Real-World Data Related to Non-Metastatic Breast Cancer in Young Women: Experience of a Single Institution

Introduction: Breast cancer is the leading cause of cancer-related deaths in women aged 20-59 years. Younger women usually have more aggressive tumors and more advanced disease with larger size and axillary lymph node involvement. There have been few studies assessing the characteristics of breast cancer in very young women. Objective: evaluate the epidemiological and clinical profile of non-metastatic very young patients with breast cancer. Method: We performed a retrospective analysis to evaluate the epidemiological and clinical profile of non-metastatic breast cancer in patients ≤ 30 years of age treated between 1993 and 2011 at the Brazilian national cancer institute José alencar Gomes da silva. We evaluated relapse-free survival (rFs) and overall survival (os). Results: of the 196 patients evaluated, 181 (90%) had ductal carcinoma, 79 (40%) had high-grade tumors, and 102 (52%) had hormone receptor-positive tumors. 117 patients (60%) had stage iii disease at diagnosis. The median age was 29 years (range, 17-30 years). of 185 patients who underwent surgery, 156 (84.3%) underwent total mastectomy and 171 (92%) underwent axillary lymph node dissection. 119 patients received neoadjuvant chemotherapy, and 14 patients (9.3%) underwent neoadjuvant radiotherapy. after a median follow-up of 81.5 months, 109 patients (55%) had relapsed and 81 (41%) had died. The median rFs and os were 49.5 months and 134 months, respectively. lymph node involvement and neoadjuvant chemotherapy were associated with shorter rFs and os. Conclusion: Breast cancer is uncommon in young patients, especially in those ≤ 30 years of age. We found a predominance of locally advanced disease and worse prognostic pathological characteristics. despite the aggressive treatment, our patients had worse outcomes than those reported by other authors.

inTRODUCTiOn Breast cancer remains the leading cause of cancerrelated deaths in women aged 20 to 59 years in the united states. The american cancer society estimated that, in 2015, 231,840 women would be diagnosed with breast cancer and 40,290 would die from the disease 1  in younger women, breast cancer is typically diagnosed after a palpable mass has been detected, given that such women rarely undergo screening mammograms 3 . The Brazilian recommendation for breast cancer screening is an annual clinical breast examination starting at age 40 and biennial mammograms between the ages of 50 and 69 years. For high-risk women, an annual clinical breast examination and mammogram is recommended beginning at age 35 4 .
Young women with breast cancer usually have more aggressive tumors i.e., tumors that are poorly differentiated, are hormone receptor-negative, and show overexpression of human epidermal growth factor receptor 2 (Her2) and more advanced disease, with larger tumors and axillary lymph node involvement 5 . such women often need, and receive, more aggressive multimodal treatment.
Breast cancer, at any age, has great psychological, functional, and social impacts. Women with breast cancer face the treatment of a potentially fatal disease, the effects of aggressive treatment, and the destruction of their self-image. in the younger age groups, there is an associated impact on plans for motherhood and professional career goals.
There have been few studies assessing the characteristics of breast cancer in younger women in Brazil. We performed a retrospective analysis to evaluate the epidemiological and clinical profiles of young female patients with nonmetastatic breast cancer treated at the Brazilian Instituto Nacional do Câncer (inca, national cancer institute), in the city of rio de Janeiro, Brazil.

METHOD
This study was approved by the ethics in Human research committee of the inca in november 2014 (reference no. 37517314.5.0000.5274) and was conducted in accordance with the declaration of Helsinki and Good clinical Practice guidelines. all participating patients gave written informed consent.
Through a search of the inca database, we identified 249 young women with breast cancer treated at the inca between 1993 and 2011. We considered "very young women" those ≤ 30 years of age at diagnosis. We retrospectively reviewed the medical records and collected data about clinicopathological and treatment characteristics.
all of the patients underwent biopsy, and the tumor samples were reviewed at our institution. Pathological variables such as histological grade, estrogen-receptor (er) status, and progesterone-receptor (Pr) status had always been evaluated at the inca, whereas we began evaluating Her2 status in 2007. tumors with > 1% nuclearstained cells were considered positive for er or Pr. The histological grade was reported in accordance with the Bloom and richardson histologic grading scheme: welldifferentiated (low grade, G1); moderately differentiated (intermediate grade, G2); and poorly differentiated (high grade, G3). The Her2 immunohistochemical staining (Herceptest; dako a/s, Glostrup, denmark) was scored from 0 to 3+: scores of 0 and 1+ were considered negative; a score of 3+ was considered positive; and a score of 2+ was considered inconclusive, requiring additional testing with fluorescent in situ hybridization (FisH, PathVysion Her2 dna probe kit; Vysis inc., downers Grove, il, usa).
The tumor stage was based on the 7th Edition of the American Joint Committee on Cancer Staging Manual. We defined the pathological complete response (pcr) as ypt0/is ypn0: no invasive residual disease in breast tissue or lymph nodes. Weight and height information was collected during the first visit with the oncologist. Body mass index (BMi) categories were selected according to the World Health organization definition: underweight, < 18.5 kg/m 2 ; normal weight, 18.5-25.0 kg/m 2 ; overweight, 25.0-30.0 kg/m 2 ; and obese ≥ 30.0 kg/m 2 .

