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Breast cancer in very young women
Available online at www.sciencedirect.com
EJSO 37 (2011) 1030e1037
www.ejso.com
Breast cancer in very young women S. Liukkonen a, M. Leidenius b, T. Saarto a, J. Sj€ ostr€ om-Mattson a,* a
Department of Oncology, Helsinki University Central Hospital, P.O. Box 180, 00029 HUS, Helsinki, Finland b Breast Surgery Unit, Helsinki University Central Hospital, P.O. Box 180, 00029 HUS, Helsinki, Finland Accepted 24 August 2011 Available online 21 September 2011
Abstract Aims: The purpose was to analyse the characteristics, treatment, recurrences and survival of very young women with breast cancer. Methods: 212 female breast cancer patients 35 years old were treated during 1997e2007. The median follow-up time was 78 months. Results: 117 patients had lymph node metastases and 14 distant metastases at diagnosis. 81 (38%) tumours were hormone receptor negative and 130 (65%) grade 3. HER2 positivity was seen in 47 (34%) and triple negativity in 35 (26%) of the 137 tumours with known HER2 status. 140 women were treated with mastectomy and 68 with breast conserving surgery. 163 patients received postoperative radiotherapy, 175 adjuvant chemotherapy, 95 endocrine therapy and 18 trastuzumab. 63 patients experienced a recurrence, of which 20 had only a locoregional recurrence. 10 (15%) of the women with breast conserving surgery experienced ipsilateral breast tumour recurrence while ipsilateral thoracic wall recurrence was seen in 8 patients (6%) after mastectomy. Seven of these eight patients did not receive postmastectomy radiotherapy. DFI was shorter in patients with hormone receptor positive tumours. At the end of follow-up 44 women had died. The 5-year OS was 80%. Conclusions: The 5-year OS for young women has become better but is still lower than for all breast cancer patients. DFI was shorter in patients with hormone receptor positive disease. Locoregional recurrences were seen more often after breast conserving surgery. Ó 2011 Elsevier Ltd. All rights reserved. Keywords: Breast cancer; Young women; Surgery; Prognosis; Overall survival; Locoregional recurrence
Introduction
Patients
Although breast cancer is the most common cancer in women in the western world only 1% of the patients are younger than 35 years old.1 Breast cancer in young women is considered aggressive and associated with a poor prognosis.2,3 Earlier data from the Finnish Cancer Registry in the 1990’s showed that very young women had a more advanced breast cancer at diagnosis and poorer 5-year survival than older premenopausal patients.4 Similar results have been reported from other countries.2,3 The aim of the present study was to analyse the current treatment outcome of very young women with breast cancer and describe the risk factors, tumour characteristics and treatment for these patients.
Female patients aged 35 years diagnosed with breast cancer during 1997e2007 at the Department of Oncology at the Helsinki University Central Hospital (HUCH) were ascertained from the patient database. The initial number of patients was 214. Two cases were excluded because diagnosis and operation were done elsewhere. Data regarding risk factors, presenting signs and symptoms, patient and primary tumour characteristics, treatment, details of recurrence and survival were obtained by chart review. Obesity was estimated by calculating body mass index (BMI, > 30 obese) from height and weight recorded in patient charts or estimated and recorded by attending physician.
Methods
Tumour biological techniques
The study was approved by the local ethical committee. * Corresponding author. Tel.: þ358 407371642; fax: þ358 947173181. E-mail address: [email protected] (J. Sj€ostr€om-Mattson). 0748-7983/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejso.2011.08.133
Steroid hormone receptor status, Ki-67 and HER2 expression of the primary tumours were determined by immunohistochemistry. When HER2 expression was considered positive in immunohistochemistry (either 2þ or 3þ on a scale
S. Liukkonen et al. / EJSO 37 (2011) 1030e1037
from 0 to 3þ), gene amplification status was determined using chromogenic in situ hybridisation. Cancers with six or more gene copies were considered HER2 positive. Statistical methods Missing causes of death and death dates were confirmed by the national Cause of death registry. Statistical analyses were performed using SPSS software. Disease free interval (DFI) and overall survival (OS) were estimated by using the KaplaneMeier method. In the DFI analyses only the patients without distant metastases at primary diagnosis were included. The univariate analyses of DFI and OS according to hormone receptor status were done by the Cox logistic regression model. Results The patient characteristics and risk factors for breast cancer The median age at diagnosis was 33 (range 20e35), and 48 women were 35 years old. According to the Finnish Cancer Registry during the study years 174 women <35 years old were diagnosed in the Helsinki University Hospital area1 so our patient cohort with 164 patients in that age group is very representative. The occurrence of risk factors for breast cancer is presented in Table 1. 40 (19%) patients had been tested for a BRCA1/2 mutation, and of these, six (15%) were carriers of a BRCA1 mutation and in one (3%) a BRCA2 mutation was found. A prior or subsequent malignancy was diagnosed in seven patients. Three of these patients had Hodgkin’s disease and two of them had been treated with mantle field radiation prior to breast cancer. Two patients with Li-Fraumeni syndrome had been diagnosed with sarcoma previously, one of them with two primary sarcomas. The patient with a BRCA2 mutation had been treated for contralateral breast cancer previously and the second breast cancer was a new primary. Diagnostics All the patients were diagnosed due to an initial symptom which was a self-detected lump in the breast in 189, in the axilla in five and in the contralateral breast in one women. Additionally seven patients experienced nipple discharge, one nipple retraction, two inflammatory skin and seven pain. Mammography and ultrasonography were done for 192 patients as the first diagnostic procedure. In 14 patients mammography was negative and ultrasound positive and in one mammography was positive and ultrasound negative. In 12 patients, both mammography and ultrasound were negative, of which eleven tumours were palpable, and one was detected with MRI due to a palpable metastasis in the axilla. MRI was done in only two patients. In three patients the initial symptom was caused by distant metastases.
