The Association Between Breast Cancer And Renal Cell Carcinoma

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Khalid Jazieh, Firas Baidoun, & et al.

Abstract

Purpose 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.

Methods We studied the association between BC(breast cancer) and RCC(renal cell carcinoma) in the 2000-2016 Surveillance, Epidemiology, and End Results (SEER)database. We then reviewed our hospital records of patients with both BC(breast cancer) and RCC(renal cell carcinoma) and collected information including personal and family history of cancers, genetic testing, and patient outcomes.

Results Ofthe 813,477 females diagnosed with BC(breast cancer) in the SEER database,1914 later developed RCC(renal cell carcinoma). The risk of developing RCC was significantly increased within the first 6months,7-12 months, and 1-5 years following BC(breast cancer) diagnosis with standardized incidence ratios(SIRs)of 5.08(95%CI4.62-5.57),2.09(95% CI 1.8-2.42), and 1.15(95%CI1.06-1.24), respectively Of 56,200 females with RCC(renal cell carcinoma),1087 later developed BC(breast cancer). The risk of developing BC(breast cancer) following RCC(renal cell carcinoma) 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(breast cancer) and RCC(renal cell carcinoma).427(97.71%)were female, and 358(81.92%)were white, and breast cancer was diagnosed before RCC(renal cell carcinoma) in 246(56.3%)patients. There were 15 germline mutations in those with genetic testing.

Conclusion Our findings suggest that BC(breast cancer) patients are at higher risk of developing RCC(renal cell carcinoma) and vice versa. BC(breast cancer) tended to precede RCC(renal cell carcinoma), and patients frequently had personal histories of other malignancies and a family history of cancer, particularly, BC(breast cancer).

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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-and-neck 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(renal cell carcinoma) and malignant breast neoplasms [4-9]. It is estimated that in the US 281,550 women and 2650 men will be diagnosed with BC(breast cancer) in 2021[10]. Furthermore, an expected 43,600 women and 530 men will die in the US due to BC(breast cancer) 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(renal cell carcinoma),26(1.8%)had a history of breast cancer as well[11]. Another study by Demir et al. with 1129 cases of RCC(renal cell carcinoma) had 13 patients(1.15%)with BC(breast cancer) [12]. These data prompted us to evaluate the potential association between BC(breast cancer) and RCC(renal cell carcinoma). 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 ).

Methods

SEER national population analysis methods

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 2010census)of the US population between 2000 and 2017 [13,14].

Study population

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

Outcomes

We calculated the Standardized Incidence Ratios(SIR)of RCC(renal cell carcinoma) following BC(breast cancer) diagnosis and the SIR of BC following RCC(renal cell carcinoma) diagnosis. The 'Observed'value represents the number of the second BC(breast cancer) or RCC(renal cell carcinoma) cancer cases diagnosed after the initial BC(breast cancer) or RCC(renal cell carcinoma) diagnosis, while the 'Expected'value represents the number of BC(breast cancer) or RCC(renal cell carcinoma) cases expected to be diagnosed in a demographically similar population within the same period. The SIR represents the change in RCC(renal cell carcinoma) risk following BC(breast cancer) 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(CD). A significant positive increase in the risk of BC(breast cancer)/RCC(renal cell carcinoma) was defined as the number of observed BC(breast cancer)/RCC(renal cell carcinoma) cases being more than the number of expected BC(breast cancer)/RCC(renal cell carcinoma) 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 ofp<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(breast cancer) and RCC(renal cell carcinoma). 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(breast cancer) and RCC(renal cell carcinoma), tumor markers, cancer stages at diagnosis, genetic testing done, interventions for breast and renal cancer, and patient outcomes. Patient characteristics were summarized in the median for continuous variables, and in frequencies and percentages for categorical variables. Out-comes 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.

Results

SEER population analysis results

During 2000-2016,of 813,477 females with BC(breast cancer),a total of 1914 later developed RCC(renal cell carcinoma)(patient characteristics in Table 1). A total of 456 cases(23.82%)of RCC(renal cell carcinoma) were diagnosed within the first 6 months of BCdiagnosis,179(9.35%) within7-12months,647 (33.8%)within 1-5 years,and 632 (33.01%)after more than 5 years. The risk of developing RCC(renal cell carcinoma) following BC(breast cancer) was significantly elevated within the first6months,7-12 months, and 1-5 years of a BC(breast cancer) diagno-sis with standardized incidence ratios(SIRs)of 5.08(95%CI4.62-5.57),2.09(95%CI1.8-2.42), and 1.15(95%CI 1.06-1.24), respectively(Fig.1A). Beyond 5 years, the risk was similar to the general population (SIR=1.01,95% CI [0.93-1.09]).

