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Cite this article: Fouda MA, Sherif FZ, Ghannam AA, Al-shorbagy SH (2017) Prognostic Value of Breast Cancer Subtypes Based On ER/PR, Her2 Expression and Ki-67 Index in Women Received Adjuvant Therapy after Conservative Surgery for Early Stages Breast Cancer a Retrospective Clinical Study. JSM Clin Oncol Res 5(2): 1056.

*Corresponding authorMenna A. Fouda, Department of Clinical oncology and Nuclear Medicine, Tanta University, Tanta, Gharbia, Egypt, Email:

Submitted: 08 December 2016

Accepted: 29 July 2017

Published: 31 July 2017

Copyright© 2017 Fouda et al.

OPEN ACCESS

Case Report

Prognostic Value of Breast Cancer Subtypes Based On ER/PR, Her2 Expression and Ki-67 Index in Women Received Adjuvant Therapy after Conservative Surgery for Early Stages Breast Cancer a Retrospective Clinical StudyMenna A. Fouda*, Fawzy Z. Sherif, Amr A. Ghannam, and Safinaz H. Al-shorbagyDepartment of Clinical oncology and Nuclear Medicine, Tanta University, Egypt

INTRODUCTIONBreast cancer is the most common malignancy in women,

accounting for 29% of all female cancers; it accounts for <1% of all cancer cases in men. Breast cancer also is responsible for 14% of cancer deaths in women, making it the second cause of cancer death. Breast cancer is the most common non cutaneous cancer in US [1].

In a population based cancer registries in Gharbia, Egypt, breast cancer was the most frequent cancer among Egyptian females. Breast cancer represented 15.4% of all incident cancers

in Egypt, accounting for 32.04% of all newly diagnosed female cancers. The incidence rate for females was 35.8/100.000 female population [2].

The proportion of women choosing BCT has also increased among breast cancer patients of all ages and racial/ethnic groups [3]. Breast cancer is a heterogeneous disease with variations in the biological profile and subsequent clinical prognosis. Prognostic information for the individual patient is based on the analysis of biological markers in the primary tumour including oestrogen receptor (ER), progesterone receptor (PR), human epidermal

Keywords•Breast cancer subtype•Breast cancer survival•Breast cancer treatment•Estrogen/progesterone receptor•Human epidermal growth factor receptor 2 (HER2/

neu)•Immunohistochemistry•Triple negative

Abstract

Purpose: To evaluate the prognostic effect of breast cancer subtypes on local relapse rates, distant metastases, and survival in women underwent breast conservative surgery for early stages breast cancer.

Patients and methods: Data of 100 patients affected by early stage breast cancer and treated with breast-conserving therapy were reviewed. Patients were grouped, based on the basis of receptor status and HER-2 status, patients were grouped, as: luminal A (ER + and/or PR+, Ki67 low and HER2-), luminal B (ER + and/or PR+, Ki67 high and/or HER2+), HER2-positive (ER-, PR- and HER2+) and triple negative (ER-, PR, HER2-). Distribution of variables among subtypes was evaluated with Pearson’s test. Survival rates were calculated with life tables; Cox regression stepwise method was used to identify predictive variables of survival.

Results: Median age was (range 18-50) and median follow up time of 40 months (range 36.83-43.17). Breast cancer specific survival and distant metastases rates were different among breast cancer subtypes (both outcomes P= 0.001) , there was significant difference regarding local relapse rates (P= 0.002 ). Axillary nodes status (P= 0.007), adjuvant therapy (P= <0.001) and breast cancer subtypes resulted prognostic factors of breast cancer specific survival; axillary node status (P= 0.007) and breast cancer subtypes had an impact on distant metastases.

Conclusions: In our study, breast cancer subtype seems a prognostic factor of breast cancer specific survival and distant metastases rates & of local relapse rate. Patients could be submitted to conservative surgery, if feasible, but considering the differences in survivals, patients with worse prognosis should receive more aggressive adjuvant treatment.

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growth factor receptor 2(HER2) and Ki67, together with age, tumour size, histological grade and lymph node involvement [4].

In 2013, the St Gallen International Breast Cancer Conference suggested a surrogate definition of intrinsic subtypes of breast cancer: Luminal A (ER + and/or PR+, Ki67 low and HER2-), Luminal B (ER + and/or PR+, Ki67 high and/or HER2+), HER2-positive (ER-, PR- and HER2+) and Triple negative (ER-, PR-, HER2-) [5].