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Table 1 The occurrence of risk factors for breast cancer (n ¼ 212). Median (range) Age at menarche
12 (10e16)
Parameter
Number of patients (%)
Number of live births 0 1 2 3 Oral contraception use Yes No Unknown Obesity (BMI>30) Obese Normal weight Unknown Smoking Smoker Non-smoker Unknown Family history of breast carcinoma Positive Negative Unknown Family history of ovarian cancer Positive Negative Unknown Family history of prostate carcinoma Positive Negative Unknown A genetic consultation Yes No BRCA BRCA1 BRCA2 Negative Not tested Li-Fraumeni syndrome Other malignancy (prior or subsequent) Hodgkin’s lymphoma Sarcoma Papillary thyroid cancer Contralateral breast cancer Previous radiotherapy to chest A benign breast lesion removed previously
86 60 45 21
(41) (28) (21) (10)
168 (79) 23 (11) 21 (10) 24 (11) 171 (81) 17 (8) 79 (37) 101 (48) 32 (15) 92 (43) 107 (50) 13 (6) 15 (7) 148 (70) 49 (23) 21 (10) 133 (63) 58 (27) 74 (35) 138 (65) 6 1 33 172 3 7 3 2 1 1 2 4
(3) (0.4) (16) (81) (1) (3) (1.4) (1) (0.5) (0.5) (1) (2)
Tumour characteristics Tumour characteristics are listed in Table 2. 109 tumours were T1, and only 2 patients had a T4 tumour. 117 patients had axillary lymph node metastases, and 14 distant metastases at diagnosis. 81 (38%) tumours were negative for both ER and PR and 130 (65%) grade 3. The median value of Ki-67 was 35% (range 2e90). 152 patients were tested for HER2 status, 65 with immunohistochemistry, 5 with ISH and 82 with both. HER2 was positive in 47 (34%) of the 137 cases
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S. Liukkonen et al. / EJSO 37 (2011) 1030e1037
Table 2 Tumour characteristics (n ¼ 212). Characteristic
Table 2 (continued ) Characteristic No. (%)
Breast carcinoma laterality Left 125 (59) Right 84 (40) Bilateral 3 (1) Location of tumour Upper lateral 116 (56) Lower lateral 30 (14) Upper medial 37 (18) Lower medial 11 (5) Central 14 (7) Multifocal in several quadrants 1 (0.04) Bilateral 2 (1) Unknown 1 (0.4) Tumour size (mm) Median 20 (9) Range 1.5e120 Multifocal 48 (23) DCIS with microinvasion 3 (1) Unknown 5 (2) T (primary tumour) 1 109 (52) 2 85 (41) 3 12 (6) 4 2 (1) Unknown 4 (2) N (lymph nodes) N0/N0i91 (43) N1 75 (35) N2 25 (12) N3 17 (8) Unknown 4 (2) Lymph nodes examined in axillary lymph node dissection Median 15 Mean 16 Range 3e38 Distant metastases at diagnosis No 198 (93) Yes 14 (7) Histologic tumour type Ductal 192 (91) Lobular 10 (5) Ductal and lobular 3 (1) Medullary 4 (2) Metaplastic 3 (1) DCIS component included 107 (50) ER status Positive 127 (60) Negative 84 (40) Unknown 1 (0.5) PgR status Positive 95 (45) Negative 115 (55) Unknown 1 (0.5) Grade 1 13 (6) 2 58 (29) 3 130 (65) Unknown 11 (5) Proliferation Ki-67/mib-1 (%) Median 35
Range Unknown Her2 Positive ISH Negative (IHC or ISH) Positive IHC(ISH not done) Unknown
No. (%) 2e90 54 (25) 47 90 16 60
(22) (42) (8) (29)
with known HER2 status i.e. either tested with ISH or negative with imunnohistochemistry. 35 (26%) of these 137 tumours were triple negative. Treatment Primary treatment is described in Table 3. Six patients received neoadjuvant chemotherapy, three for inflammatory breast cancer, two for a large tumour and one who refused surgery. Three other patients were not operated because of an inoperable tumour and distant metastases at primary diagnosis. 140 women were treated with mastectomy and 68 with breast conserving surgery. Axillary lymph node dissection was performed in 150, sentinel node biopsy with axillary lymph node dissection in 33 and without axillary lymph node dissection in 25 patients. 163 women received postoperative radiotherapy. 29 of the 68 patients with breast conserving surgery were given radiotherapy with a booster close to the tumour bed. 94 women received postmastectomy radiotherapy and the main criteria were a T3-T4 tumour or lymph node metastases. Eighteen of the 198 patients without distant metastases at diagnosis did not receive any systemic adjuvant therapy. 175 patients received adjuvant chemotherapy. The most commonly used chemotherapy regimens were CMF (cyclophosphamide, methotrexate, fluorouracil) or FEC (fluorouracil, epirubicin, cyclophosphamide) in the early years and docetaxel followed by FEC in the later years. Chemotherapy treatments varied also because many patients participated in clinical trials. Adjuvant trastuzumab was given to 18 patients either according to the FinHer protocol or the Hera protocol. 95 of the 123 patients with only locoregional and hormone receptor positive disease received adjuvant endocrine therapy. 92 of these 123 women were treated with tamoxifen and 32 either with LHRH analogues or oophorectomy. Six women were given aromatase-inhibitors combined with either goserelin or oophorectomy alone or sequentially after tamoxifen. One patient underwent a prophylactic oophorectomy because of hereditary breast-ovarian cancer syndrome (no BRCA1/2 mutation found). Recurrence rate and overall survival The median follow-up time was 78 months (range 1e160 months). The DFI of the 198 patients without distant
S. Liukkonen et al. / EJSO 37 (2011) 1030e1037 Table 3 Primary treatment. Number of patients (%) Local treatment (n ¼ 212) Surgery - breast Mastectomy Wide local excision None Surgery - axilla Axillary lymph node dissection Sentinel node biopsy without axillary lymph node dissection Sentinel node biopsy and axillary lymph node dissection None Radiotherapy None Thoracic wall after mastectomy Remaining breast tissue after breast conserving operation Locoregional lymph nodes Radiotherapy without surgery Systemic treatment (M0 disease, n ¼ 198) No adjuvant systemic treatment Neoadjuvant therapy Docetaxel þ FEC Adjuvant chemotherapya None FEC AC 4 Docetaxel 3 þ FEC 3 Docetaxel þ capecitabine 3 þ XEC 3 Vinorelbine 3 þ FEC 3 Docetaxel CMF FEC 3 þ high-dose chemotherapy and autologous stem cell support Other Adjuvant trastuzumab FinHer protocol Hera protocol Adjuvant hormone therapy (hormone receptor positive disease, n¼123) Tamoxifen Tamoxifen & ovarian suppression Tamoxifen, ovarian suppression & aromatase inhibitor Aromatase inhibitor & ovarian suppression Oophorectomy None
140 (66) 68 (32) 4 (2) 150 (71) 25 (12) 33 (16) 4 (2) 49 (23) 94 (44) 67 (32) 93 (44) 1 (0.5) 18 (9) 6 (3) 23 32 8 58 7 8 3 43 3
(12) (16) (4) (29) (4) (4) (2) (22) (2)
7 18 11 7
(4) (9) (6) (4)
63 (51) 25 (20) 4(3) 2 (2) 1 (1) 29 (24)
a FEC ¼ 5-fluorouracil, epirubicin, cyclophosphamide; AC ¼ adriamycin, cyclophosphamide; XEC ¼ capecitabine, epirubicin, cyclophosphamide; CMF ¼ cyclophosphamide, methotrexate, 5fluorouracil.