STATISTICAl ANAlySIS
relapse-free survival (rFs) was defined as the time from the histological diagnosis to relapse, death, or the last follow-up evaluation. overall survival (os) was defined as the time from the histological diagnosis to death or the last follow-up evaluation. The rFs and os were estimated using the Kaplan-Meier method and compared by log-rank test.
We used cox proportional regression to estimate hazard ratios and the 95% confidence intervals. The variables with p < 0.05 in the univariate analysis were included in the multivariate analysis. We conducted multivariate analysis through manual selection, using a hierarchical model, beginning with demographic characteristics, then tumor characteristics and treatment. in each block, the non-significant variables were excluded.
Baseline characteristics were compared with Fisher's exact test or the chi-square test, as appropriate. Values of p < 0.05 were considered significant. all analyses were performed with the statistical Package for the social sciences, version 18.0 (sPss inc., chicago, il, usa).

RESULTS
Between January 1993 and July 2011, 249 patients aged 30 years or younger were diagnosed with breast cancer at the inca. of those patients, 53 were excluded (41 had metastasis at diagnosis and 21 were treated elsewhere).
of the 119 patients who received neoadjuvant chemotherapy, 21 (17.5%) were diagnosed with stage ii, 98 (81.6%) were diagnosed with stage iii, 103 (85.8%) underwent radical mastectomy, and 106 (88.3%) underwent axillary dissection. only three patients (2.5%) had a pcr: two were initially diagnosed with stage ii and one was initially diagnosed with stage iii. eleven patients (9.2%) received neoadjuvant therapy and did not undergo surgery, because the tumor remained inoperable or had metastasized (stage iii at diagnosis). Fourteen patients (9.3%) underwent neoadjuvant radiotherapy as a secondline neoadjuvant treatment.
the chemotherapy regimens most often applied consisted of anthracyclines, with or without a taxane. as can be seen in table 2, 60 patients (31.5%) received sequential anthracyclines plus a taxane (6-8 cycles); 119 (62.6%) received an anthracycline-based regimen without a taxane (4-6 cycles), and 11 (5.7%) received the cyclophosphamide, methotrexate, and 5-fluorouracil regimen. 150 patients (76%) underwent radiotherapy, most often as adjuvant treatment. ninety-five (94.1%) of the 101 hormone receptor-positive patients received adjuvant tamoxifen, and one patient received neoadjuvant endocrine therapy. six hormone receptor-positive patients did not receive any hormone therapy: one patient missed the follow-up appointment, and five had relapsed before starting the adjuvant treatment.
Because of the small sample size, we were unable to evaluate the use of trastuzumab or the use of radiotherapy as prognostic factors.

DiSCUSSiOn
Breast cancer is uncommon in young patients, especially in those 30 years of age or younger. However,
Patients with tumors of the Her2-positive and triplenegative subtypes have shorter survival regardless of the age at diagnosis 6 . We also found that hormone receptor positivity was associated with longer overall survival. although the early Breast cancer trialists' collaborative Group (eBctcG) showed, in a meta-analysis, a 29% reduction in cancer-related mortality in women under 45 years of age who had been treated with tamoxifen for 5 years 7 , being younger seems to be associated with worse outcomes in patients with hormone receptorpositive tumors, even with adjuvant endocrine therapy 6,8 . That distinct age-related benefit could be explained by lower adherence to endocrine therapy, less occurrence of chemotherapy-related amenorrhea 9 , tamoxifen resistance, the need for incremental ovarian suppression, or a combination of any of those factors 10 . in 2011, Hershman et al. 11 showed that early discontinuation of and nonadherence to hormonal therapy (below 80% of dose) were both common and were both associated with increased mortality 11 . Furthermore, the suppression of ovarian Function trial reported the benefits of adding ovarian suppression with aromatase inhibitor in premenopausal patients at high risk when compared with tamoxifen, with or without ovarian suppression 10 .
in Brazil, patients have more advanced tumors, at diagnosis, than do those in other countries, possibly due to the delays in diagnosis and disparities in the quality of health care service 12,13 . in the present study, 60% of the patients had stage iii disease at the time of diagnosis and 60% had lymph node involvement, whereas studies conducted in other countries have reported that 20% of patients have stage iii tumors 8 , 20% have t3/t4 lesions 14 , and 35-50% have lymph node involvement 5 . in our study, lymph node involvement was an independent predictor of relapse and death, as reported in previous studies 5,14 . The chemotherapy regimens most commonly applied in our sample were those consisting of anthracyclines plus a taxane or consisting of higher-cumulative-dose anthracyclines. there was no significant difference between the chemotherapy regimens in terms of relapse or survival. That is in line with the eBctcG meta-analysis findings, suggesting that extra cycles of a taxane could be counterbalanced by extra cycles of other cytotoxic drugs 15 .