The classification has highlighted the heterogeneity of ER positive tumors in terms of prognosis. The luminal A subtype has a favourable prognosis compared to the luminal B subtype and the systemic therapy advocated for the patients with luminal A tumors is generally restricted to endocrine therapy. The luminal B subtype has a high proliferation rate and/or a high histological grade and systemic treatment with chemotherapy followed by endocrine therapy is recommended [6].

The triple negative breast cancer phenotype is commonly associated with younger age, black race, and BRCA1 mutations and has an underlying aggressive natural history that includes early relapse, more distant metastasis, and worse overall survival. TNBC carries a higher risk of loco regional relapse compared with luminal subtypes after both breast conserving therapy and mastectomy (with or without radiation) [7]. Molecular subtypes also differ in their response to treatment and outcome. Molecular sub typing of breast cancer may provide additional prognostic information regarding patient outcome [8].

PATIENTS AND METHODS

Inclusion criteria

1. Age 18-70 years

2. Early stage breast cancer (pT1-2 N0-2).

3. Patients underwent breast conserving surgery for primary breast cancer.

4. No previous malignancy, pre-operative chemotherapy or radiotherapy.

Clinical and pathological data were collected from medical records from January 2008 to end of June 2011.The medical files of all patients included in this study were gathered; scientific data were properly collected, revised and analyzed to evaluate survival rate and loco-regional treatment failure and metastases.

History and clinical examination

Clinical examination including assessment of performance status, general examination, loco regional evaluation, chest, heart, abdominal and neurological examination.

Treatment received

Surgical treatment: Patients under went surgical treatment in the form of Breast conservative surgery (BCS) with axillary dissection.

Chemotherapy: Patients were treated with adjuvant chemotherapy protocols including FAC (Adriamycin, Cyclophosphamide, 5 Fluorouracil) or FEC (Cyclophosphamide, Farmarubcin, 5Fluorouracil) regimens, intravenously on

day 1every 21 days for 6 cycles or FAC (Cyclophosphamide, Adriamycin, 5Fluorouracil) or FEC (Cyclophosphamide, Farmarubcin, 5Fluorouracil) regimens, intravenously on day 1every 21 days for 3 cycles followed by another 3 cycles of Taxanes either Docetaxel on day 1 every 21 days or Paclitaxel on day 1 every 21 days.

Adjuvant radiation therapy (RT): Patients were treated by 6 Mev Linear Accelerator or Cobalt-60 with dose 50 GY over 5 weeks (2GY/Fraction), or 42.4GY/16 Fraction (2.65GY/Fraction), after the end of chemotherapy (CT) (A sequential boost dose of 10 Gy (16 Gy in all cases of positive or close margins) was added on tumor bed with a variable electron energy dose (9-12 MeV). In cases of positive axillary nodes, a supraclavicular irradiation (total dose 50 Gy) was added.

Hormonal therapy: For patients with endocrine-responsive disease, adjuvant endocrine therapy was indicated started after surgery or after completion of chemotherapy in case of systemic treatment. The combination of Tamoxifen 20 mg /day for 5 years +/- luteinizing hormone-releasing hormone (LHRH) analogue was given for a minimum of 2 years for premenopausal women and Aromatase inhibitors 1mg/day for postmenopausal women.

Target therapy (Trastuzumab): Trastuzumab administered for 1 year combined with chemotherapy was given to the patients with HER2 overexpression (luminal B patients with Her2 overexpression and HER2 patients) [9] (Table 1).

Immunohistochemical study

Follow-up: The median follow-up period was 40 months .Patients were generally observed in follow-up 4 to 6 weeks after RT completion and every 6 months thereafter with annual breast imaging. Follow-up time was counted from the date of end of treatment to the date of the first event or last confirmed date of disease-free status.

Table 1: ER/PR and Her2 scoring system and criteria.

The ER/PR scoring system and criteria

Scoring system 0 Negative for receptor1+ Borderline 2+ to 3+ Positive for receptor

Criteria 0 0% nuclear staining1+ <10% nuclear staining2+ 10% to 75% nuclear staining3+ >75% nuclear staining

Her2 scoring system and criteriaScoring system 0 Negative1+ Negative2+ Weak positive (borderline)3+ Positive

Criteria 0 Negative. No staining is observed, or membrane staining is <10% of the tumor cells.1+Negative. A faint /barely perceptible membrane staining is detected in >10% of the tumor cells. The cells are only stained in part of the membrane.2+ Weak positive. A weak to moderate complete membrane staining is observed in >10% of the tumor cells.3+ Positive. A strong complete membrane staining is observed in >10% of the tumor cells.