metastases at diagnosis is shown in Fig. 1. The median disease free interval was 30 months (range 8e103 months). 70% of the patients were disease free five years after primary diagnosis. During follow-up 63 patients (32%) experienced recurrence. The first relapse was locoregional in 20 patients (10%) and occurred most often (15 patients) in the ipsilateral breast, axilla or thoracic wall. Additionally, ten locoregional recurrences were diagnosed either after distant metastases or
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at the same time as distant disease so in toto locoregional recurrence was seen in 30 (15%) of the 198 patients. Of the 67 patients treated with breast conserving surgery and radiotherapy, 10 (15%) experienced ipsilateral breast tumour recurrence. Ipsilateral thoracic wall recurrence was seen in 8 (6%) of the 140 patients after mastectomy. Seven of these eight patients did not receive postmastectomy radiotherapy. In the group of 94 patients with postmastectomy radiotherapy only one patient (1%) experienced an ipsilateral thoracic wall recurrence while 7 (15%) ipsilateral thoracic wall recurrences were seen among 46 women without postmastectomy radiotherapy. Contralateral breast tumour was diagnosed in 7 patients one of whom had Li-Fraumeni syndrome. Four (20%) of the twenty patients with locoregional recurrence as the first event experienced distant metastases during follow-up. Fig. 1 presents also the OS. At the end of follow-up 44 (21%) women had died, 43 of breast cancer and 1 due to another cause. The 5-year OS was 80%. DFI and OS were similar among the youngest patients (<30 years) and others (30e35 years) (data not shown). DFI and OS are shown according to the hormone receptor status in Fig. 2. DFI was significantly longer in patients with hormone receptor negative disease ( p ¼ 0.001). The results were similar also after exclusion of the 35 patients who had hormone receptor positive disease but did not receive endocrine therapy (data not shown). Discussion Overall survival and prognostic factors The 5-year OS of 80% for our patient population of very young women is high and better than 70% reported for similar Finnish patients diagnosed twenty years earlier.4 Notably, many patients in our study did not receive adjuvant systemic therapy according to present guidelines. For instance only 38% of the patients who were tested positive for HER2 gene amplification were treated with trastuzumab because trastuzumab was not in use during the first years of the study. Today trastuzumab is recommended for all HER2 positive patients without a contraindication of the drug. Additionally, 23% of the women with hormone receptor positive tumours did not receive adjuvant endocrine therapy, most of them being diagnosed during the early years of the study. It is unknown why so many of these patients did not receive hormonal therapy although it was widely accepted already at that time. The OS of the young women in our study is less than the 5year OS of 89% for Finnish breast cancer patients in general.1 The reason for the poorer disease free and overall survival of young women remains unclear. Some studies report age as an independent prognostic factor,2 while in others the differences in survival seem to be due to different tumour characteristics and treatments.5 In the present study we detected an excess of adverse prognostic factors among these women.
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S. Liukkonen et al. / EJSO 37 (2011) 1030e1037
Figure 1. Survival a) Disease free interval (n ¼ 198) and b) Overall survival (n ¼ 212).
65% of the breast tumours were of high grade, and 40% ER negative, compared to 15% and 18%, respectively, in Finnish breast cancer patients in general.6 More than half of the patients had lymph node metastases at diagnosis which is higher than 34% in general.7 These findings are in line with previous reports, where breast cancers that occur in young women have been described to be larger, have lower ER positivity, poorer differentiation, and to be locally advanced more often2,3,5. HER2 was positive in 34% of the cases with known HER-2 status which is more than 15e20% in unselected breast cancer patients. The amount of triplenegative tumours in the present study was higher than the previously reported 15% in all age groups on average and similar to reported by others in young patients and BRCA1 mutation carriers.
Prognosis in hormone receptor positive disease Interestingly, the DFI was worse in women with hormone receptor positive disease and also the curves of OS differed after several years from diagnosis although not statistically significantly at this point of follow-up. In earlier studies very young women with endocrine-responsive tumours have had higher risk of relapse than older premenopausal patients with such tumours while prognosis has been similar for all premenopausal women with endocrine nonresponsive tumours.8 The prognostic impact of ER positivity may vary over time and OS became inferior for women with ER positive tumours compared to women with ER negative tumours only five years after diagnosis in the study by Bentzon.9 Our results are also in line with the study by Aebi et al. where
Figure 2. Survival by hormone receptor status a) Disease free interval for patients with hormone receptor positive (n ¼ 123) and hormone receptor negative (n ¼ 75) disease ( p ¼ 0.001) and b) Overall survival for patients with hormone receptor positive (n ¼ 131) and hormone receptor negative (n ¼ 81) disease ( p ¼ NS).
