In the present study, conducted in a predominantly Asian population, we demonstrate the presence of a double-peaked mortality hazard pattern among women treated with mastectomy alone. This double-peaked pattern is observed in the various patient subgroups regardless of hormone receptor status, menopausal status, node status, or T stage; this hints at a true biological phenomenon, as opposed to distinct patient subsets accounting for the separate peaks.

Confining our attention to patients of Chinese origin, we were able to confirm the presence of a double peak but, compared with the data reported by Demicheli and coworkers 5, these peaks occurred at slightly different timings (2.5 and 9.0 years, with corresponding peak hazards of 0.041 and 0.059; Figure 3a). We further verified that double peaks were more prominent in those women with positive nodes and more advanced stage. In addition, although not reported in the Milanese data 5, a double-peak was also found to be present in those with ER-negative tumours.

Our findings are also consistent with those observed in other published reports 5678910 and our study is, to the best of our knowledge, the only one to date that confirms such findings in a non-Caucasian population.

A second important finding was the absence of any double-peaked mortality hazard pattern in women who received adjuvant systemic therapy (with or without radiotherapy; Figures 2f and 3f). In contrast, the double-peak pattern was evident in women who received local therapy (Figures 2e and 3e). This difference may be attributed to the fact that patients in these two groups were biologically distinct, with a larger proportion of women having nodal positivity and higher tumour grade in the combined modality group compared with the mastectomy alone group or radiotherapy alone group. The absence of a double peak in the combined modality arm could also reflect the impact of adjuvant therapy on the natural history of the disease. For example, Demicheli and coworkers 16 found a single peak in the recurrence hazard (which is limited to the first 4 years) in patients with node-positive breast cancer receiving adjuvant treatment (cyclophosphamide, methotrexate and 5-fluorouracil) as compared with a double peak in the control arm (in which patients underwent no further treatment after mastectomy). Saphner and coworkers 17 examined the recurrence hazard of 3,585 women with early breast cancer entered into seven Eastern Cooperative Oncology Group adjuvant trials and demonstrated essentially single-peaked hazard patterns.

It has been shown that mortality risk is associated with menopausal status 5. In the Milan series, node-positive premenopausal patients exhibited an initial mortality wave covering about 6 years, with a maximum at year 4, followed by a second peak 8 years after surgery; postmenopausal patients, however, exhibited an early high mortality surge peaking at year 3, followed by a modest increase at 8 years. In contrast, we found only a weakly discernable double-peak among the premenopausal and postmenopausal Chinese patients (Figure 4e,f). Part of this may be due to the greater heterogeneity of the Singaporean patients, who were from a population cohort; this contrasts with the Milan series of patients, who were recruited in controlled clinical trials that would have applied carefully defined eligibility criteria.

Patterns among the four broad treatment groups in those of Malay and Indian origin suggest a peak hazard at about 2 years, but this should not be overstated because patient numbers are relatively small in these groups (Table 1, and Figures 5 and 6).

The study has some limitations because we did not have access to recurrence data and were therefore unable to study the association between relapse and mortality hazards. In addition, 70% of women in the mastectomy alone group did receive adjuvant tamoxifen, which is regarded as a form of systemic therapy. However, excluding these patients from the analysis, a double-peak mortality hazard pattern remains (data not shown).

The kernel method of smoothing allows one to conduct a more detailed examination of the changing hazard as compared with the 'annual-bin' method utilized by, for example, Demicheli and coworkers (Figure 1 in that report 5) and our Figure 2. However, the kernel method of smoothing also involves a degree of subjectivity, so that the relatively minor differences in peak times noted may only reflect chance variations (or differences in statistical methodology) and not systematic differences between Singaporean and Italian women. The smoothed and nonsmoothed estimates become less reliable as postsurgery follow-up time increases and the number of observed deaths declines. The follow up of the Singaporean women continues, and patterns at 10 years after surgery and beyond will be examined in due course.

In conclusion, we confirm the validity of findings of earlier reports from Milan and elsewhere in some 2,105 South East Asian women, mainly of Chinese ethnicity, who underwent mastectomy for unilateral breast cancer. The risks close to the identified double peaks suggest a hazard that is often double that of the mean hazard for the particular treatment group over time. We therefore provide further evidence for the view presented by Demicheli and coworkers 3 that a double-peak pattern in the hazard function reflects an acceleration in growth of metastases caused by primary tumour removal and activation of dormant sites of micrometastases years after initial treatment. The presence of this phenomenon serves as a reminder of the need for prolonged follow up and surveillance in breast cancer survivors, and suggests that extended or novel antiangiogenic adjuvant therapy may confer benefit in selected patients. Only long-term follow-up research will be able to establish whether newer generation therapies can change the nature history of treated breast cancer and eliminate the second peak.

ER = oestrogen receptor; PR = progesterone receptor.

The authors declare that they have no competing interests.

All authors were involved in the analysis of the study as well as in the preparation of the manuscript. All authors read and approved the final manuscript.