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Statistics: Statistical presentation and analysis of the present study was conducted, using the mean, standard deviation and Chi-square and Kaplan-Meier test by SPSSV17. Local recurrence was defined as the reappearance of carcinoma in the treated remnant breast, skin, or chest wall. Events determining regional relapse were defined as recurrences in the ipsilateral axillary, supraclavicular, or internal mammary lymph nodes.

Disease-free survival (DFS) time was measured from the date of the first curative surgery to the date of the first loco regional or systemic relapse (including ipsilateral breast recurrence), the appearance of a second primary cancer (including contralateral breast cancer) or death, whichever occurred first. Overall

survival (OS) time was calculated from the date of the first definite operation to the date of the last follow-up, or death from any cause.

Patient characteristics

The median follow-up period was 40 months .The clinical features & characteristics of all patients are shown in (Table 2).

The age of patients ranged from 18 to 70 years & more than half of patients (54%) were (≤ 50) years old. Regarding the pathological tumor size, T2 was the most frequent size (92%). Patients with negative lymph node represented (50%) of patients while patients with N1 were (24 %) and N2 were (26%).In this

Table 2: Disease Free Survival according to breast cancer molecular subtypes: Median = 36 SE = 2.2 95% Confidence Interval (31.69-40.31).

SubtypesChi-square

Luminal A Luminal B Basal-like Her2 TotalN % N % N % N % N % X2 P-value

Age

18-35. 7 22.58 6 14.63 4 19.05 0 0.00 17 17.00

7.661 0.56936-50. 9 29.03 18 43.90 6 28.57 4 57.14 37 37.0051-64 13 41.94 16 39.02 9 42.86 2 28.57 40 40.0065-70 2 6.45 1 2.44 2 9.52 1 14.29 6 6.00Total 31 100.00 41 100.00 21 100.00 7 100.00 100 100.00

Histology

Ductal 20 64.52 36 87.80 17 80.95 7 100.00 80 80.00

17.716 0.007*Lobular 10 32.26 5 12.20 1 4.76 0 0.00 16 16.00Other 1 3.23 0 0.00 3 14.29 0 0.00 4 4.00Total 31 100.00 41 100.00 21 100.00 7 100.00 100 100.00

Tumour sizeT1 3 9.68 3 7.32 1 4.76 1 14.29 8 8.00

0.795 0.851T2 28 90.32 38 92.68 20 95.24 6 85.71 92 92.00Total 31 100.00 41 100.00 21 100.00 7 100.00 100 100.00

MarginsNegative 31 100.00 37 90.24 19 90.48 6 85.71 93 93.00

5.563 0.135Positive/close 0 0.00 4 9.76 2 9.52 1 14.29 7 7.00Total 31 100.00 41 100.00 21 100.00 7 100.00 100 100.00

Axillary node status

N0 23 74.19 14 34.15 11 52.38 2 28.57 50 50.00

17.660 0.007*N1 5 16.13 14 34.15 2 9.52 3 42.86 24 24.00N2 3 9.68 13 31.71 8 38.10 2 28.57 26 26.00Total 31 100.00 41 100.00 21 100.00 7 100.00 100 100.00

Tumour grade

Grade I 4 12.90 1 2.44 2 9.52 0 0.00 7 7.00

14.198 0.027*Grade II 25 80.65 38 92.68 14 66.67 4 57.14 81 81.00Grade III 2 6.45 2 4.88 5 23.81 3 42.86 12 12.00Total 31 100.00 41 100.00 21 100.00 7 100.00 100 100.00

Adjuvant therapy

Hormonetherapy 5 16.13 5 12.20 0 0.00 0 0.00 10 10.00

90.511 <0.001*Chemotherapy 2 6.45 1 2.44 20 95.24 7 100.00 30 30.00Hormonetherapy &Chemotherapy 24 77.42 35 85.37 1 4.76 0 0.00 60 60.00

Total 31 100.00 41 100.00 21 100.00 7 100.00 100 100.00

Hormonal therapy

Yes 29 93.55 41 100.00 0 0.00 0 0.00 70 70.00107.341 <0.001*No 2 6.45 0 0.00 21 100.00 7 100.00 30 30.00

Total 31 100.00 41 100.00 21 100.00 7 100.00 100 100.00

ChemotherapyYes 25 80.65 36 87.80 21 100.00 7 100.00 89 89.00

8.436 0.038*No 6 19.35 5 12.20 0 0.00 0 0.00 11 11.00Total 31 100.00 41 100.00 21 100.00 7 100.00 100 100.00

Distance metsNo 28 90.32 30 73.17 7 33.33 3 42.86 68 68.00

21.680 <0.001*Yes 3 9.68 11 26.83 14 66.67 4 57.14 32 32.00Total 31 100.00 41 100.00 21 100.00 7 100.00 100 100.00

