Studying the association between breast cancer and renal cell carcinoma

There are case reports of patients with both primary breast cancer (BC) and renal cell carcinoma (RCC). We explore the association between these two malignancies using SEER population data and our institutional records. We studied the association between BC and RCC in the 2000–2016 Surveillance, Epidemiology, and End Results (SEER) database. We then reviewed our hospital records of patients with both BC and RCC and collected information including personal and family history of cancers, genetic testing, and patient outcomes. Of the 813,477 females diagnosed with BC in the SEER database, 1914 later developed RCC. The risk of developing RCC was significantly increased within the first 6 months, 7–12 months, and 1–5 years following BC diagnosis with standardized incidence ratios (SIRs) of 5.08 (95% CI 4.62–5.57), 2.09 (95% CI 1.8–2.42), and 1.15 (95% CI 1.06–1.24), respectively. Of 56,200 females with RCC, 1087 later developed BC. The risk of developing BC following RCC was elevated within the first 6 months (SIR of 1.45 [95% CI 1.20–1.73]). For our hospital patients, 437 had both BC and RCC. 427 (97.71%) were female, and 358 (81.92%) were white, and breast cancer was diagnosed before RCC in 246 (56.3%) patients. There were 15 germline mutations in those with genetic testing. Our findings suggest that BC patients are at higher risk of developing RCC and vice versa. BC tended to precede RCC, and patients frequently had personal histories of other malignancies and a family history of cancer, particularly, BC.


Introduction
Several cancers are known to be associated with one another, usually due to having common risk factors. Classic examples of such risk factors include mutations in genes such as BRCA that increase the risk of breast cancers and ovarian cancers [1], as well as smoking and alcohol intake that are associated with increased risk of both lung and head-andneck cancers [2]. Additionally, patients who have undergone chemotherapy with specific agents are at higher risk for future cancers such as leukemia [3].
There are several case reports describing patients with both primary RCC and malignant breast neoplasms [4][5][6][7][8][9]. It is estimated that in the US 281,550 women and 2650 men will be diagnosed with BC in 2021 [10]. Furthermore, an expected 43,600 women and 530 men will die in the US due to BC in 2021. The American Cancer Society also estimates that there will be approximately 76,080 new cases of renal cancer in the US resulting in 13,780 deaths.
Aside from a handful of case reports, studies elaborating on the phenomenon of patients with both primary breast and renal cancer are very limited. In a study by Beislan et al. assessing 1425 patients with RCC, 26 (1.8%) had a history of breast cancer as well [11]. Another study by Demir et al. with 1129 cases of RCC had 13 patients (1.15%) with BC [12]. These data prompted us to evaluate the potential association between BC and RCC. We started by conducting a population analysis using the Surveillance, Epidemiology, and End Results (SEER) database, then we reviewed our hospital records to explore the population of patients with both breast cancer and RCC.

Data source
We obtained data from the Surveillance, Epidemiology, and End Results (SEER) database of the US National Cancer Institute, using the SEER * stat software (version 8.3.5). We used the SEER 18 registries (2017 submission) covering about 27.8% (based on the 2010 census) of the US population between 2000 and 2017 [13,14].

Study population
We reviewed patients diagnosed with BC between 2000 and 2016 and followed them for a later RCC diagnosis, and then reviewed patients diagnosed with RCC in the same time frame and followed them for a later diagnosis of BC. We only included cases with histologic confirmation. In order to eliminate the possibility of an incorrect order of cancer onset, we excluded cases with RCC diagnosed less than 2 months from the initial BC diagnosis and vice versa.

Outcomes
We calculated the Standardized Incidence Ratios (SIR) of RCC following BC diagnosis and the SIR of BC following RCC diagnosis. The 'Observed' value represents the number of the second BC or RCC cancer cases diagnosed after the initial BC or RCC diagnosis, while the 'Expected' value represents the number of BC or RCC cases expected to be diagnosed in a demographically similar population within the same period. The SIR represents the change in RCC risk following BC diagnosis and vice versa compared to the general US population.

Statistical analysis
We used the Multiple Primary SIR session of the SEER * stat software (version 8.3.5) to calculate the standardized incidence ratios (SIR) with 95% confidence intervals (CI). A significant positive increase in the risk of BC/RCC was defined as the number of observed BC/ RCC cases being more than the number of expected BC/ RCC cases in the general population. The SIR analyses were adjusted for age, sex, race, and year of diagnosis. The patient baseline characteristics and demographics were compared, categorical variables were compared with the Mantel-Haenszel chi-square test, and continuous variables were compared with student t test if normally distributed and expressed as means or by the analysis of variance testing and expressed as medians if not normally distributed. Statistical analyses were conducted using RStudio software (RStudio, Boston, Massachusetts) or SPSS software, version 26 (IBM SPSS Statistics, IBM, Armonk, New York) [15, 16] A 2-sided value of p < 0.05 was set for statistical significance.