S. Liukkonen et al. / EJSO 37 (2011) 1030e1037
younger patients with ER positive tumours had a significantly worse disease-free survival than younger patients with ER negative tumours.10 Another study in node-negative disease shows that younger age was significantly correlated with worse prognosis especially among hormone receptor positive patients and a particularly poor outcome was observed in very young patients without endocrine therapy.11 In fact, preclinical data indicate that there is a subpopulation of young women with ER positive tumours characterised by a strong expression of cell cycle-associated genes and poor prognosis.12 Locoregional disease control Systemic adjuvant therapies have an impact also on locoregional control and reduce the risk of locoregional recurrence and contralateral cancer by 50% in women diagnosed 40 years of age.13 Locoregional recurrence was seen in 15% of the patients which can be considered high. It has been estimated that every fourth prevented locoregional relapse preserves one breast cancer death.14 Surprisingly, the locoregional relapse reduction after postmastectomy radiotherapy was translated into largest survival advantage in the good prognosis group according to a Danish study.15 Maybe therefore, no increased risk of death has been observed among young women after breast conserving surgery despite higher risk of locoregional recurrence.16 We did not, however, analyse the possible association between locoregional recurrence and OS due to the short follow-up. Nevertheless, the association between the locoregional disease control and OS may need re-evaluation because of improved prognosis of breast cancer. The most common type of locoregional recurrence in the present study was the ipsilateral breast tumour recurrence in 15% of the patients treated with breast conserving surgery. Young age and high grade invasive ductal cancer seem to be the most important risk factors for locoregional recurrence after breast conserving surgery and these patients benefit most of a radiation booster close to the tumour bed.17e19 In the study by Bartelink et al the local recurrence rate after breast conserving operation and radiotherapy was 19.5% without radiotherapy booster and 10.2% with the booster in five years.20 In the present study only 43% of the patients received booster irradiation. Regardless of the booster the incidence of local recurrences is still very high with breast conserving surgery so to reduce locoregional recurrences mastectomy with or without immediate reconstruction should be considered as the first choice for very young women (35 years) like it was also done in the great majority of our patients. However, young age is the only independent predictor of locoregional recurrence also after mastectomy without postoperative radiotherapy in patients with T1 and T2 breast cancer with 0e3 metastatic lymph nodes.21 Ipsilateral thoracic wall recurrence was seen in 8 (6%) of our patients after mastectomy and seven of these patients did not receive postoperative radiotherapy. To minimise locoregional recurrences in
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very young women the combination of mastectomy and postoperative radiotherapy is recommended. Ovarian suppression Every fourth patient with hormone receptor positive tumours in the present study were treated with goserelin or oophorectomy. In the literature, there seems to be a possible beneficial role for ovarian suppression in very young patients with hormone receptor positive disease. Treatment-induced amennorhea has been considered one mechanism of action for chemotherapy in young women with endocrineresponsive cancers.22 A Cochrane review evaluating the use of LHRH agonists for adjuvant therapy of early breast cancer in premenopausal women, updated in 2009 and including 14 studies, concluded that compared to chemotherapy alone, combining an LHRH agonist plus chemotherapy plus tamoxifen seem to reduce the risk of breast cancer recurrence and possibly death.23 On the basis of these studies it is impossible to make conclusions whether LHRH agonists add anything on the combination of chemotherapy plus tamoxifen. However, ovarian suppression is nowadays widely used in addition to chemotherapy and tamoxifen in hormone responsive breast cancer of women under 40 years. Risk factors Half of the patients in the present study reported a positive family history of breast or ovarian cancer similarly to other studies.24,25 However, only 74 women were referred to a clinical genetician of whom 40 were tested for a BRCA1/2 mutation and seven women had a BRCA1/2 mutation. The prevalence of BRCA1/2 mutations has previously been reported to be 1.8% in unselected Finnish breast cancer patients and 9.9% in women diagnosed under 40 years.26 Nowadays a referral to a clinical genetician is recommended for all very young patients (aged <30) and for those with familial history of breast cancer. Notably, it has become more difficult to get a reliable picture of the patient’s familial cancer risk since the number of family members on average has decreased and many families have only few female members. Consequently, the need for genetic consultation may not be noted in some patients. Of other known risk factors we found earlier mantle field radiation for Hodgkin’s lymphoma in two patients. The role of oral contraceptives for breast cancer risk is unclear. Previous studies have reported that in young women oral contraceptive use 1 year or longer is associated with a 2,5-fold increased risk only for triplenegative breast cancer27 or that the oral contraceptive use within five years prior to diagnosis increases the risk for breast cancer.28 On the contrary, in a large study regarding a little older women aged 40e59 years with a family history of breast cancer, ever use of oral contraceptives was associated with a 12% reduction in risk of breast cancer.29 In our study most patients reported use of oral contraceptives like young women in general in Finland.
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Diagnostics As mammography screening is done only for women aged 50e69 of old in Finland, all tumours were diagnosed due to symptoms. The most common symptom was palpable mass in breast. In 91% of the cases the tumour could be detected by mammography and ultrasound but twelve (6%) patients had a tumour undetected by both mammography and ultrasound, eleven of which were palpable highlighting the importance of the triple diagnostic approach. The sensitivity of mammography and ultrasound in breast cancer patients under 35 years old have been reported to be 85% and 88%, respectively.30 MRI was done in only two patients. The role of MRI in breast cancer diagnosis is controversial but it might be beneficial in very young women with dense breast tissue. Its use is recommended at least in young women with BRCA1/2 mutation. Conclusions DFI was worse in patients with hormone receptor positive disease. Locoregional recurrences were seen more often after breast conserving surgery but also after mastectomy especially if the patient did not receive radiotherapy. To minimise locoregional recurrences in very young women the combination of mastectomy and postoperative radiotherapy is recommended. The 5-year OS of 80% for this patient population of young women with adverse prognostic factors has become better and is quite high but still lower than the 5-year OS of 89% for all Finnish breast cancer patients. With new treatment modalities and guidelines an even better outcome is most likely to be achieved. Conflict of interest The authors have no disclosures.
Acknowledgements The study was financially supported by the SalonojaFoundation, the Finnish Oncology Society and the Finnish Breast Cancer Group without any involvement in the conduction of the study.