Revista
in the present study, 60% of the patients received neoadjuvant chemotherapy, usually to ensure tumor resectability. currently, neoadjuvant treatment is widely used to allow more conservative surgery 16 , which leads to lower morbidity and provides better cosmetic results 17 . However, it was initially applied in patients with locally advanced tumors in an attempt to make those tumors resectable. randomized studies have shown that the timing of chemotherapy has no impact on survival 18 but allows the evaluation of tumor response, surgical procedures that are more conservative 16 , and the early treatment of micrometastases.
The achievement of a pcr is an important prognostic factor 16 , especially in triple-negative and Her2-positive tumors. in 2005, the Herceptin adjuvant (Hera) trial showed that trastuzumab increased disease-free survival in patients with Her2-positive breast cancer 19 . in 2006, the u.s. Food and drug administration approved trastuzumab for the adjuvant treatment of breast cancer in patients with Her2-positive tumors. However, at the inca, it was not possible to evaluate Her2 until 2007, and it was therefore evaluated in only 40% of the patients in our sample. despite the Hera results in 2005, trastuzumab was not available at after the inca until 2008. Because only 12 of the patients in our sample received the drug, we were unable to evaluate its use as a prognostic factor. neoadjuvant chemotherapy is the gold standard treatment for locally advanced breast cancer, producing an objective clinical response in 80-90% of patients 20 and a pcr in 20-40% 16 . We found pcr rates of 2.5% and the tumors remained unresectable after neoadjuvant chemotherapy in 21 patients (17.6%). Fourteen patients (11.7%) received neoadjuvant radiotherapy, with or without chemotherapy, and 10 (71.4%) of those patients underwent surgery thereafter. This approach has been tested in patients with chemotherapy-refractory tumors, in whom it was found to be well-tolerated and to produce a good clinical response 21 . in 2007, Gaui et al. 21 reported that 23 of 28 patients became candidates for surgery after having been submitted to this approach. However, coelho et al. 22 reported frequent surgical complications, although no deaths were related to the procedure. a pcr has been found to be more common among patients who carry the BRCA1 gene mutation than among those who do not or who carry the BRCA2 mutation 23 . However, it is not recommended to select the chemotherapy regimen on the basis of the genetic findings. Genetic counseling should be considered for all patients under 40 years of age, especially for those with a family history of breast cancer or with a triple-negative tumor 24 . during the present study, neither genetic counseling nor genetic testing were available.
conservative breast surgery in patients ≤ 30 years of age is a controversial issue in the literature, and there are conflicting findings regarding the increased risk of local relapse. randomized trials conducted in the 1980s and 1990s showed equivalence between treatments. However, those trials evaluated outdated chemotherapy and radiotherapy treatments, with few younger patients in their samples. The most recent trials have shown that, despite the fact that it increases the risk of local relapse, conservative surgery has no significant impact on survival 25 . Being young is no longer a contraindication to breast-conserving therapy. in our sample, nearly 90% of the patients underwent mastectomy, with or without axillary lymph node dissection, because of locally advanced disease.
our study has some limitations. The retrospective design raises the possibility of missing clinical data in the patient records. other possible limitations include the fact that the Her2 status was evaluated in very few of the cases, the lack of comparison with other age groups or a control population, and the relatively short follow-up period, especially for hormone receptor-positive patients. However, it is one of the largest studies conducted to date including such young patients and reflects the reality in developing countries.

COnCLUSiOn
our analysis showed that, in a very young population of women with breast cancer, locally advanced disease was more common and the pathological characteristics indicated a worse prognosis. despite aggressive treatment, our patients had poor outcomes.

AUTHOR COnTRiBUTiOnS
Juliana cunha e silva ominelli de souza and Jesse lopes da silva conceived and designed the work; collected, analyzed, and interpreted the data; revised the manuscript; and approved the final version for submission. andrew sá nunes collected, analyzed, and interpreted the data; revised the manuscript; and approved the final version for submission. aline coelho Gonçalves and susanne crocamo Ventilari da costa conceived and designed the Revista Brasileira de Cancerologia 2018; 64(1): 45-53 work; interpreted the data; revised the manuscript; and approved the final version for submission.

DECLARATiOn Of COnfLiCTS Of inTEREST
nothing to declare.