Hospital patient population analysis methods
IRB approval was obtained via our institutional IRB review committee, and informed consent was waived as this was a retrospective study. We used various ICD diagnoses for breast cancer (e.g., primary breast adenocarcinoma-C50.919, personal history of breast cancer-Z85.3) and renal cancer (e.g., kidney neoplasm-D49.519, renal cell carcinoma-C64.9) to search our Epic © patient database for all patients who combined a diagnostic label of breast cancer and renal cancer. For a comprehensive search, we used 5143 breast labels and 1414 renal labels.
We then chart reviewed the patients and excluded those who did not have both a malignant BC and RCC. Patients with carcinoma-in-situ were included in our sample of patients. Data collected for each patient included their age, gender, personal and family history of cancers, age at cancer diagnoses, histologic subtypes of their BC and RCC, tumor markers, cancer stages at diagnosis, genetic testing done, interventions for breast and renal cancer, and patient outcomes. Patient characteristics were summarized in median for continuous variables, and in frequencies and percentages for categorical variables. Outcomes were labeled as progression, partial response, or complete remission based on RECIST criteria [17]. If a patient developed progression at any point their outcome was labeled as progression. Patients who were cancer-free for 10 years or more were labeled as cured.
On the other hand, during the same period, of 56,200 females with RCC, a total of 1087 later developed BC (patient characteristics in Table 2), of which 121 (11.13%)  Table 3). There were 15 confirmed germline mutations/variants of uncertain significance in the patients who underwent genetic testing (Table 4), the most common of which was BRCA1/2 (present in 5 patients).
The most common identified BC stages at diagnosis for these patients was stage IA (16.93%) and stage IIA (11.9%) ( Table 5a), but the stage at diagnosis was unavailable for > 56% of the patients. Invasive ductal carcinoma was the most common pathological subtype identified. Regarding treatment, 89.47% underwent a surgical intervention such as a lumpectomy or mastectomy, 45.77% received radiation therapy, 31.81% received chemotherapy, and 38.9% got anti-estrogen or anti-HER2 agents. More than a third of the patients (39.58%) were determined to have been cured of their breast cancer (either by being disease-free for > 10 years or by documentation from their oncologist), and 16.71% were in remission (Table 5a).

Fig. 1 A Standardized incidence ratio (SIR) of RCC diagnosis after being diagnosed with BC. B SIR of BC diagnosis after being diagnosed with RCC
As for RCC, the most common confirmed stage at diagnosis was stage I disease (34.78%) but the stage was unknown in 48.28% of cases, and clear cell carcinoma represented 45.54% of cases followed by papillary cell carcinoma (7.55%) and chromophobe cell tumors (4.12%) (Table 5b). More than 90% of the patients underwent a surgical intervention (e.g., complete or partial nephrectomy), 38.92% were cured of RCC, and 14.87% were in remission following therapy. At the time of our data collection, 92 (21.05%) of the patients studied were deceased (Table 3). RCC was the most common identified cause of death (20.65%), and BC accounted for 10.87% of the deaths.

Discussion
To our knowledge, this study has the largest scale of both national data and institutional records showing an association between BC and RC. We analyzed the data of more than 3000 US patients via SEER and 437 patients treated our facility who had a history of both BC and RCC. Based on SEER population analysis results, patients with BC are at a higher risk of being diagnosed with RCC within 5 years of their BC diagnosis after adjusting for age, sex, race, and year of diagnosis, and the risk is highest within the first 6 months. Conversely, RCC patients are also at a higher risk of being diagnosed with BC within 6 months of their RCC diagnosis, but this risk is lower. Notably, these cases occurring within 6 months of each other would be classified as synchronous cancers.
It is unclear why such an association exists. One theory is that RCC cases are being detected incidentally due to imaging done for patients with high-risk BC who undergo indicated staging workup, which may explain why there is a higher chance of being diagnosed with RCC within the first 6 months following a BC diagnosis. However, this does not account for why there is such an increased number of RCC cases among BC patients. This points to a patient population that is predisposed to both BC and RCC, potentially due to similar risk factors, and possibly due to a common underlying genetic mutation. The fact that the risk declines with time indicates that the development of the second cancer is less likely due to a specific treatment modality of the initial malignancy. Our exploration of internal records of patients with BC and RCC showed a population that was predominantly female and white, and that the diagnosis of BC tended to precede that of RCC. Patients frequently had personal histories of other malignancies and a family history of cancer, particularly, BC. A small number of patients had germline genetic testing from which we identified 15 mutations/ variants of uncertain significance, the most common of which was BRCA1/2. Of note, there are other mutations that can predispose to both breast cancer and renal cancer such as the CHEK2 variant [18], but these were not tested for in our patients.
The implications of our findings are of particular importance to healthcare providers managing patients with either BC or RCC. More than half of patients with RCC are asymptomatic and are diagnosed incidentally. When patients do present, they can have gross hematuria, flank pain, and a palpable abdominal mass [19]. Oncologists managing breast cancer patients can consider screening for these symptoms and be on the lookout for palpable renal masses during their exam. Likewise, it is particularly important for RCC patients to remain up-to-date with their BC screening.
The limitations of our study include its retrospective nature and the absence of some data from the records of a number of our patients. Based on our findings though, we conclude that it is important to be aware that patients with BC may be at higher risk of having or developing concomitant RCC and vice versa. More epidemiological research is needed to study this association between BC and RCC in particular to explore the potential risk factors contributing to development of these diseases, and ideally more genetic testing should be carried out on this patient population to elaborate on any underlying mutations and genetic variants.

Conflict of interest No conflicts of interest to disclose.
Ethical approval IRB approval was obtained via our institutional IRB review committee, and informed consent was waived as this was a retrospective study.