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4. Holli K, Isola J. Effect of age on the survival of breast cancer patients. Eur J Cancer 1997;33(3):425–8. 5. Figueiredo JC, Ennis M, Knight JA, et al. Influence of young age at diagnosis and family history of breast or ovarian cancer on breast cancer outcomes in a population-based cohort study. Breast Cancer Res Treat 2007;105(1):69–80. 6. Seppanen J, Heinavaara S, Holli K, Hakulinen T. Comparison of cancer registry and clinical data as predictors for breast cancer survival. Cancer Causes Control 2008;19(10):1299–304. 7. Lundin J, Lehtimaki T, Lundin M, et al. Generalisability of survival estimates for patients with breast cancerea comparison across two population-based series. Eur J Cancer 2006;42(18):3228–35. 8. Goldhirsch A, Gelber RD, Yothers G, et al. Adjuvant therapy for very young women with breast cancer: need for tailored treatments. J Natl Cancer Inst Monogr 2001;44–51. (30). 9. Bentzon N, During M, Rasmussen BB, Mouridsen H, Kroman N. Prognostic effect of estrogen receptor status across age in primary breast cancer. Int J Cancer 2008;122(5):1089–94. 10. Aebi S, Gelber S, Castiglione-Gertsch M, et al. Is chemotherapy alone adequate for young women with oestrogen-receptor-positive breast cancer? Lancet 2000;355(9218):1869–74. 11. Colleoni M, Rotmensz N, Peruzzotti G, et al. Role of endocrine responsiveness and adjuvant therapy in very young women (below 35 years) with operable breast cancer and node negative disease. Ann Oncol 2006;17(10):1497–503. 12. Dai H, van’t Veer L, Lamb J, et al. A cell proliferation signature is a marker of extremely poor outcome in a subpopulation of breast cancer patients. Cancer Res 2005;65(10):4059–66. 13. van der Leest M, Evers L, van der Sangen MJ, et al. The safety of breast-conserving therapy in patients with breast cancer aged < or ¼ 40 years. Cancer 2007;109(10):1957–64. 14. Clarke M, Collins R, Darby S, et al. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005;366(9503):2087–106. 15. Kyndi M, Overgaard M, Nielsen HM, Sorensen FB, Knudsen H, Overgaard J. High local recurrence risk is not associated with large survival reduction after postmastectomy radiotherapy in high-risk breast cancer: a subgroup analysis of DBCG 82 b&c. Radiother Oncol 2009;90(1):74–9. 16. Kroman N, Holtveg H, Wohlfahrt J, et al. Effect of breast-conserving therapy versus radical mastectomy on prognosis for young women with breast carcinoma. Cancer 2004;100(4):688–93. 17. Anderson SJ, Wapnir I, Dignam JJ, et al. Prognosis after ipsilateral breast tumor recurrence and locoregional recurrences in patients treated by breast-conserving therapy in five National Surgical Adjuvant Breast and Bowel Project protocols of node-negative breast cancer. J Clin Oncol 2009;27(15):2466–73. 18. Poortmans PM, Collette L, Bartelink H, et al. The addition of a boost dose on the primary tumour bed after lumpectomy in breast conserving treatment for breast cancer. A summary of the results of EORTC 22881-10882 “boost versus no boost” trial. Cancer Radiother 2008;12(6e7):565–70. 19. Jones HA, Antonini N, Hart AA, et al. Impact of pathological characteristics on local relapse after breast-conserving therapy: a subgroup analysis of the EORTC boost versus no boost trial. J Clin Oncol 2009;27(30):4939–47. 20. Bartelink H, Horiot JC, Poortmans P, et al. Recurrence rates after treatment of breast cancer with standard radiotherapy with or without additional radiation. N Engl J Med 2001;345(19):1378–87. 21. Sharma R, Bedrosian I, Lucci A, et al. Present-day locoregional control in patients with T1 or T2 breast cancer with 0 and 1 to 3 positive lymph nodes after mastectomy without radiotherapy. Ann Surg Oncol 2010. 22. Parulekar WR, Day AG, Ottaway JA, et al. Incidence and prognostic impact of amenorrhea during adjuvant therapy in high-risk premenopausal breast cancer: analysis of a National Cancer Institute of Canada Clinical Trials Group StudyeNCIC CTG MA.5. J Clin Oncol 2005; 23(25):6002–8.
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EJSO 37 (2011) 1030e1037
www.ejso.com
Breast cancer in very young women S. Liukkonen a, M. Leidenius b, T. Saarto a, J. Sj€ ostr€ om-Mattson a,* a
Department of Oncology, Helsinki University Central Hospital, P.O. Box 180, 00029 HUS, Helsinki, Finland b Breast Surgery Unit, Helsinki University Central Hospital, P.O. Box 180, 00029 HUS, Helsinki, Finland Accepted 24 August 2011 Available online 21 September 2011
Abstract Aims: The purpose was to analyse the characteristics, treatment, recurrences and survival of very young women with breast cancer. Methods: 212 female breast cancer patients 35 years old were treated during 1997e2007. The median follow-up time was 78 months. Results: 117 patients had lymph node metastases and 14 distant metastases at diagnosis. 81 (38%) tumours were hormone receptor negative and 130 (65%) grade 3. HER2 positivity was seen in 47 (34%) and triple negativity in 35 (26%) of the 137 tumours with known HER2 status. 140 women were treated with mastectomy and 68 with breast conserving surgery. 163 patients received postoperative radiotherapy, 175 adjuvant chemotherapy, 95 endocrine therapy and 18 trastuzumab. 63 patients experienced a recurrence, of which 20 had only a locoregional recurrence. 10 (15%) of the women with breast conserving surgery experienced ipsilateral breast tumour recurrence while ipsilateral thoracic wall recurrence was seen in 8 patients (6%) after mastectomy. Seven of these eight patients did not receive postmastectomy radiotherapy. DFI was shorter in patients with hormone receptor positive tumours. At the end of follow-up 44 women had died. The 5-year OS was 80%. Conclusions: The 5-year OS for young women has become better but is still lower than for all breast cancer patients. DFI was shorter in patients with hormone receptor positive disease. Locoregional recurrences were seen more often after breast conserving surgery. Ó 2011 Elsevier Ltd. All rights reserved. Keywords: Breast cancer; Young women; Surgery; Prognosis; Overall survival; Locoregional recurrence
Introduction
Patients
Although breast cancer is the most common cancer in women in the western world only 1% of the patients are younger than 35 years old.1 Breast cancer in young women is considered aggressive and associated with a poor prognosis.2,3 Earlier data from the Finnish Cancer Registry in the 1990’s showed that very young women had a more advanced breast cancer at diagnosis and poorer 5-year survival than older premenopausal patients.4 Similar results have been reported from other countries.2,3 The aim of the present study was to analyse the current treatment outcome of very young women with breast cancer and describe the risk factors, tumour characteristics and treatment for these patients.
Female patients aged 35 years diagnosed with breast cancer during 1997e2007 at the Department of Oncology at the Helsinki University Central Hospital (HUCH) were ascertained from the patient database. The initial number of patients was 214. Two cases were excluded because diagnosis and operation were done elsewhere. Data regarding risk factors, presenting signs and symptoms, patient and primary tumour characteristics, treatment, details of recurrence and survival were obtained by chart review. Obesity was estimated by calculating body mass index (BMI, > 30 obese) from height and weight recorded in patient charts or estimated and recorded by attending physician.
