This large retrospective study showed the chemosensitivity of young patients aged < 35 years having ER-positive breast cancer with minimal endocrine effect. When other confounding factors were controlled, young patients were not found to respond to chemotherapy better than older patients in the ER-positive group. Although there was no change in odds ratio in the ER-negative group after adjustment, it was notable that odds ratio changed in the ER-positive group, albeit not statistically significantly. In other words, there was no difference of chemosensitivity beween young and older patients in ER-positive group while chemosensitivity of young patients was better than that of older pateints in ER-negative group. This suggests that benefit of chemotherapy in young patients with ER-positive breast cancers cannot be big, relatively.
Neoadjuvant chemotherapy is generally performed in patients with locally advanced breast cancers Physicians tend to give patients with advanced disease more aggressive treatment because of their high tumor burden and increased risk of recurrence and death.(17) In addition, as chemotherapy is considered more effective in younger patients with poor prognosis and shorter disease-free survival regardless of the type of treatment, tumor size, grade or progesterone receptor status, these patients are administered neoadjuvant chemotherapy for breast-conserving surgery or a lower threshold when determining chemotherapy.(1, 2, 18) A large study of patients aged < 50 years reported that among patients with lower risk disease, those who were not treated with adjuvant systemic therapy and were aged < 35 years had the worst prognosis. This age-related trend was not seen in high-risk patients with a greater number of metastatic nodes or a larger primary tumor size.They suggested that young women with breast cancer should be regarded as high risk patients and be given adjuvant cytotoxic treatment on the basis of age alone.(9) This recommendation is under the assumption that young patients would respond better to cytotoxic treatment even in lower risk disease.(19) However, steroid hormone status was not considered in this analysis.(9)
The association of young age with response to chemotherapy has not been clearly defined, particularly according to ER status.(20) In this study, young age was not an independent predictor of response to chemotherapy in ER-positive tumors. Patient age of < 35 years was found to be associated with pCR in ER-negative tumors but not in ER-positive tumors. Better response to chemotherapy was related to aggressiveness of tumors in ER-positive breast cancers. High proliferative index was an independent factor only in ER-positive tumors. Therefore, in ER-positive tumors, it is hard to expect that complete pathologic response would be achieved in low proliferative tumors, even though they developed in young patients. Conversely, Early Breast Cancer Trialists’ Collaborative Group reported that adding adjuvant polychemotherapy to tamoxifen was associated with 7.6% of 5-year survival gain in patients aged < 50 years with ER-positive tumors.(21) The survival benefit of chemotherapy in young patients was greater than in older patients. However, because survival benefit may not come from a cytotoxic effect of chemotherapy and the criteria for age were different, response to polychemotherapy in young women cannot be interpreted clearly. Furthermore as tamoxifen is the only endocrine therapy, the endocrine effect of chemotherapy would play an important role in benefit of chemotherapy for patients less than 50 years with ER-positive tumors as in most other studies.
