
| Progesterone receptor positive | |
| Yes | 204 (56.7%) |
| No | 156 (43.3%) |
| HER2 positive | |
| Yes | 103 (28.6%) |
| No | 257 (71.4%) |
| Molecular subtypes | |
| Luminal A | 71 (19.7%) |
| Luminal B HER2 negative | 109 (30.3%) |
| Luminal B HER2 positive | 61 (16.9%) |
| HER2 enriched | 41 (11.4%) |
| Triple negative breast cancer (TNBC) | 78 (21.7%) |
Molecular Subtypes
The most common molecular subtype in our study was luminal B HER2 negative (30.3%) followed by triple negative breast cancer (TNBC) (21.7%). Luminal A, luminal B HER2 positive and HER2-enriched subtype were seen in 19.7%, 16.9% and 11.4% patients, respectively (Table 2).
Age Distribution
Patients with luminal A tumours had the highest mean age of 56.8 years and HER2-enriched subtype the lowest mean age of 50.2 years. Among the various age groups, TNBC and HER2-enriched subtypes were most prevalent present in patients ≤ 40 years accounting for 24% and 22% of patients, respectively. Luminal A was the predominant tumour in age group > 70 years (36.1% of cases) (Table 3).
Table 3.
Clinicopathological features of various molecular subtypes
| Luminal A (n = 71) | Luminal B HER2 negative (n = 109) | Luminal B HER2 positive (n = 61) | HER2 enriched (n = 41) | Triple negative breast cancer (TNBC) (n = 78) | P value | |
|---|---|---|---|---|---|---|
| Age (mean) in years | 56.8 | 55.5 | 53.2 | 50.2 | 54 | 0.03 |
| Age group | 0.04 | |||||
| ≤ 40 years | 8 (16%) | 10 (20%) | 9 (18%) | 11 (22%) | 12 (24%) | |
| 41–70 years | 50 (18.2%) | 89 (32.5%) | 48 (17.5%) | 29 (10.6%) | 58 (21.2%) | |
| > 70 years | 13 (36.1%) | 10 (27.8%) | 4 (11.4%) | 1 (2.8%) | 8 (22.2%) | |
| Mean tumour size (cm) | 3.2 | 3.5 | 3.9 | 4 | 3.9 | 0.03 |
| ≤ 2 cm | 16 (22.9%) | 25 (35.7%) | 9 (12.9%) | 7 (10%) | 13 (18.6%) | 0.58 |
| 2–5 cm | 49 (20.8%) | 69 (29.2%) | 42 (17.8%) | 25 (10.6%) | 51 (21.6%) | |
| > 5 cm | 6 (11.1%) | 15 (27.8%) | 10 (18.5%) | 9 (16.7%) | 14 (25.9%) | |
| Lymphovascular invasion (LVI) | 0.006 | |||||
| Present | 9 (12.7%) | 23 (21.1%) | 23 (37.7%) | 14 (34.1%) | 17 (21.8%) | |
| Absent | 62 (87.3%) | 86 (78.9%) | 38 (62.3%) | 27 (65.9%) | 61(78.2%) | |
| Grade (n = 334) | 0.000 | |||||
| Grade I | 46 (73%) | 46 (46.5%) | 13 (22.8%) | 6 (14.6%) | 10 (13.5%) | |
| Grade II | 13 (20.6%) | 38 (29.5%) | 29 (50.9%) | 22 (53.7%) | 27 (36.5%) | |
| Grade III | 4 (6.3%) | 15 (15.2%) | 15 (26.3%) | 13 (31.7%) | 37 (50%) | |
| Lymph node status | ||||||
| Negative | 32 (45.1%) | 49 (45%) | 16 (26.2%) | 14 (34.1%) | 44 (56.4%) | 0.006 |
| Positive | 39 (54.9%) | 60 (55%) | 45 (73.8%) | 27 (65.9%) | 34 (43.6%) | |
| Groups | 0.004 | |||||
| 1–3 | 19 (26.8%) | 31 (28.4%) | 16 (26.2%) | 8 (19.5%) | 12 (15.4%) | |
| 4–9 | 16 (22.5%) | 15 (13.8%) | 12 (19.7%) | 10 (24.4%) | 9 (11.5%) | |
| > 9 | 4 (5.6%) | 14 (12.8%) | 17 (27.9%) | 9 (22%) | 13 (16.7%) | |
| Perinodal extension | 0.46 | |||||
| Present | 20 (28.2%) | 28 (25.7%) | 22 (36.1%) | 14 (36.6%) | 20 (25.6%) | |
| Absent | 51 (71.8%) | 81 (74.3%) | 39 (63.9%) | 26 (63.4%) | 58 (74.4%) | |
| Ki-67 (mean value) | 9.5% | 32.3% | 34.64% | 42% | 57.1% | 0.000 |
Tumour Size
There was a significant difference in the mean tumour size among the various subtypes with luminal A subtype having smallest mean tumour size of 3.2 cm and HER2enriched having largest mean tumour size of 4 cm (Table 3).