Methods
Tumour biological techniques
The study was approved by the local ethical committee. * Corresponding author. Tel.: þ358 407371642; fax: þ358 947173181. E-mail address: [email protected] (J. Sj€ostr€om-Mattson). 0748-7983/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejso.2011.08.133
Steroid hormone receptor status, Ki-67 and HER2 expression of the primary tumours were determined by immunohistochemistry. When HER2 expression was considered positive in immunohistochemistry (either 2þ or 3þ on a scale
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from 0 to 3þ), gene amplification status was determined using chromogenic in situ hybridisation. Cancers with six or more gene copies were considered HER2 positive. Statistical methods Missing causes of death and death dates were confirmed by the national Cause of death registry. Statistical analyses were performed using SPSS software. Disease free interval (DFI) and overall survival (OS) were estimated by using the KaplaneMeier method. In the DFI analyses only the patients without distant metastases at primary diagnosis were included. The univariate analyses of DFI and OS according to hormone receptor status were done by the Cox logistic regression model. Results The patient characteristics and risk factors for breast cancer The median age at diagnosis was 33 (range 20e35), and 48 women were 35 years old. According to the Finnish Cancer Registry during the study years 174 women <35 years old were diagnosed in the Helsinki University Hospital area1 so our patient cohort with 164 patients in that age group is very representative. The occurrence of risk factors for breast cancer is presented in Table 1. 40 (19%) patients had been tested for a BRCA1/2 mutation, and of these, six (15%) were carriers of a BRCA1 mutation and in one (3%) a BRCA2 mutation was found. A prior or subsequent malignancy was diagnosed in seven patients. Three of these patients had Hodgkin’s disease and two of them had been treated with mantle field radiation prior to breast cancer. Two patients with Li-Fraumeni syndrome had been diagnosed with sarcoma previously, one of them with two primary sarcomas. The patient with a BRCA2 mutation had been treated for contralateral breast cancer previously and the second breast cancer was a new primary. Diagnostics All the patients were diagnosed due to an initial symptom which was a self-detected lump in the breast in 189, in the axilla in five and in the contralateral breast in one women. Additionally seven patients experienced nipple discharge, one nipple retraction, two inflammatory skin and seven pain. Mammography and ultrasonography were done for 192 patients as the first diagnostic procedure. In 14 patients mammography was negative and ultrasound positive and in one mammography was positive and ultrasound negative. In 12 patients, both mammography and ultrasound were negative, of which eleven tumours were palpable, and one was detected with MRI due to a palpable metastasis in the axilla. MRI was done in only two patients. In three patients the initial symptom was caused by distant metastases.
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Table 1 The occurrence of risk factors for breast cancer (n ¼ 212). Median (range) Age at menarche
12 (10e16)
Parameter
Number of patients (%)
Number of live births 0 1 2 3 Oral contraception use Yes No Unknown Obesity (BMI>30) Obese Normal weight Unknown Smoking Smoker Non-smoker Unknown Family history of breast carcinoma Positive Negative Unknown Family history of ovarian cancer Positive Negative Unknown Family history of prostate carcinoma Positive Negative Unknown A genetic consultation Yes No BRCA BRCA1 BRCA2 Negative Not tested Li-Fraumeni syndrome Other malignancy (prior or subsequent) Hodgkin’s lymphoma Sarcoma Papillary thyroid cancer Contralateral breast cancer Previous radiotherapy to chest A benign breast lesion removed previously
86 60 45 21
(41) (28) (21) (10)
168 (79) 23 (11) 21 (10) 24 (11) 171 (81) 17 (8) 79 (37) 101 (48) 32 (15) 92 (43) 107 (50) 13 (6) 15 (7) 148 (70) 49 (23) 21 (10) 133 (63) 58 (27) 74 (35) 138 (65) 6 1 33 172 3 7 3 2 1 1 2 4
(3) (0.4) (16) (81) (1) (3) (1.4) (1) (0.5) (0.5) (1) (2)
Tumour characteristics Tumour characteristics are listed in Table 2. 109 tumours were T1, and only 2 patients had a T4 tumour. 117 patients had axillary lymph node metastases, and 14 distant metastases at diagnosis. 81 (38%) tumours were negative for both ER and PR and 130 (65%) grade 3. The median value of Ki-67 was 35% (range 2e90). 152 patients were tested for HER2 status, 65 with immunohistochemistry, 5 with ISH and 82 with both. HER2 was positive in 47 (34%) of the 137 cases
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Table 2 Tumour characteristics (n ¼ 212). Characteristic
Table 2 (continued ) Characteristic No. (%)
Breast carcinoma laterality Left 125 (59) Right 84 (40) Bilateral 3 (1) Location of tumour Upper lateral 116 (56) Lower lateral 30 (14) Upper medial 37 (18) Lower medial 11 (5) Central 14 (7) Multifocal in several quadrants 1 (0.04) Bilateral 2 (1) Unknown 1 (0.4) Tumour size (mm) Median 20 (9) Range 1.5e120 Multifocal 48 (23) DCIS with microinvasion 3 (1) Unknown 5 (2) T (primary tumour) 1 109 (52) 2 85 (41) 3 12 (6) 4 2 (1) Unknown 4 (2) N (lymph nodes) N0/N0i91 (43) N1 75 (35) N2 25 (12) N3 17 (8) Unknown 4 (2) Lymph nodes examined in axillary lymph node dissection Median 15 Mean 16 Range 3e38 Distant metastases at diagnosis No 198 (93) Yes 14 (7) Histologic tumour type Ductal 192 (91) Lobular 10 (5) Ductal and lobular 3 (1) Medullary 4 (2) Metaplastic 3 (1) DCIS component included 107 (50) ER status Positive 127 (60) Negative 84 (40) Unknown 1 (0.5) PgR status Positive 95 (45) Negative 115 (55) Unknown 1 (0.5) Grade 1 13 (6) 2 58 (29) 3 130 (65) Unknown 11 (5) Proliferation Ki-67/mib-1 (%) Median 35
Range Unknown Her2 Positive ISH Negative (IHC or ISH) Positive IHC(ISH not done) Unknown
No. (%) 2e90 54 (25) 47 90 16 60
(22) (42) (8) (29)
with known HER2 status i.e. either tested with ISH or negative with imunnohistochemistry. 35 (26%) of these 137 tumours were triple negative. Treatment Primary treatment is described in Table 3. Six patients received neoadjuvant chemotherapy, three for inflammatory breast cancer, two for a large tumour and one who refused surgery. Three other patients were not operated because of an inoperable tumour and distant metastases at primary diagnosis. 140 women were treated with mastectomy and 68 with breast conserving surgery. Axillary lymph node dissection was performed in 150, sentinel node biopsy with axillary lymph node dissection in 33 and without axillary lymph node dissection in 25 patients. 163 women received postoperative radiotherapy. 29 of the 68 patients with breast conserving surgery were given radiotherapy with a booster close to the tumour bed. 94 women received postmastectomy radiotherapy and the main criteria were a T3-T4 tumour or lymph node metastases. Eighteen of the 198 patients without distant metastases at diagnosis did not receive any systemic adjuvant therapy. 175 patients received adjuvant chemotherapy. The most commonly used chemotherapy regimens were CMF (cyclophosphamide, methotrexate, fluorouracil) or FEC (fluorouracil, epirubicin, cyclophosphamide) in the early years and docetaxel followed by FEC in the later years. Chemotherapy treatments varied also because many patients participated in clinical trials. Adjuvant trastuzumab was given to 18 patients either according to the FinHer protocol or the Hera protocol. 95 of the 123 patients with only locoregional and hormone receptor positive disease received adjuvant endocrine therapy. 92 of these 123 women were treated with tamoxifen and 32 either with LHRH analogues or oophorectomy. Six women were given aromatase-inhibitors combined with either goserelin or oophorectomy alone or sequentially after tamoxifen. One patient underwent a prophylactic oophorectomy because of hereditary breast-ovarian cancer syndrome (no BRCA1/2 mutation found). Recurrence rate and overall survival The median follow-up time was 78 months (range 1e160 months). The DFI of the 198 patients without distant
