Breast cancer in women aged 35 and under: prognosis and survival

S. JIMOR^1$, H. AL-SAYER¹, S.D. HEYS¹, S. PAYNE², I. MILLER², A. AH-SEE¹, T.K. SARKER³, A. HUTCHEON³ and O. EREMIN^1#

Department of Surgery¹, Pathology², Clinical and Medical Oncology³,University of Aberdeen, Foresterhill, Aberdeen, UK $Current address: Southport and Ormskirk Hospital NHS Trust, Wigan Road, Ormskirk, L39 2AZ #Current address: Lincoln and Louth NHS Trust, County Hospital, Greetwell Road, Lincoln, LN2 5QY

Introduction Patients and methods Results

Pathological assessment Chemotherapy and radiotherapy Discussion References

Keywords: Breast cancer, young patients, survival

Background: Breast cancer comprises 22% of all cancers occurring in females but only 2% of cases occur in women aged 35 years and less. The presentation, behaviour and prognosis of breast cancer in such women, when compared with older women, are unclear and conflicting results have been reported. This study has audited clinical and pathological features in patients aged 35 years and under with breast cancer. Methods: One hundred and thirteen patients were identified. The details of clinical staging, local and distant disease recurrence and overall survival were obtained for all patients. Histological sections of tumours were examined for type, grade, size, presence of surrounding intraductal carcinoma, presence of vascular space invasion, lymph node involvement and oestrogen receptor (ER) status. Results: Histological examination of the tumours revealed that 94% were invasive ductal carcinoma. In 73% of the cases the tumours were grade 3, 49% of patients who underwent axillary surgery had lymph node involvement and 20% of tumours expressed ERs. The overall 5-year survival was 64%. Predictors of a poorer survival (univariate analysis) were: increasing tumour size, absence of ERs, presence of lymphovascular space invasion, axillary lymph node involvement and detectable metastases at the initial presentation. Multivariate analysis revealed that only lymphovascular space invasion was an independent predictor of a poor survival. Conclusion: Breast cancer in young (= 35 years) women is biologically aggressive, compared with older women. Factors predicting survival and overall survival rates, however, were comparable with those previously reported for older women with breast cancer

J.R.Coll.Edinb., 47, October 2002, 693-699 

INTRODUCTION

Breast cancer is one of the most common cancers affecting women, compromising 22% of all female cancers and accounting for approximately 14,000 deaths per annum in the United Kingdom.¹ Although breast cancer is less common in younger women, it has been estimated that approximately 2% of all cases of breast cancer occur in women under the age of 35 years.² It has been suggested previously that breast cancers arising in young women may be biologically different than those arising in older women.

Breast cancer in younger women may be more aggressive in their behaviour and more advanced at their initial presentation in younger patients. However, the prognosis of these younger patients with breast cancer, when compared with older patients, is unclear. In attempting to answer this question conflicting results have been reported with some studies demonstrating that younger patients may have either a worse or similar prognosis, when compared with older patients with breast cancer.^1-19 The reason for these differences are unclear, but these studies have frequently included small numbers of patients, differences in selection of patients, and differences in the age groupings of patients which have been used for comparative analysis.¹⁹ The aims of this study, therefore, were to examine and audit the experience of our institution in treating young patients with breast cancer (35 years of age and under), focussing on the clinical presentation and pathological findings, and to identify prognostic factors that may identify those patients with a better prognosis. In addition, a secondary aim of this study was to compare those patients 30 years of age and under with those who were over 30 years of age at initial diagnosis as this former group has been shown previously to have a poorer prognosis.¹²

PATIENTS AND METHODS

Patients

113 female patients aged 35 years and under with breast cancer, who had presented to Aberdeen Royal Infirmary, between 1970 and 1992, were identified. The case records of all patients were examined for details of their initial presentation and subsequent treatment. Details of local and disseminated recurrence of disease and overall survival were also obtained for all patients.

Histological examination of tumours

Archival material for all patients was obtained from the Department of Pathology Aberdeen Royal Infirmary. From these paraffin-embedded blocks of tumour tissue, microscopic sections, 4µm in thickness, were cut and stained with haematoxylin and eosin for light microscopic examination.

Figure 1: Presentation of patients with breast cancer by age. 

Figure 2: Survival of patients treated for breast cancer (Kaplan-Meier analysis).

Figure 3: Survival of patients treated for breast cancer according to age catagory (Cox proportinal hazard analysis).

The details of tumour size, tumour type, histological grade were obtained and the presence of insitu cancer, lymphovascular space invasion and ER status were determined from this archival material.

