Introduction
Young adult (YA) cancers are relatively rare and represent a minority of cases. Consequently, data are lacking concerning intellectual and other psychosocial issues affecting this specific patient population [
1]. YA cancer patients are significantly more likely to indicate unmet needs for supportive care services [
2]. Moreover, fewer clinical trials have been conducted for YA cancers compared to other adult cancers, suggesting that there may be little evidence of high impact. Among YA cancers in women, breast cancer has the highest incidence rates (30–34 years, 13.3 per 100,000 population, and 35–39 years, 31.6 per 100,000 population [
3]. However, even breast cancers account for a very small proportion (approximately 7 %) of the total number of breast cancers in these age groups [
4‐
6].
YA breast cancer patients diagnosed in their twenties or thirties tend to have a poorer prognosis than women diagnosed in middle age (MA) [
7]. Differences in survival may reflect clinical and biological variations. Indeed, YA breast cancer patients are reported to present with more aggressive biological characteristics and to behave more poorly compared to older breast cancer patients [
8]. Previously, we reported the clinicopathological features of YA patients as having advanced TNM staging and human epidermal growth factor receptor 2 (HER2)-positive/oestrogen receptor (ER)-negative breast cancers compared to older patients [
6]. Similarly, aggressive and unfavourable characteristics, including TNM classification, ER status, and HER2 status for YA patients with breast cancer have been reported [
9‐
13].
However, to our knowledge, most of the data on the biological characteristics and treatment to evaluate these patients were derived from older and relatively smaller cohort studies. Moreover, whether age remains an independent predictive prognostic factor, after adjustment of breast cancer subtype (ER, PR, and HER2 status), as well as, other known prognostic factors (TNM classification, adjuvant systemic therapy, etc.) has yet to be determined, given YA patients are at risk of developing more aggressive and more advanced breast cancers.
The aim of this study was to investigate whether young age at onset of breast cancer is an independent negative prognostic factor in patients from the Japanese Breast Cancer Registry (which includes >25,000 newly treated breast cancers between 2004 and 2006).
Discussion
YA breast cancer accounts for a minority of breast cancer cases [
6].
Consequently, it is unlikely that a prospective clinical trial would ever be conducted to define the optimal treatment strategy for this disease subset.
We analysed data from a large number of breast cancer patients registered by the Japanese Breast Cancer Registry database in order to characterise and advance our understanding of YA breast cancer. Using nationwide, population-based data representing approximately 70 % of all newly diagnosed breast cancer patients in Japan between 2004 and 2006, we were able to circumvent many problems associated with single institutional experiences or limited sample sizes. Our study demonstrated that a young age at onset was an independent predictive factor for poor prognosis in patients with breast cancer, after adjustment of well-known clinicopathological factors, including breast cancer receptor status, tumour size, and nodal status. Classically, it has been suggested that YA breast cancer patients are associated with a poorer prognosis because of delayed diagnosis at an advanced stage, a larger tumour size, and higher incidences of HER2-positive/ER-negative tumours [
6,
9]. These reports proved consistent with our findings in the present study. Some previously published studies have already established a poorer prognosis in YA breast cancer patients as independent from other clinicopathological factors, such as tumour size, nodal status, histological grade, and hormone receptor status [
8,
18,
19]. However, these reports are relatively old, have smaller sample sizes, and patients may have been treated with a classical adjuvant chemotherapy and endocrine therapy regimen. Recently, some studies using large databases have also reported similarly poor prognostic outcomes in YA breast cancer patients after stratifying on multiple prognostic factors [
20‐
23]. Conversely, a single study has found that a young age at onset has no influence on the prognosis of individual breast cancer patients from a database of almost 3000 cases [
24]. Partridge et al. [
12] also reported no effect of age on breast cancer outcomes in patients with HER2-positive breast cancer from a large, randomised controlled trial. At the St Gallen International Expert Consensus meetings, a younger age at onset had been considered a high-risk factor from the 1990s to 2009. Later, a younger age at onset was no longer considered to be a poor prognostic factor and treatment strategies were recommended based on biological subtype or the concept of a ‘threshold for indication’ of each systemic treatment modality to be respected without a young age at onset [
25]. Then, YA patients were treated according to various predictive factors and the subtype of the tumour, including ER, PR, and HER2 status, proliferation markers, and TNM classification and a young age itself had no impact on the treatment strategy. Based on our findings and the results of several previously published reports of large cohorts [
20‐
23], YA breast cancer patients have a poor prognosis independent of other aggressive breast cancer features.
Another interesting finding was distinct recurrence pattern between ER-positive and -negative entities according to age at onset (Fig.
3). These differences between age at onset and ER status may lead to the distinct biological and molecular processes of age at onset by ER status. Research highlighting the genetic differences between YA and other breast cancer entities by ER status is lacking. Anders et al. [
11] reported that YA breast cancer represents a unique biological entity driven by unifying a higher probability of phosphoinositide 3-kinase and Myc pathway dysregulation. Investigating how high-risk genetic mutations affect age at onset, Ford et al. [
26] observed that 5.3 % of breast cancers in <40 year olds are attributable to
BRCA1 mutations compared 2.2 % and 1.1 % in 40- to 49-year olds and 50- to 70-year olds, respectively. It has been established that patients with
BRCA1 mutations are more likely to develop basal-like breast cancers, including the triple-negative subtype [
27,
28] [
29,
30]. Further research to elucidate the development of disease in this high-risk YA population and to determine the prognosis following a diagnosis of breast cancer is clearly warranted. An improved understanding of breast cancer genetics through molecular profiling may provide information that can be applied to patients with YA breast cancer.
Efficacy to adjuvant therapy in YA breast cancer patients remains controversial. Ahn et al. [
10] reported that the survival differences according to age in hormone receptor-positive breast cancer patients were significant in patients who received hormone therapy as well as those who did not. This suggests YA breast cancer patients may need another strategy of treatment instead of conventional adjuvant hormone and chemo therapy. A similarly insufficient efficacy to chemotherapy has also been reported. YA breast cancer patients treated with adjuvant cyclophosphamide, methotrexate, and fluorouracil are at a higher risk of relapse and death compared to older breast cancer patients [
31].
These distinct genetic patterns and clinical outcomes may lead to individual management of breast cancer patients. Previous studies reported significantly higher rates of local recurrence in YA patients who received BCT compared to OA patients who underwent a mastectomy [
32,
33]. Freedoman et al. [
34] reported that YA breast cancer patients were significantly more likely to have a mastectomy than BCT compared to older breast cancer patients. Efforts are required to confirm whether different types of surgery effect not only local recurrence rates but also OS rates. [
35].
This study had several limitations. First, the relatively short follow-up period (median 4.5 years), which limited the power of the survival analysis. Nevertheless, prognostic analyses from this database that have previously been published were relatively consistent with the well-known consensus and clinical outcomes [
36‐
38]. Second, during the study period, trastuzumab (which should exert a favourable effect on HER2-positive breast cancers) had not been widely prescribed as the standard agent and was only partially received. Third, we have no proliferation data, such as grade and genomic signatures. They are primarily prognostic and secondary predictive markers to chemotherapy response especially in ER-positive cases.
In conclusion, the present study confirmed that YA breast cancer patients have a poor prognosis independent of well-known clinicopathological prognostic factors. The different prognoses between YA, MA, and OA patients may require different screening algorithms, therapies, and follow-up. In order to establish an optimal strategy for YA breast cancer patients, further studies will need to be conducted.
Compliance with ethical standards