S. Liukkonen et al. / EJSO 37 (2011) 1030e1037 Table 3 Primary treatment. Number of patients (%) Local treatment (n ¼ 212) Surgery - breast Mastectomy Wide local excision None Surgery - axilla Axillary lymph node dissection Sentinel node biopsy without axillary lymph node dissection Sentinel node biopsy and axillary lymph node dissection None Radiotherapy None Thoracic wall after mastectomy Remaining breast tissue after breast conserving operation Locoregional lymph nodes Radiotherapy without surgery Systemic treatment (M0 disease, n ¼ 198) No adjuvant systemic treatment Neoadjuvant therapy Docetaxel þ FEC Adjuvant chemotherapya None FEC AC 4 Docetaxel 3 þ FEC 3 Docetaxel þ capecitabine 3 þ XEC 3 Vinorelbine 3 þ FEC 3 Docetaxel CMF FEC 3 þ high-dose chemotherapy and autologous stem cell support Other Adjuvant trastuzumab FinHer protocol Hera protocol Adjuvant hormone therapy (hormone receptor positive disease, n¼123) Tamoxifen Tamoxifen & ovarian suppression Tamoxifen, ovarian suppression & aromatase inhibitor Aromatase inhibitor & ovarian suppression Oophorectomy None
140 (66) 68 (32) 4 (2) 150 (71) 25 (12) 33 (16) 4 (2) 49 (23) 94 (44) 67 (32) 93 (44) 1 (0.5) 18 (9) 6 (3) 23 32 8 58 7 8 3 43 3
(12) (16) (4) (29) (4) (4) (2) (22) (2)
7 18 11 7
(4) (9) (6) (4)
63 (51) 25 (20) 4(3) 2 (2) 1 (1) 29 (24)
a FEC ¼ 5-fluorouracil, epirubicin, cyclophosphamide; AC ¼ adriamycin, cyclophosphamide; XEC ¼ capecitabine, epirubicin, cyclophosphamide; CMF ¼ cyclophosphamide, methotrexate, 5fluorouracil.
metastases at diagnosis is shown in Fig. 1. The median disease free interval was 30 months (range 8e103 months). 70% of the patients were disease free five years after primary diagnosis. During follow-up 63 patients (32%) experienced recurrence. The first relapse was locoregional in 20 patients (10%) and occurred most often (15 patients) in the ipsilateral breast, axilla or thoracic wall. Additionally, ten locoregional recurrences were diagnosed either after distant metastases or
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at the same time as distant disease so in toto locoregional recurrence was seen in 30 (15%) of the 198 patients. Of the 67 patients treated with breast conserving surgery and radiotherapy, 10 (15%) experienced ipsilateral breast tumour recurrence. Ipsilateral thoracic wall recurrence was seen in 8 (6%) of the 140 patients after mastectomy. Seven of these eight patients did not receive postmastectomy radiotherapy. In the group of 94 patients with postmastectomy radiotherapy only one patient (1%) experienced an ipsilateral thoracic wall recurrence while 7 (15%) ipsilateral thoracic wall recurrences were seen among 46 women without postmastectomy radiotherapy. Contralateral breast tumour was diagnosed in 7 patients one of whom had Li-Fraumeni syndrome. Four (20%) of the twenty patients with locoregional recurrence as the first event experienced distant metastases during follow-up. Fig. 1 presents also the OS. At the end of follow-up 44 (21%) women had died, 43 of breast cancer and 1 due to another cause. The 5-year OS was 80%. DFI and OS were similar among the youngest patients (<30 years) and others (30e35 years) (data not shown). DFI and OS are shown according to the hormone receptor status in Fig. 2. DFI was significantly longer in patients with hormone receptor negative disease ( p ¼ 0.001). The results were similar also after exclusion of the 35 patients who had hormone receptor positive disease but did not receive endocrine therapy (data not shown). Discussion Overall survival and prognostic factors The 5-year OS of 80% for our patient population of very young women is high and better than 70% reported for similar Finnish patients diagnosed twenty years earlier.4 Notably, many patients in our study did not receive adjuvant systemic therapy according to present guidelines. For instance only 38% of the patients who were tested positive for HER2 gene amplification were treated with trastuzumab because trastuzumab was not in use during the first years of the study. Today trastuzumab is recommended for all HER2 positive patients without a contraindication of the drug. Additionally, 23% of the women with hormone receptor positive tumours did not receive adjuvant endocrine therapy, most of them being diagnosed during the early years of the study. It is unknown why so many of these patients did not receive hormonal therapy although it was widely accepted already at that time. The OS of the young women in our study is less than the 5year OS of 89% for Finnish breast cancer patients in general.1 The reason for the poorer disease free and overall survival of young women remains unclear. Some studies report age as an independent prognostic factor,2 while in others the differences in survival seem to be due to different tumour characteristics and treatments.5 In the present study we detected an excess of adverse prognostic factors among these women.
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Figure 1. Survival a) Disease free interval (n ¼ 198) and b) Overall survival (n ¼ 212).
65% of the breast tumours were of high grade, and 40% ER negative, compared to 15% and 18%, respectively, in Finnish breast cancer patients in general.6 More than half of the patients had lymph node metastases at diagnosis which is higher than 34% in general.7 These findings are in line with previous reports, where breast cancers that occur in young women have been described to be larger, have lower ER positivity, poorer differentiation, and to be locally advanced more often2,3,5. HER2 was positive in 34% of the cases with known HER-2 status which is more than 15e20% in unselected breast cancer patients. The amount of triplenegative tumours in the present study was higher than the previously reported 15% in all age groups on average and similar to reported by others in young patients and BRCA1 mutation carriers.
Prognosis in hormone receptor positive disease Interestingly, the DFI was worse in women with hormone receptor positive disease and also the curves of OS differed after several years from diagnosis although not statistically significantly at this point of follow-up. In earlier studies very young women with endocrine-responsive tumours have had higher risk of relapse than older premenopausal patients with such tumours while prognosis has been similar for all premenopausal women with endocrine nonresponsive tumours.8 The prognostic impact of ER positivity may vary over time and OS became inferior for women with ER positive tumours compared to women with ER negative tumours only five years after diagnosis in the study by Bentzon.9 Our results are also in line with the study by Aebi et al. where
Figure 2. Survival by hormone receptor status a) Disease free interval for patients with hormone receptor positive (n ¼ 123) and hormone receptor negative (n ¼ 75) disease ( p ¼ 0.001) and b) Overall survival for patients with hormone receptor positive (n ¼ 131) and hormone receptor negative (n ¼ 81) disease ( p ¼ NS).