The evidence of the benefit of adding chemotherapy to endocrine therapy in hormone-responsive breast cancer of young women is not strong.(22, 23) A pooled analysis of patients aged ≤ 40 years enrolled in EORTC trials showed that prolonged adjuvant CMF chemotherapy did not bring survival advantage to hormone receptor-positive patients compared with hormone receptor-negative patients.(23) Several studies suggest very good prognosis with optimal endocrine therapy alone, particularly in low-risk young patients.(24) Treatment advances with endocrine agents, such as ovarian function suppression or aromatase inhibitor, to overcome resistance to endocrine therapy in young breast cancer patients could improve patient outcomes without chemotherapy in young women with ER-positive breast cancers.(25, 26) Improvement of outcome in these patients is attributed to the endocrine effect. Particularly in ER-positive early breast cancer, the role of chemotherapy can be limited to endocrine effect, not cytotoxic effect. A STEPP analysis for patients with ER-positive tumors who received dose-intensive epirubicin and cyclophosphamide suggested a correlation between the achievement of ovarian function suppression and efficacy of chemotherapy despite no interaction of age and chemotherapy.(27)
The bigger reason for the less benefit in these patients may be that ER-positive breast tumors resist chemotherapy. This study showed that the effect of ER status was greater than the effect of age. Some reports explain that the lower frequency of receptor positivity in premenopausal women may account for their increased response to cytotoxic chemotherapy.(28) Low response to chemotherapy of ER-positive breast cancers can counteract the effect of age. Even in palliative setting, endocrine treatment is recommended first in ER-positive breast cancer patients without visceral crisis. In addition, resistance to chemotherapy of estrogen receptor-positive breast tumors can be explained by biologic factors. Cancer stem cells in the ER-positive cells escape the effect of doxorubicin treatment by the elevation of p53 expression.(29) More tumors in young women had abnormal expression of p53.(4)
Predictive value for response to chemotherapy of young agein ER-positive breast cancers should be considered differently from that in ER-negative breast cancers. Most studies have focused on the endocrine effect of chemotherapy regarding the prognosis of young patients with ER-positive tumors. Although indirectly, this study shows the cytotoxic effect of chemotherapy in young patients with ER-positive tumors while excluding the endocrine effects as much as possible. Age was an important predictor of pCR in ER-negative tumors but not in ER-positive tumors in this study. In previous studies, it has been reported that young breast cancer patients had better response to chemotherapy than older breast cancer patients.(30) However, this result does not take ER status into consideration even though the proportion of ER-positive tumors was significantly different between both groups. A recent German study by Loibl et al. also reported that pCR was significantly higher following neoadjuvant treatment in patients aged < 35 years than in those aged over 35 years, and the outcomes were similar only for the triple-negative breast cancer subtype. The conventional perception that young women respond better to chemotherapy needs to be accepted as limited to ER-negative breast cancers.
In ER-positive tumors, the effect of endocrine therapy following adjuvant chemotherapy makes it difficult to determine the cytotoxic effect of chemotherapy only on the outcome unclear in an adjuvant setting. Conversely, in a neoadjuvant setting, low rate of complete response to neoadjuvant chemotherapy may suggest resistance to chemotherapy because neoadjuvant chemotherapy is an in vivo measure of chemosensitivity.(31) However, chemotherapy inevitably has an endocrine effect, and response to chemotherapy may have less impact on prognosis relatively in ER-positive tumors when compared to ER-negative tumors. This may be a cause of a weak relationship between pCR and outcome of ER-positive tumors when it is compared to ER-negative tumors.
In this study, there are some limitations because it is a retrospective cohort study using multicenter database. Even though TNM stage at diagnosis was recorded, the exact tumor size or axillary lymph node status before neoadjuvant chemotherapy was uncertain. Some patients did not receive fine needle aspiration or sentinel lymph node biopsy for axillary lymph nodes. Therefore, only patients with pathologic complete response were included. In addition, pCR indicates high tumor chemosensitivity and is a meaningful factor to investigate the relationship between response to chemotherapy and disease outcome.(32) In addition, the neoadjuvant chemotherapy regimen including trastuzumab administration was not the standard treatment during the study period. For HER2-positive tumors, this study does not reflect the current treatment.
In an adjuvant setting, only the cytotoxic effect of chemotherapy could not be compared between young and older patients with ER-positive tumors due to the effect of adjuvant endocrine therapy. Therefore, despite these limitations, this study suggests that young age alone is not an immediate factor in determining a chemotherapy escalation or neoadjuvant chemotherapy in ER-positive breast cancers. If other predictive factors for response to chemotherapy are not found, even increasing breast-conserving rate after neoadjuvant chemotherapy may be hard to expect As in ER-positive breast cancers, response to neoadjuvant chemotherapy was not correlated with long-term outcomes, and poor response to chemotherapy based on pCR would not mean survival benefit of chemotherapy.(33)