Statistical analysis

Survival curves were calculated using the Kaplan-Meier method and survival of patients according to different age categories (30 years and under versus over 30 years of age) were compared using the log rank test.²⁰ To determine prognostic factors for overall survival a stepwise Cox proportional hazard model was used, with p<0.05 accepted for each additional variable to enter.^21,22 For comparing features of the tumours between different age groups of patient, a Chi-square analysis was undertaken with p<0.05 being accepted as statistically significant.

RESULTS

Patient characteristics and tumour stage

The age distribution of patients with breast cancer is shown in Figure 1. There were 44 patients 30 years of age and under and 69 patients were over 30 years. The clinical stage of the tumours in terms of size and nodal involvement is shown in Table 1. In addition, nine (8%) patients had a metastatic disease detected at their initial presentation. It can be seen that 29 women (26% of all patients), presented with locally advanced breast cancers, defined as being either T3, T4 or any T stage associated N2 lymph node stage.

Clinical assessment of the patient’s tumour

A definitive clinical diagnosis of breast cancer or a clinical suspicion of breast cancer was made in 24 (21%) and 33 (29%) of women, respectively. The other breast lesions were diagnosed as benign (49%) on clinical examination with the exception of 1 patient in whom the lump was deemed to be “ indeterminate” (Table 2). A total of 111 out of 113 patients presented with a palpable lump in the breast. Seven (6.5%) women also had nipple retraction and three had clinically obvious Paget’s disease of the nipple. In addition, 16 (14%) patients had skin involvement by the tumour with one also having skin ulceration. In 6 (5%) women the tumour was fixed to the chest wall and in all these latter cases the tumour size was greater than 4cm. Of the 9 (8%) patients presenting with metastatic disease, 6 had bone metastases, two lung and one had liver metastases.

Time to presentation to General Practitioner

Forty-eight (42%) patients presented within 4 weeks of the onset of their symptoms, 27 patients presented within 8 weeks, and 12 patients within twelve weeks of the onset of their symptoms. In all other cases there was a delay of greater than 12 weeks prior to the patients seeking medical attention.

Table 1: TNM staging of patients

Family history

In 21 (18%) patients, there was a family history of breast and other cancers as follows: In 10 cases the mother had breast cancer, 5 had maternal aunts who had been diagnosed with breast cancer, one patient had two sisters with various cancers, in two patients the mother had colonic cancer and, in a further three patients, their mothers had either stomach, uterine or lung cancer.

Diagnostic investigations

Mammography was undertaken in 58 (51%) patients and in 44 (76%) of these mammograms a diagnosis of breast cancer was made. In 8 patients a diagnosis of benign disease was reported on mammography and in a further 6 patients a mammographic appearance were indeterminate with the radiologists unsure of the nature of the mammographic appearances.

Fine needle aspiration cytology (FNAC) was performed in 41 (36%) cases and in 34 (83) of these a diagnosis of malignancy was made. Of the remaining patients, FNAC was reported to be benign in 3 and the appearance was indeterminate in another 4 women. Breast ultrasound scan was performed in only 8 (7%) patients, with 5 of these having features of malignancy, two were reported as benign and in one woman the appearance was indeterminate.

Surgery undertaken

In 72 patients mastectomy was undertaken (2 radical and 70 simple mastectomy), with 41 patients undergoing breast conserving surgery. As regards axillary surgery, this was undertaken in 84 (74%) patients, with 28 having axillary clearance and 56 undergoing an axillary sample.

PATHOLOGICAL ASSESSMENT

Primary tumour

Histological examination revealed that in 107 (94%) cases the tumour was an invasive ductal carcinoma and the other histological types are shown in Table 2. The invasive ductal carcinomas were graded as follows: 2 patients having grade 1 tumour, in 22 (20%) the tumour was grade 2 and in 83 (77%) patients it was grade 3. There was no difference in tumour type or grade between patients 30 years of age and under and those over 30 years (Table 2 and 3). Further examination of those with grade 3 tumours, in relation to the pathological tumour size, showed that in those patients with tumours less than 1cm in size, 11 (65) were categorised as grade 3. If the tumour size was 2cm or less then 38 (72%) were grade 3, and for tumours 3cm or less 56 (75%) were grade 3. Lymphovascular invasion occurred in 35 % of cases and in 21 (19.6%) patients ERs were expressed.

*DCLS: ductal carcinoma insitu

Table 2: Tumour type according to age

Table 3: Tumour grade according to age

Lymph node status

Axillary surgery was undertaken in 84 (74%) patients, and histologically detected tumour involved axillary lymph nodes were documented in 41 (49%) of these women.