On the other hand, during the same period, of 56,200 females with RCC(renal cell carcinoma), a total of 1087 later developed BC(breast cancer) (patient characteristics in Table 2), of which 121(11.13%) were within the first 6 months of the RCC(renal cell carcinoma) diagnosis, 65 (5.98%)within 7-12months,472(43.42%)within 1-5 years, and 429(39.47%)were after more than5 years. The risk of developing BC(breast cancer) following RCC(renal cell carcinoma) was significantly elevated within the first 6 months of RCC(renal cell carcinoma) diagnosis with an SIR of 1.45(95% CI 1.20-1.73), while the risk in other latency periods was not significantly different when compared to the general population (Fig. 1B).

Fig. 1 A Standardized incidence ratio (SIR) of RCC(renal cell carcinoma) diagnosis after being diagnosed with BC(breast cancer). B SIR of BC diagnosis after being diagnosed with RCC

Hospital population results

822 patients within our institutional records had a breast cancer and renal cancer diagnostic label. After reviewing the charts 437 patients were identified to have both breast cancer and renal cell cancer. Patients with other diagnoses such as breast fibroadenomas, or cancers that had metasta-sized to the kidneys were excluded. Among the 437 patients, 427 (97.71%) were female,and 358(81.92%)where white (Table 3).

Table 3 Patient characteristics

Breast cancer was diagnosed before RCC(renal cell carcinoma) in 246 (56.3%)of the patients.152 patients had BC(breast cancer) and RCC(renal cell carcinoma) on the same side(76on the right side,76 on the left side),35 had BC(breast cancer) bilaterally,and 16 had RCC(renal cell carcinoma) bilaterally. No patient had both cancers bilaterally. Among the 437 patients, there were another 142 malignancies such a colorectal cancer and ovarian cancer diagnosed, and the most common malignancies reported in the patients'family histories were breast cancer(125), colorectal cancer(51),lung cancer(45),and prostate cancer(34)(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).

Table 4 Genetic mutations and variants identifed

The most common identified BC(breast cancer) 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 radia-tion 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).

Table 5 a: Features of breast cancer, b: Features of renal cell carcinoma

As for RCC(renal cell carcinoma),the most common confirmed stage at diagno-sis was stageI 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(renal cell carcinoma), 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(renal cell carcinoma) was the most common identified cause of death (20.65%),and BC(breast cancer) 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(breast cancer) 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(breast cancer) and RCC(renal cell carcinoma). Based on SEER population analysis results, patients with BC(breast cancer) are at a higher risk of being diagnosed with RCC(renal cell carcinoma) within 5 years of their BC(breast cancer) diagnosis after adjusting for age, sex, race, and year of diagnosis, and the risk is highest within the first 6months. Conversely, RCC(renal cell carcinoma) patients are also at a higher risk of being diagnosed with BC(breast cancer) within 6 months of their RCC(renal cell carcinoma) 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(renal cell carcinoma) cases are being detected incidentally due to imaging done for patients with high-risk BC(breast cancer) who undergo indicated staging workup, which may explain why there is a higher chance of being diagnosed with RCC(renal cell carcinoma) within the first 6 months following a BC(breast cancer) diagnosis. However, this does not account for why there is such an increased number of RCC(renal cell carcinoma) cases among BC(breast cancer) patients. This points to a patient population that is predisposed to both BC(breast cancer) and RCC(renal cell carcinoma), potentially due to similar risk factors, and possibly due to a common underlying genetic mutation. The fact that the risk declines with time indicate 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(breast cancer) and RCC(renal cell carcinoma) showed a population that was predominantly female and white, and that the diagnosis of BC(breast cancer) tended to precede that of RCC(renal cell carcinoma). Patients frequently had personal histories of other malignancies and a family history of cancer, particularly, BC(breast cancer). 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(breast cancer) or RCC(renal cell carcinoma). More than half of patients with RCC(renal cell carcinoma) 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(renal cell carcinoma) patients to remain up-to-date with their BC(breast cancer) 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(breast cancer) may be at higher risk of having or developing concomitant RCC(renal cell carcinoma) and vice versa. More epidemiological research is needed to study this association between BC(breast cancer) and RCC(renal cell carcinoma) in particular to explore the potential risk factors contributing to the 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.

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