Pathological profiles and clinical management challenges of breast cancer emerging in young women in Indonesia: a hospital-based study

Breast cancer has emerged as the most diagnosed cancer and the leading cause of cancer-related mortality among women worldwide [1]. More than 2 million females are diagnosed each year with annual mortality over 600,000 [1]. In Indonesia, the total incidence of breast cancer in 2014 was ~ 50,000 and annual mortality was ~ 20,000 [2]. In general, the incidence of breast cancer in young women is relatively low worldwide. Median age at diagnosis is 68 years in developed nations [3, 4], while in Indonesia median age at diagnosis is ~ 48 years-old including more than 5000 women under 40 years who are annually diagnosed with breast cancer [2].

Young age is associated with worse prognosis in breast cancer [5, 6] which may be partly explained by different biological mechanisms in young patients. Young breast cancers (YBCs) exhibit more aggressive characteristics [7] including higher rates of mitotic index, poor tumor differentiation, triple-negative subtype, with higher propensity for relapse and distant metastasis [6, 7]. In low and middle-income countries (LMIC) including Indonesia, a delayed presentation may additionally play a role as there is a lack of population-based screening programs [8]. There is also low cancer awareness in Indonesian women, particularly those with lower household expenditure and education levels, which may contribute to a delayed diagnosis of breast cancer including among young women [8]. Specific considerations in comprehensive cancer care, surveillance plans, adherence to adjuvant therapy as well as management of side effects in YBC patients are required to achieve optimal therapeutic and long-term outcome results. However, little is known regarding the clinical characteristics associated with prognosis of young women with breast cancer in Indonesia, which could be used to better inform strategies to improve care for these patients.

To gain further understanding regarding young women with breast cancer in Indonesia, in this study we presented baseline clinicopathological factors and treatment choice and prognosis of YBC patients in a tertiary referral hospital-based case series in Indonesia. We also assessed the relationship between these factors and progression free survival (PFS) then discussed these findings in relation to other determining factors and made recommendations to improve clinical management of young patients with breast cancer in Indonesia.

The proportion of YBCs in our study (11.4%) was twice as high as the frequency in the US and Europe (5–7%) [13, 14]. This finding supports earlier data suggesting lower age at diagnosis in Indonesia than those countries [2]. The reason for these differences is not clear. Biologically, YBCs in our study showed aggressive phenotypes with relatively high proportion of large tumor size, lymph node involvement, advanced and metastatic diseases, high histology grade, angiolymphatic invasion, Her-2 positivity, TNBC subtype, as well as frequent progression and relapse during follow-up (Table 2) in accordance with previous studies [6, 15‐17]. In a large prospective study (N = 2956) investigating factors related to poor prognosis in YBCs, 50% subjects were lymph node positive, 30% were hormone receptor negative, 20% patients were TNBC subtype, and 60% had histologically poor differentiation [18].

Breast-conserving surgery (BCS) and sentinel node biopsy followed by breast radiation are recommended for YBCs [19]. Only 5% of our patient cohorts were assigned for BCS for the reason of high proportion of advanced stages and the long waiting list for radiotherapy. In addition, cosmetic consideration, immediate breast reconstruction surgery, and impact on body image and sexuality should be offered to YBCs [19]. In advanced cancer, however, radical surgery is preferred to achieve locoregional control and reduce relapse.

Around 88 and 70% of YBCs in this study completed chemotherapy and radiotherapy, respectively. Hormonal therapy was delivered in 84% of patients with hormone receptor positive. No specific chemotherapeutic regiment is recommended for YBCs and regiments are usually assigned according to IHC-subtyping [19]. Recent trials using multigene assays suggest that ER-positive and premenopausal early-stage breast cancer (node negative) with low recurrence score might not require chemotherapy [20, 21]. The trials included YBCs (3.5 and 2% in TAILORx and MINDACT, respectively) [20, 21] although application of multigene tests is still far from a practice routine in LMICs including Indonesia. However, the most important challenge in Indonesia is to diagnose young women in the early stages (T1-T2, node negative). Hormonal therapy is recommended in premenopausal women with hormonal-receptor positive (≥1% cell positive for ER or PR) although patients with ≥10% cell positive are the most responsive to adjuvant hormonal therapy [22]. Radiotherapy with the addition of regional nodal irradiation (RNI) is correlated with better PFS and stronger effect is found in patients with ER-negative which is more common in YBCs [23]. Despite following general recommendations for treatment of young breast cancer, the frequency of disease progression in our cohort is relatively high (24%). We also found a high proportion of patients who did not receive chemotherapy and radiotherapy. Factors associated with barriers to treatment (surgery, chemotherapy, and radiation) as well as to therapy adherence in YBCs require further study [24]. In addition to the aggressive biology of YBCs, advanced stages at diagnosis contribute to the frequent relapse and unfavorable PFS (Fig. 1 section A). The majority of YBC patients were living in a rural residence with low education levels which might contribute to the late presentation for medical treatment although our study indicated that those factors were not associated with barriers to receive chemotherapy and radiotherapy. Our previous study showed relatively low breast cancer awareness among Indonesian women particularly those with low social economic status and low education levels [8]. Misunderstanding about breast cancer and the benefits of early detection might also hamper health-seeking attitudes.

More than 13% of patients in our study developed bilateral breast cancer and 7.6% with positive family history implicating the increased genetic risk in YBCs. However, genetic service, in general, is not available in most LMICs including in Indonesia. One previous study suggested that genetic counseling and understanding of personal genetic risk is associated with distress reduction and improvement of patient’s wellbeing [25]. YBC patients also need particular attention regarding psychosocial factors and fertility concern [26, 27]which were not yet adequately addressed in our clinics. Identification of unmet psychosocial needs and appropriate interventions are important to promote psychological acceptance to the disease [26, 28, 29]. In addition, advanced cancers also are associated with increasing cancer-related disability and poor functioning which require rehabilitation to improve quality of life. However, we previously reported that cancer rehabilitation is also either not available or sub-optimally delivered in developing countries [30, 31].

This present study appears as the first in a series focusing on the clinicopathological profile, treatment choice, and prognosis in Indonesian YBCs. A limitation in this study was that we only included breast cancer patients who were treated in the Department of Surgery, thereby our data may have not included terminally ill patients for whom any surgery was not indicated. This may have resulted in an underestimation of disease progression in our study. A population-based study is, therefore, necessary to replicate our findings in a wider population. Additionally, the hospital is a tertiary referral hospital that treats more complex and advanced stage cancers because a vertical referral system has been implemented in the national health insurance [32]. More collaborative studies are required since the nation-wide cancer registry in Indonesia is not yet comprehensively available [33] to record all YBCs, demographic data, pathological profiles, and survival rates.

There was a higher proportion of YBC compared to the rates in developed countries. Identification of both biological and clinical factors associated with effective treatment and prognosis are essential to improve YBC patients’ outcome and well-being. Several challenges in managing YBCs in Indonesia are a late presentation at diagnosis, frequent relapse and poor survivals, and aggressive type of cancer, with high rates of non-adherence to adjuvant chemotherapy and radiotherapy which may be addressed through further research.