Local Recurrence

No 31 100.00 36 87.80 14 66.67 3 60.00 84 84.0014.235 0.002*Yes 0 0.00 5 12.20 7 33.33 2 40.00 14 14.00

Total 31 100.00 41 100.00 21 100.00 7 100.00 100 100.00

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study, Infiltrating duct carcinoma (IDC) was the predominant histopathological subtype (80%) while (ILC) represented (16%) & patients with other types were (6%).Most patients were Grade II tumors (81%). Local recurrence occurred in (14) patients while thirty two patients developed distant metastases. There was a significant correlation between breast cancer molecular subtypes and hitsopthological type, tumor grade, axillary lymph node status &adjuvant therapy.

Treatment characteristics

In this study, BCS was done for all patients. Patients who had negative margin were (93%) & (7%) had positive/close margin.

Eighty nine patients completed their chemotherapy course while only (11) patients did not receive chemotherapy. In our study all patients received post operative radiotherapy.

Concerning adjuvant hormonal therapy, (70 %) of patients was hormonal receptor positive and received adjuvant hormonal therapy. Sixty percent of patients received combined chemotherapy and hormonal therapy, (30%) received adjuvant chemotherapy alone &only (10%) received adjuvant hormonal therapy alone.

Survival

With median follow-up duration of 40 months, 95% Confidence Interval (36.83-43.17) .There was a significant correlation between breast cancer subtypes and prognosis (DFS&OS) (Figure 1&2). The 3-year DFS and OS of patients with was 51.77 % and 67.48% respectively. Breast cancer molecular subtypes were positively associated with survival outcomes in all patients.

DISCUSSIONBreast cancer is a molecularly heterogeneous disease that

appears to include at least four major tumour subtypes [10]. Our study showed a significant correlation between breast cancer molecular subtypes, histological subtype, axillary node status,

tumour grade and adjuvant therapy. Our results showed that breast cancer subtypes distribution did not vary significantly with age (P.value= 0.569). However results from other studies showed a relationship between age and breast cancer subtypes. Caldarella et al. [11], reported that out of 1,487 patients, 34% were luminal A subtype, 25% luminal B HER2−, 11 % luminal B HER2+, 19 % triple negative, and 10.2% HER2+; 58.5% of cancers were ductal NOS types.

Negative surgical margins do not guarantee the absence of residual cancer within the breast; Our results showed that there was a non significant correlation between surgical margin & breast cancer molecular subtypes (P-value 0.135). In contrast, Sanpaolo et al. [12], reported that there was a significant correlation between breast cancer subtypes and surgical margin. Regarding the axillary node status, this represents a reliable. Prognostic factor in breast carcinoma, there was a significant correlation between lymph node status and breast cancer molecular distribution in our study [13].

Si et al. [14], showed that the highest occurrence of LN metastases in triple positive breast cancer, and the lowest occurrence in TNBC. Both Luminal B type (Luminal HER2-, Luminal HER2+) showed significant higher probability of LN involvement. LN involvement is an intrinsic characteristic for molecular subtype of breast cancer. Triple positive and triple negative breast cancer accounts the most and least possibility of LN involvement

In our study, there was also a significant correlation between received hormonal therapy &breast cancer molecular subtypes (P-value <0.001). Endocrine therapies appear to be an essential component of an effective adjuvant therapy program and retrospective analyses indicate that the endocrine effects of chemotherapy alone are insufficient for the younger patients with endocrine-responsive breast cancer [5]. Recently, a retrospective analysis by Cancello [11], also identified PR negativity as high

Survival Functions

DFS

6050403020100

Cum

Sur

vival

1.2

1.0

.8

.6

.4

.2

0.0

-.2

Subtypes

Her2

Her2-censored

Basal like

Basal like-censored

LuminalB

LuminalB-censored

LuminalA

LuminalA-censored

Figure 1 Kaplan–Meier plot; shows correlation between disease free survival (DFS) & breast cancer molecular subtypes. Patients with the Triple negative subtype (basal-like) had the worst disease-free survival while Luminal A had the most favorable DFS.

Survival Functions

OS

605040302010

Cum

Sur

viva

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1.2

1.0

.8

.6

.4

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-.2

Subtypes

Her2

Her2-censored

Basal like

Basal like-censored

LuminaB

LuminaB-censored

LuminalA

LuminalA-censored

Figure 2 Kaplan–Meier plot; Shows correlation between overall survival (OS) & breast cancer molecular subtypes. Patients with the Triple negative subtype (basal-like) had the worst overall survival while Luminal A had the most favorable OS.

