Our population-based cohort study showed that patients with a breast FPC diagnosed with an SPC had a higher hazard of death of 1.5-fold for synchronous SPCs and almost three-fold for metachronous SPCs compared with patients with a breast FPC only. The sites with higher HRs were similar for synchronous and metachronous SPCs, namely lung, stomach, breast, non-Hodgkin lymphoma, liver, genital, and colon and rectum. Overall, the cumulative mortality estimates were higher for patients with a synchronous or metachronous SPC compared to patients with a breast FPC only.

Previous research has described a higher mortality among patients with an SPC compared to patients with a breast FPC only [11,12,13,14]. Deng and colleagues published data from a large cohort including over 60 thousand women with breast cancer from the USA, using the Surveillance, Epidemiology, and End Results, diagnosed between 2000 to 2016, with an average follow-up time of 42 months [14]. They found that patients with any SPC diagnosed more than six months after the FPC had an HR of death of 1.18 compared to patients with a breast cancer only. The SPC sites with higher HRs were breast, lung, colon, rectum, uterus, lymphoma, melanoma, thyroid, and leukemia [14], which is in line with our findings. Their 15-year cumulative mortality estimates were 67.5% for patients with an SPC and 60.4% for patients with an FPC only [14]. Many previous studies have considered breast cancer as the FPC and/or SPC [12, 13, 26]. A systematic review by Pan and colleagues included 15 relevant studies, with patients with unilateral breast cancer only and patients with bilateral breast cancer. They compared the HRs of death among those with a unilateral breast cancer and a bilateral breast cancer, combining different definitions for synchronous and a metachronous within three, six and 12 months as the cut-off time. Compared to patients with a unilateral breast cancer only, they estimated an HR of 1.68 for bilateral breast cancer, 2.01 for synchronous breast SPC and 3.22 for a metachronous breast SPC [12]. Using data from the Danish Breast Cancer Cooperative Group database, Langballe and colleagues studied nearly 70 thousand women with breast cancer diagnosed between 1978 and 2012, and followed until 2015 for cancer-specific death. Compared to patients with a unilateral breast FPC, those with a bilateral breast cancer had a two-fold higher hazard of death [13].

We found that patients with synchronous and metachronous SPCs both have a higher mortality compared to patients with a breast FPC only, though mortality was lower among those with synchronous SPCs. Patients diagnosed with synchronous SPCs may be under closer medical monitoring due to their breast FPC being more recently diagnosed. Consequently, there is a possibility that a subsequent SPC is detected at an earlier stage and given the closer medical surveillance, prompt initiation of treatment may contribute to their lower mortality compared to those with metachronous SPCs. Conversely, patients diagnosed with metachronous SPCs might be detected at later stages or be associated with more aggressive tumor characteristics, resulting in an even worse prognosis among these patients. A previous systematic review described above by Pan and colleagues estimated higher HR for synchronous breast SPC and metachronous breast SPC compared to patients with a unilateral breast cancer only [12]. Moreover, a study by Pacheco-Figueiredo and colleagues reported that the survival of patients with metachronous SPCs may be more influenced by the site of the SPC whereas in patients with synchronous SPCs, survival varied considering the site of the FPC [18]. In the current study, we may hypothesize that the breast FPC is contributing to the higher survival observed among patients with a synchronous SPC.

Our data was collected from a population-based registry, RORENO, which is highly representative of patients with breast cancer from Northern Portugal. It has a large catchment area, integrating public and private institutions involved in the diagnosis and care of patients with cancer; and has a long-term and complete follow-up with only 1% losses identified. Furthermore, we provide sensitivity analyses considering the cut-off for defining synchronous and metachronous SPCs at two and six months. However, some limitations should be discussed. Patients were followed for the occurrence of an SPC until 2015, which was the maximum data available from RORENO at the time of the study. This allowed a minimum follow-up of five years and a maximum follow-up of 15 years. Although we would likely have a larger number of patients with metachronous SPCs if there was a longer follow-up to identify multiple primary cancers, we do not believe that the results of our study would be any different. In the present work, we are assuming, that all other causes of death, besides cancer related death, influence the survival of patients with an FPC only or an FPC + SPC in a similar manner. However, HRs will inherently be influenced by the timing of SPC diagnoses relative to the FPC, while synchronous SPCs occur almost concurrently with the FPC. Nevertheless, our study considers the FPC and SPC by calculating survival time for all patients from the moment the SPC is diagnosed, irrespective of whether they had an SPC or not, to ensure that patients with FPCs only have at least the same duration of survival until the occurrence of the SPC of the matched patient. This is necessary because the effect measures will be influenced by the SPC time from the first primary to the second primary. Some site-specific HRs may lack the statistical power needed for robust interpretation on an individual basis, particularly for SPCs with small sample sizes or low event rates, these estimates should be interpreted with caution. Information on clinical data that could influence the prognosis of patients with a breast cancer was not available, namely stage at FPC and SPC diagnosis, hormonal receptor status of the tumor, treatment regime, as well as menopausal status, family history or genetic susceptibility. Previous studies have shown that lifestyle risk factors, such as obesity, tobacco, treatment side-effects, or even modified standard therapy may impact the survival of patients with multiple cancers [12, 14, 23, 27].

This is the first comprehensive analysis in Northern Portugal evaluating the impact of breast cancer, which is the most incident cancer worldwide and in Portugal, on SPC survivorship. We found patients with an SPC following a breast FPC have a higher mortality than those with a breast FPC only and mortality was higher for those with a metachronous SPC. Lung, stomach, breast, non-Hodgkin lymphoma, liver, genital, and colon and rectum were SPC sites with the worst prognosis. These findings highlight the need for surveillance of patients with a breast cancer and management of the expectations of these patients.