Grade
There was a significant difference in the grade of tumour among the various subtypes. Seventy-three per cent of total cases in luminal A were in grade I, and 50% of patients in TNBC were in grade III (Table 3).
Lymphovascular Invasion
There was significant difference between various subtypes with respect to vascular invasion (p = 0.006) with a highest percentage of positivity seen in luminal B HER2 positive (37.7%) and HER2-enriched tumours (34.1%) and least in luminal A tumours (12.7%) (Table 3).
Lymph Node Status
Among the various subtypes, luminal B HER2 positive (73.8%) and HER2-enriched (65.9%) subtype had the maximum nodal positivity, whereas TNBC had the lowest nodal positivity rate (43.6%). Luminal B HER2 positive had the maximum percentage of patients (27.9%) with > 9 nodes. Though there was a significant difference between the groups with respect to nodal positivity (p = 0.006) and number of lymph nodes positive, (p = 0.004), there was no difference with respect to perinodal extension (p = 0.46) (Table 3).
Ki-67 Value
There was a significant difference among various molecular subtypes (p = 0.000) with luminal A having the lowest mean Ki-67 value of 9.5% and TNBC having the maximum mean of 57.1% (Table 3). The difference in the various molecular subtypes remained significant even when luminal A were excluded from analysis (p = 0.000).
Discussion
The most common prevalent molecular subtype in our study population was luminal B HER2 negative constituting 30.3% of our patients. In our study, we have used both Ki-67 and progesterone receptor positivity > 20% for classification of luminal tumours. A major limiting factor in the use of Ki-67 is that there is no optimal cut-off value. St. Gallen panel 2011 recommended cut-off value of ≥ 14% for classification into luminal B subtype, but in 2013, the majority of panel voted for using cut-off value of ≥ 20% [8, 15]. Another important addition in the classification of luminal tumours in St. Gallen 2013 was the percentage of progesterone positivity. This criterion has been shown to influence the prognosis in luminal HER2 negative tumours with cut-off value of positivity > 20% proving significant in predicting survival [16, 17].
Our results were comparable with other reported studies from India with respect to TNBC and HER2-enriched subtype, but a wide difference was seen with respect to luminal A and luminal B tumours (Table 4). This difference in luminal subtypes was seen not only in our study but also among other Indian studies with percentage of luminal A tumours varying from 43.8% in study by Mane et al. to 23.7% in study by Kunheri et al. (Table 4). On comparing the overall hormone receptor positivity and HER2/neu receptors, the difference is not as wide as seen in luminal tumours (Table 5). The wide difference in luminal subtypes is most likely due to different criteria used for the classification of luminal subtypes in the above referred studies (Table 5).
Table 4.
Comparison of various other studies with regard to molecular subtypes
| Study | Luminal A | Luminal B HER2 negative | Luminal B HER2 positive | HER2 enriched | Triple negative breast cancer (TNBC) | Total number of patients |
|---|---|---|---|---|---|---|
| Pandit et al.a [6] | 37% | N/A | 8% | 11% | 26% | 2,062 |
| Kunheri et al.b [12] | 23.7% | 27.7% | 9.3% | 12.6% | 26.6% | 635 |
| Mane et al.c [13] | 43.8% | N/A | 14.8% | 16.1% | 25.3% | 521 |
| Rathnam et al.d [14] | 36.7% | 9.8% | 13.1% | 14.9% | 25.4% | 837 |
| Howlader et al.e [10] | 66.6% | N/A | 9.7% | 4.3% | 10.8% | 1,96,094 |
| Fallahpour et al.f [11] | 59% | N/A | 7.7% | 4% | 8.6% | 29,833 |
| Hennings et al. [18] | 44.7% | 31.8% | 6.2% | 5% | 12.3% | 3,454 |
| Our study | 19.7% | 30.3% | 16.9% | 11.4% | 21.7% | 360 |
a 18% patients with equivocal HER2 were not classified into any group
e 8.7% patients were not classified into any group
f 20.6% patients were not classified into any group
a, b, c, d Studies from India
Table 5.