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risk of relapse in luminal B breast cancer. It also showed that higher risk of early relapse was linked to PR negativity in luminal B/HER2 negative breast cancer in spite that chemotherapy and endocrine therapy was already employed. Concerning the LR and its relation with BC subtype, Cheang [10], reported that higher rates of LR among HER2 and triple-negative subtypes, with a trend toward higher LR among patients with luminal B subtype. This is consistent with our results that showed that Her2 type& basal-like tumors had the higher rates of local recurrence (40%, 33.33%, respectively), compared with luminal subtypes.

Voduc [15], investigated local and regional relapse rates in 2,985 patients stratified by molecular subtype. With a median follow-up of 12 years, they found that after BCS and RT, patients with luminal A tumors had the most favorable prognosis, with local relapse and regional relapse rates of only 8% and 3%, respectively, at 10 years. The HER2-enriched and basal-like groups exhibited the highest rates of local recurrence (21% and 14%, respectively) and regional relapse (16% and 14%, respectively). Arvold et al. [16], reported on a modern series of 1,434 patients with invasive breast cancer treated with BCS and RT. With a median follow-up of 85 months, the 5-year rate of local recurrence was 2.1%; 0.8% for luminal A, 2.3% for luminal B, 1.1% for luminal HER2, 10.8% for HER2-enriched, and 6.7% for triple-negative disease.

Five-year local RFS rate was reported to be 97.2% for 541 Asian breast cancer patients after BCT but found to be different among subtypes: 0.8% for luminal A, 1.4% for luminal B, 3.6% for HER2 and 12.7% for triple-negative breast cancers, respectively [17]. Our results showed that there was a significant correlation between systemic treatment & breast cancer molecular subtypes (P-value <0.001). Chen et al. [17], compared between triple-negative and non- triple-negative subtypes & showed the biggest risk difference for overall recurrence (HR = 3.19) and LR (HR =3.31) among all molecular typing comparisons. When setting Luminal A as a baseline, the HR value of triple negative subtype (HR = 2.90) remains larger than that of Luminal B (HR = 2.23) or Her-2 subtypes (HR = 2.26) for overall recurrence.

Andreu [18], reported that triple-negative subtype should be considered the biggest risk factor for recurrence and adjuvant C T should be administered .Our results showed that patients with the triple negative subtype (basal-like) had the worst overall survival and worst disease-free survival while luminal A carry the best DFS& OS [19].

These results could be explained with the fact that basal-like and HER2 tumors recur both more frequently and also earlier when compared with luminal tumors [20]. Moreover ER and PR positive breast cancers (luminal A and luminal B) respond to adjuvant therapies (chemotherapy and hormone therapy), leading to better survivals, while ER and PR negative breast cancers (basal-like and HER2) seem resistant to adjuvant therapies [21].

CONCLUSION• Molecular subtyping of breast cancer may provide

additional prognostic information regarding patient outcome. The molecular subtypes display highly significant differences in prediction of overall survival, as

well as disease-free survival. In this retrospective study, we demonstrated variability in BCSS and DM rates among the four subtypes. New technologies allow, nowadays, gene profiling of breast cancer: nevertheless, clinicians, in their daily practice, have to make decisions on how to treat patients based on classic prognostic factors. An important question is whether a “surrogate” classification, instead of gene profiling, is corrected to classify breast tumors: the answer should come out from randomized trials that could lead to new guidelines of breast cancer treatment [22].

• Local control rate is not different among subgroups in our study, but, considering the retrospective nature of this study, breast cancer subtypes classification should not be used to choice surgery management. Triple-negative subtype shows the biggest risk for overall recurrence and LR among all molecular subtypes and adjuvant CT should be considered [23].

• Our study showed the triple negative subtype (ER/PR-, Her2-) has the worst overall and disease-free survival compared to the other subtypes. Considering the insufficient number of original studies, further research with different ethnicities is needed on this topic, especially the intensity of association between molecular typing and DR risk after BCT [24].

• In the future, molecular subtypes will be used in large clinical trials in a prospective manner to help identify molecular markers predictive of loco regional outcomes and to identify patients in whom RT may be safely omitted.

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Fouda MA, Sherif FZ, Ghannam AA, Al-shorbagy SH (2017) Prognostic Value of Breast Cancer Subtypes Based On ER/PR, Her2 Expression and Ki-67 Index in Women Received Adjuvant Therapy after Conservative Surgery for Early Stages Breast Cancer a Retrospective Clinical Study. JSM Clin Oncol Res 5(2): 1056.

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