CHEMOTHERAPY AND RADIOTHERAPY

Thirty-nine (34%) patients received chemotherapy (either cyclophosphamide, doxorubicin, vincristine, prednisolone or cyclophosphamide, methotrexate and 5-flurouracil). These patients had tumour involved lymph nodes and were considered to be at high risk of metastatic disease. Four patients were prescribed chemotherapy for metastatic disease following initial presentation and assessment.

Following breast conservation surgery, 31 of the 39 patients received radiotherapy to the breast. Twenty-two of the 72 patients undergoing mastectomy received radiotherapy to the chest wall and mastectomy site. Radiotherapy was given if it was considered that the patients were at high risk of local recurrence of disease, for example, as assessed by the initial tumour size or if the tumour was close to the resection margin. Following axillary sample, 26 patients received radiotherapy to the axilla and supraclavicular nodal areas and 11 patients received radiotherapy to these areas after undergoing axillary clearance (extensive nodal disease). Of the 28 patients who did not undergo axillary surgery, 8 received radiotherapy to the lymph draining areas as they had clinically palpable lymph nodes, which were judged to be involved with tumour.

Hormonal therapy

Seventy-eight patients (68%) had hormonal therapy in the form of tamoxifen, oophorectomy or both. Prior to 1987, no patients received tamoxifen and the use of hormone therapy was at the discretion of the consultant responsible for the care of the patient. However, after 1989 all patients (ER positive and negative tumours) received tamoxifen.

Patient outcome

Twenty-three (51%) out of 44 patients aged 30 and under died, and 25(36%) out of 69 over 30 years of age died. The 5-year survival for all patients was 64% and 10-year survival for all patients was 52%. (Figure 2) When the survival of patients aged 30 years and under was compared with those older than 30, although the trend was favouring better survival for those over 30 years of age, there was no statistically significant difference. In terms of local recurrence of disease, 24(21%) patients had local recurrence in either the breast or chest wall. A further 4 patients had tumour recurrence in the axilla, and 5 patients had recurrence in the supraclavicular nodes.

Prognostic factors

Univariate analysis for prognostic factors showed that increasing tumour grade, increasing T stage, absence of ER, presence of lymphovascular space invasion, lymph node metastasis, increasing pathological tumour size and the presence of distant metastasis were indicators of a poor prognosis. (Table 4) The difference in age (30 years and under versus over 30 years) was not a significant prognostic factor.

Multivariate analysis showed that only lymphovascular space invasion was a significant prognostic factor (p=0.0001). Tumour grade, T stage, lymph node metastasis and M stage and ER status were not independent indicators of overall survival (Table 5).

Table 4: Univariate analysis for prognostic factors

DISCUSSION

Carcinoma of the breast in young women is an uncommon disease, accounting for approximately 2% of all cases of breast cancer. There is still considerable debate as to whether or not the prognosis is worse for young women or no different, when compared with older women presenting with breast cancer.^1-19

Many of these studies have frequently reviewed small numbers of patients and have compared patients in different age groups and this may account for some of the discrepancies documented.

In the study reported here, the diagnosis of malignancy was made on clinical examination in approximately one half of the patients, with the other patients having been diagnosed as having benign disease at the initial hospital consultation. Although this is comparable with figures previously reported, it is at variance with the sensitivity of 89% for clinical examination for breast cancer in women of all ages, which have been reported previously from specialist breast units.^23,24 However, in this series of patients in Aberdeen, women with breast disease were seen by general surgeons until the establishment of a specialist breast clinic in 1986 and the development of specialist breast services, subsequently.²⁴

Mammography, which was carried only in one half of the patients, and, therefore, used selectively, did demonstrate the tumour in three quarters of patients. This is comparable with the findings from previous studies but is less than the 93% detection for patients of all age groups reported by our unit.²⁴ In this latter study, dedicated radiologists independently reported the mammograms and coincided with the NHS breast screening programme implementation in 1990. However, mammography was probably used less frequently, as a diagnostic modality, in the 1970s and 1980s and, furthermore, the technical quality of the mammographic images has improved substantially in recent years.

In our series of patients, ultrasound examination of the breast was performed in too few cases to allow meaningful analysis. Fine needle aspiration cytology was carried out in less than 40% of patients but given the time period over which these patients were treated, this would be anticipated. Nevertheless, FNAC demonstrated malignant cells in 83% of those having the procedure performed. This is not dissimilar to figures reported for both young women and for patients of all ages.^23,24

In our study, only three quarters of patients had axillary nodes removed for histological examination; 49% of those examined were involved by tumour on presentation. This was not dissimilar to published reports for women of all ages.^16,26,26 Not all studies, however, have documented these findings and, in some reports, young patients with breast cancer have been more likely to have nodal involvement or more extensive nodal disease.^27-29 The reasons for these differences are unclear and remain to be elucidated.