Profile and classification criteria of various Indian studies
| Study | Pandit et al. [6] n = 2062 |
Mane et al. [13] n = 521 |
Ranthnam et al. [14] n = 837 |
Kunheri et al. [12] n = 635 |
Ours N = 360 |
|---|---|---|---|---|---|
| Study population | Metastatic and nonmetastatic | Non metastatic | Non metastatic | Non metastatic | Non metastatic |
| EBC | Not available | Not available | 288 (34.4%) | Not available | 319(88.6%) |
| LABC | Not available | Not available | 549 (65.6%) | Not available | 41(11.4%) |
| MBC | 10% | NA | NA | NA | NA |
| Region | Western India | Western India | South India | South India | North India |
| Criteria for classification luminal tumours | |||||
| • Ki-67 used | No | No | Yes | Yes | Yes |
| • Ki-67 cut-off value | NA | NA | > 20% | > 20% | ≥ 20% |
| • PgR positivity | No | No | Yes | No | Yes |
| • Percentage of PgR positivity | NA | NA | No percentage | NA | > 20% |
| Mean tumour size | 3.8 cm | 3 cm | NA | NA | 3.7 cm |
| % of tumours ≤ 2 cm | 31% | NA | NA | 22.5% | 19.4% |
| Overall hormone receptor positivity | 56.4% | 58.6% | 59.6% | 60.2% | 66.9% |
| Her2neu positivity | 18.7%* | 30.9% | 28% | 21.9% | 28.6% |
* 18.3% patients unclassified due to equivocal status of Her2neu
EBC, early breast cancer; LABC, locally advanced breast cancer; MBC, metastatic breast cancer; PgR, progesterone receptor
The effect of Ki-67 and progesterone positivity on the classification of luminal tumours was demonstrated by Ahn et al. who showed a reduction in luminal A subtype from 55.8% (without Ki-67) to 28.5% (with Ki-67 but without progesterone positivity) to 21.7% (using both Ki-67 and progesterone positivity) [15]. If we follow the same, our percentage of luminal A subtype reaches 50% (without Ki-67), it reduces to 26% (with Ki-67 but without progesterone positivity) to 19.7% (using both Ki-67 and progesterone positivity).
On comparing published literature from India and our data with western literature, there were higher percentages of patients in HER2 enriched and TNBC in our population as compared to western population (Table 4). These two subtypes are associated with worst overall survival among the various subtypes [10, 11, 18]. This has two important implications. Firstly, it indirectly points to the fact that the breast cancer in Indian population may be inherently more aggressive than the western population. Secondly, we may also have higher incidence of interval cancers when we use screening mammography. This is because TNBC and HER2-enriched subtypes have high mean Ki-67 index and shorter tumour doubling time as compared to other subtypes and our more likely to present as interval cancer [19–21]. It also points to the fact that the emphasis on breast self-examination (BSE) needs to stressed even with the of use screening mammography.
In our country, a very small percentage of patients as demonstrated by other published literature from India and our data have tumour size ≤ 2 cm at presentation (Table 5). This is in sharp contrast to western literature, where a large data base from the USA and Germany showed that 56% and 62.2% of the tumours were less than 2 cm [10, 18]. Given the fact that the median size at which breast lump becomes clinically palpable is postulated to be 1.5 cm, in a resource-constraint country like ours, stress on breast self-examination and creating awareness may contribute significantly in reducing overall mortality of breast cancer in India even if screening mammography is not available to a large percentage of our population [1, 22]. Stress on breast self-examination is also important as various recent studies from India have shown that necessary skills for doing breast self-examination and attitude towards early detection are lacking in Indian population [23, 24].
A major limitation of our study is that it is a retrospective analysis with limited number of patients. So, our study in concordance with other Indian studies probably points to a trend, but confirmation of these findings requires study of much larger patient cohort. We have also excluded patients having metastatic disease at presentation because we wished to have complete pathological information about the cases studied. This was only possible in nonmetastatic patients who underwent surgery. It may lead to selection bias by excluding more aggressive subtypes, viz. TNBC and HER2 enriched, which are more likely to present with metastatic disease. The exclusion of metastatic patients was also done to make comparison with other studies published from India (Table 4). TNBC was also not subclassified into basal and non-basal type using cytokeratins (CK5, CK6) and epidermal growth factor receptor [25]. The strength of our study is that we have a detailed clinicopathological report of the majority of our patients and were able to classify them into various molecular subtypes using both Ki-67 and progesterone receptor positivity as per the latest recommendations [8]. Moreover, equivocal HER2 by IHC were all confirmed by FISH.
Conclusion
Luminal B HER2 negative was the most common molecular subtype prevalent in our study population. TNBC and HER2 enriched, which are more aggressive molecular subtypes, were prevalent in our study population as well as other published studies from India as compared to western population. This points to the fact the disease in our population may be inherently more aggressive. But our findings need to be confirmed by a larger cohort of patients.
Acknowledgements
We acknowledge the contribution of all consultants of the Department of Pathology who were actively involved in reporting all our cases and whose names could not be put up in the authors’ list. We also acknowledge the contribution of Dr. Satish Jain and Dr. Veena Jain for helping in the preparation of the manuscript.
Author Contribution
Dr. Sumeet Jain, Dr. Akashdeep Singh Sohi, Dr. G. S. Brar, Dr. Kunal Jain, Dr. Davinder Pal, Dr. Jagdeep Singh, Dr. Sandhya Sood and Dr. Ritu Aggarwal were all involved in patient management and collection of data. Dr. Vikram Naranag and Dr. Neena Sood were involved in the reporting of the pathology for all our patients. Dr. Sumeet Jain and Dr. Kunal Jain were involved in the analysis and preparation of the manuscript.
Declaration
Conflict of Interest
The authors declare no competing interests.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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