In the SGBCC population comprising 1,014 chemotherapy–treated breast cancer patients, the incidence rate of FN was 16.7%. Notably, patients of non–Chinese ethnicity had higher FN incidence. The ethnic disparity was also seen in an independent the JBCR hospital–register–based population of 7,449 chemotherapy–treated breast cancer patients, where 13% of patients experienced FN episodes. In JBCR, non–Chinese were estimated to be at 1.5 times elevated risk of developing chemotherapy–induced FN. Patients of non–Chinese ethnicity also more frequently experienced multiple FN episodes. Other significant factors associated with FN include age at diagnosis, anthracycline–containing regimens, and the absence of additional treatments. While exploring differences across ethnicities, we found that Malays and Indians were more likely to be diagnosed at a later stage. These two groups were also less likely to undergo additional treatments, more likely to be prescribed with an anthracycline–containing regimen, and experienced greater dips in ANC during chemotherapy, which may contribute to the elevated FN risk. However, the ethnic disparity remained even after significantly associated patient, tumour and treatment characteristics were adjusted for.
Previously reported patient–specific FN risk factors among Asian breast cancer patients include low BMI (BMI < 23kg/m2), low baseline white blood cell count and low ANC(18–20). In addition, age, poor performance status, and particular genetic variants have all been linked to elevated FN risk(20). Similarly, our study showed that age and low baseline ANC were risk factors for FN.
Our study observed that anthracycline–containing regimens placed patients at higher risk for FN. However, this trend differs from what is commonly observed, where studies have shown that a taxane–based regimen contributes to higher FN incidence(21–23). It should be noted that most of these studies focused on Caucasian populations, which may explain the differences in toxicities observed when compared to our Asian population. A Nigerian study comprising 113 breast cancer patients reported the lack of a significant relationship between taxane–based regimen and FN risk(24). The authors attributed this finding to the fact that the majority of the patients were first started on anthracycline–based treatments, but 36% were later switched to a taxane–based regimen(24). By chemotherapy regimen in Chen et al’s study in Singapore, FN incidence observed in those treated with anthracycline– and taxane–based drugs were 15.0% and 11.7%, respectively(25), which concurs with our finding. Additionally, our study also found that compared to patients who received a combination of only anthracyclines and cyclophosphamides, those who received taxanes, anthracyclines, and cyclophosphamides were at lower risk for FN, even though this association was not significant. In agreement, a meta–analysis of 15 randomized trials by Zheng et al reported that combined cytotoxic regimens led to significantly fewer FN events than single agents(26).
Ethnicity has been suggested to be associated with FN incidence previously (6–9, 11, 12). Ethnic variance in treatment toxicity is widely acknowledged as a key element explaining inter–individual variation in cancer treatment responsiveness(13). East Asians have been reported to be particularly susceptible to toxic side effects of chemotherapy than their Caucasian counterparts, requiring dose–reduction in many studies(13). In an earlier work by Chen et al on 583 Asian cancer patients in Singapore, it was reported that FN incidence in Chinese, Malay and Indian patients were 15.6%, 24.5%, and 25%, respectively(25). In agreement, the results from our study showed that both Malay and Indian patients were at higher risk of FN, where FN incidence in Chinese, Malay and Indian patients were 12.3%, 14.6%, and 18.1% respectively.
In local clinical practice, patients diagnosed with locally advanced disease are prescribed with anthracycline in combination with taxanes while those with early–stage disease are given taxanes only. Similarly, the Malay patients in our group were observed to be diagnosed at a higher stage and were more likely to be given anthracycline in addition to taxanes, which can possibly explain their greater FN risk. However, even after accounting for significantly–associated patient, tumour, and treatment factors, the disparity between the effect of chemotherapy on FN risk persisted across ethnicities, indicating the possibility that other unidentified contributors exist. In our study, we found that Indian patients experienced larger dips in ANC during chemotherapy, which prompts further investigation in this area. Furthermore, inter–individual and ethnic differences in how docetaxel and doxorubicin are metabolized, as well as interethnic disparities in docetaxel– and doxorubicin–induced myelosuppression, have shown to impact the results of treatment(10, 27, 28). Additionally, previous studies have shown that patients with comorbidities, such as renal and liver diseases, were at higher risk of systemic toxicities, such as FN(25, 29). This, combined with the widely observed trend that Malays and Indians are more likely to suffer from chronic conditions(30–32), can possibly explain the higher FN incidence experienced. However, data on comorbidities were not properly collected for this study, which limited further investigation in this area.
This study found a consistent ethnic disparity in chemotherapy–induced FN in two large datasets comprising Chinese, Malay and Indian breast cancer patients. However, several limitations should be noted. Due to the retrospective design of this study, selection bias cannot be eliminated. Another limitation is the incompleteness of clinical records, such as detailed information on comorbidities and chemotherapy regimens. Importantly, commonly studied outcomes such as FN incidence during each cycle, or FN risk due to differences in regimen dosage were unable to be studied due to the lack of information on the chemotherapy cycle or complete regimen details.
In summary, the results of this study suggest that there are ethnic differences in the risk of chemotherapy–induced FN. Additional research is needed to investigate the possibility of pharmacogenetic differences across these ethnicities. Further studies can also explore differences in the effects of FN across ethnicities, such as the reduction in relative dose intensity or delays in chemotherapy schedules, as well as survival outcomes.