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younger patients with ER positive tumours had a significantly worse disease-free survival than younger patients with ER negative tumours.10 Another study in node-negative disease shows that younger age was significantly correlated with worse prognosis especially among hormone receptor positive patients and a particularly poor outcome was observed in very young patients without endocrine therapy.11 In fact, preclinical data indicate that there is a subpopulation of young women with ER positive tumours characterised by a strong expression of cell cycle-associated genes and poor prognosis.12 Locoregional disease control Systemic adjuvant therapies have an impact also on locoregional control and reduce the risk of locoregional recurrence and contralateral cancer by 50% in women diagnosed 40 years of age.13 Locoregional recurrence was seen in 15% of the patients which can be considered high. It has been estimated that every fourth prevented locoregional relapse preserves one breast cancer death.14 Surprisingly, the locoregional relapse reduction after postmastectomy radiotherapy was translated into largest survival advantage in the good prognosis group according to a Danish study.15 Maybe therefore, no increased risk of death has been observed among young women after breast conserving surgery despite higher risk of locoregional recurrence.16 We did not, however, analyse the possible association between locoregional recurrence and OS due to the short follow-up. Nevertheless, the association between the locoregional disease control and OS may need re-evaluation because of improved prognosis of breast cancer. The most common type of locoregional recurrence in the present study was the ipsilateral breast tumour recurrence in 15% of the patients treated with breast conserving surgery. Young age and high grade invasive ductal cancer seem to be the most important risk factors for locoregional recurrence after breast conserving surgery and these patients benefit most of a radiation booster close to the tumour bed.17e19 In the study by Bartelink et al the local recurrence rate after breast conserving operation and radiotherapy was 19.5% without radiotherapy booster and 10.2% with the booster in five years.20 In the present study only 43% of the patients received booster irradiation. Regardless of the booster the incidence of local recurrences is still very high with breast conserving surgery so to reduce locoregional recurrences mastectomy with or without immediate reconstruction should be considered as the first choice for very young women (35 years) like it was also done in the great majority of our patients. However, young age is the only independent predictor of locoregional recurrence also after mastectomy without postoperative radiotherapy in patients with T1 and T2 breast cancer with 0e3 metastatic lymph nodes.21 Ipsilateral thoracic wall recurrence was seen in 8 (6%) of our patients after mastectomy and seven of these patients did not receive postoperative radiotherapy. To minimise locoregional recurrences in
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very young women the combination of mastectomy and postoperative radiotherapy is recommended. Ovarian suppression Every fourth patient with hormone receptor positive tumours in the present study were treated with goserelin or oophorectomy. In the literature, there seems to be a possible beneficial role for ovarian suppression in very young patients with hormone receptor positive disease. Treatment-induced amennorhea has been considered one mechanism of action for chemotherapy in young women with endocrineresponsive cancers.22 A Cochrane review evaluating the use of LHRH agonists for adjuvant therapy of early breast cancer in premenopausal women, updated in 2009 and including 14 studies, concluded that compared to chemotherapy alone, combining an LHRH agonist plus chemotherapy plus tamoxifen seem to reduce the risk of breast cancer recurrence and possibly death.23 On the basis of these studies it is impossible to make conclusions whether LHRH agonists add anything on the combination of chemotherapy plus tamoxifen. However, ovarian suppression is nowadays widely used in addition to chemotherapy and tamoxifen in hormone responsive breast cancer of women under 40 years. Risk factors Half of the patients in the present study reported a positive family history of breast or ovarian cancer similarly to other studies.24,25 However, only 74 women were referred to a clinical genetician of whom 40 were tested for a BRCA1/2 mutation and seven women had a BRCA1/2 mutation. The prevalence of BRCA1/2 mutations has previously been reported to be 1.8% in unselected Finnish breast cancer patients and 9.9% in women diagnosed under 40 years.26 Nowadays a referral to a clinical genetician is recommended for all very young patients (aged <30) and for those with familial history of breast cancer. Notably, it has become more difficult to get a reliable picture of the patient’s familial cancer risk since the number of family members on average has decreased and many families have only few female members. Consequently, the need for genetic consultation may not be noted in some patients. Of other known risk factors we found earlier mantle field radiation for Hodgkin’s lymphoma in two patients. The role of oral contraceptives for breast cancer risk is unclear. Previous studies have reported that in young women oral contraceptive use 1 year or longer is associated with a 2,5-fold increased risk only for triplenegative breast cancer27 or that the oral contraceptive use within five years prior to diagnosis increases the risk for breast cancer.28 On the contrary, in a large study regarding a little older women aged 40e59 years with a family history of breast cancer, ever use of oral contraceptives was associated with a 12% reduction in risk of breast cancer.29 In our study most patients reported use of oral contraceptives like young women in general in Finland.
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Diagnostics As mammography screening is done only for women aged 50e69 of old in Finland, all tumours were diagnosed due to symptoms. The most common symptom was palpable mass in breast. In 91% of the cases the tumour could be detected by mammography and ultrasound but twelve (6%) patients had a tumour undetected by both mammography and ultrasound, eleven of which were palpable highlighting the importance of the triple diagnostic approach. The sensitivity of mammography and ultrasound in breast cancer patients under 35 years old have been reported to be 85% and 88%, respectively.30 MRI was done in only two patients. The role of MRI in breast cancer diagnosis is controversial but it might be beneficial in very young women with dense breast tissue. Its use is recommended at least in young women with BRCA1/2 mutation. Conclusions DFI was worse in patients with hormone receptor positive disease. Locoregional recurrences were seen more often after breast conserving surgery but also after mastectomy especially if the patient did not receive radiotherapy. To minimise locoregional recurrences in very young women the combination of mastectomy and postoperative radiotherapy is recommended. The 5-year OS of 80% for this patient population of young women with adverse prognostic factors has become better and is quite high but still lower than the 5-year OS of 89% for all Finnish breast cancer patients. With new treatment modalities and guidelines an even better outcome is most likely to be achieved. Conflict of interest The authors have no disclosures.
Acknowledgements The study was financially supported by the SalonojaFoundation, the Finnish Oncology Society and the Finnish Breast Cancer Group without any involvement in the conduction of the study.
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