Table 5: Multivarate analysis for prognostic factors

Pathological examination of the tumours revealed that 94% were invasive ductal carcinoma with 73% of invasive ductal carcinomas being classified as grade 3. This is a much higher percentage of grade 3 tumours, when compared with those occurring in women of all ages. Gajdos et al (2000) also demonstrated that 80% of tumours were categorised as “poorly differentiated” in-patients aged 36 years and less, in comparison with 44% of tumours occurring in-patients more than 36 years.29 Whilst other studies have shown that grade 3 cancers do occur more often in younger than in older patients, the incidence of grade 3 tumours has ranged from 22% to 47%.^{26, 27, 30, 31} The reason for these discrepancies is unclear but may reflect differences in histological grading between different pathologists.

Previous studies have documented that tumours in young patients are less likely to express ERs than those of older patients.^26,29,31 In our study, only 19.6% of tumours were categorised as expressing ERs. This is less than that found in previous studies where 28% to 56% of tumours were shown to contain ERs.^{26, 29-31} The lack of ER expression in our tumours, however, is in keeping with the high number of grade 3 tumours documented.

The histological characteristics of the tumours in our series of young patients show features of biological aggressiveness, as corroborated by TNM staging, ER status and the presence of lymphovascular invasion, and, therefore, might be expected to result in a poorer survival of the young patients in our study. In the series presented here, the overall 5-year and 10-year survival for our patients was 64% and 52%, respectively. There were no differences when comparing patients 30 years of age and under with those who were over 30 years of age but less than 35 years, which is in keeping with other studies.⁸ Large numbers of patients are necessary to document more accurately these interesting observations.

The survival figures in our study are in keeping with previously reported data for 5-year survival for young patients.^8,19,31,32 Although we do not have a direct comparison group of patients older than 35 years of age, it is interesting to compare the survival of our young patients with the reported 69% 5-year survival for the patients of all ages treated in the north-east of Scotland in 1989 and 1993. It should be remembered that our series of young patients were treated during a 22 year period, dating back to 1970, and that major advance in management have occurred during this time. One of the major advances has been the introduction of guidelines, which give clear recommendations as to the most appropriate surgery and adjuvant treatments (radiotherapy, hormone and chemotherapy) for patients.^33,34 Secondly the establishment of multi-disciplinary teams and specialist breast units for managing breast cancer also has had a major impact on the management of patients with breast cancer. Therefore, the variation in treatments given to our patients in our series should no longer occur and all women should now be receiving optimal treatment.

Another factor to consider is whether young patients with breast cancer experience delay in diagnosis, which may be crucial to survival. This has been suggested to be important but, in our series, 87% of patients were seen within three months of onset of symptoms. In only 13% of patients, was there a delay of greater than three months and which might be expected to have an adverse effect on survival.

Factors indicating a poorer prognosis were increasing tumour grade, invasive ductal carcinoma (compared with tumours of no special type), increasing tumour size, negative ER status, presence of lymphovascular space invasion, lymph node metastasis, clinical tumour size and presence of distant metastasis. However, only lymphovascular invasion was an independent predictor of a poorer prognosis when all these factors were examined in a multivariate analysis.

Recent interest has focussed on possible genetic abnormalities in patients with breast cancer at a young age of onset and, specifically, on mutations in the BRCA1 and BRCA2 genes. In young patients with breast cancer (under the age of forty years), approximately 5% of patients will have a germ-line BRCA1 mutation and 3% a BRCA2 mutation.^35,36 However, in those patients with a strong family history the incidence of BRCA1 mutation may be as high as 29%.³⁷ Moreover, patients with grade 3, ER negative tumours or those with a high proliferation rate were more likely to be mutation carriers. In our group of young patients we have previously reported on BRCA1 protein, as detected by immunohistochemistry (80% of BRCA1 mutations result in truncation of the BRCA1 protein). This revealed that BRCA1 protein was not detected in 9% of patients.³⁸ Further studies will be required to determine whether this failure to detect the protein by immunohistochemistry correlates with mutations in the BRCA1 gene or alternatively there may be other mechanisms of gene inactivation, which result in failure to produce the BRCA1 protein.³⁸

In summary, in this series of patients, carcinoma of the breast in young patients is typically invasive ductal carcinoma of a higher tumour grade. However, despite the frequent occurrence of adverse prognostic factors in these tumours, the overall survival of these young patients is comparable with that of patients of all ages. Prognostic factors were identified which predict those patients with a poorer prognosis, with lymphovascular invasion being a key factor.

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Copyright: 31 July 2002

Correspondence: S.D. Heys, Department of Surgery, University Medical Buildings, Foresterhill, Aberdeen, AB9 2ZD