Sociodemographic, Clinical, and Variation Outcomes for Breast Cancer and Breast Cancer-Related Mutations in a Ten-Year Cohort From Neiva, Huila, Colombia

Background Some breast cancer cases are related to inherited mutations, and this is the reason why early mutation screening is emerging as an area of focus for cost-effective care. However, breast cancer-related mutations vary according to race, ethnicity, geographic origin, and healthcare access. Surveillance for familial breast cancer is not performed routinely in Colombia. Our main aim in this study was to describe a cohort of breast cancer patients, carrying founder breast cancer gene (BRCA) mutations, which were followed up for up to 10 years (2010-2019) in Neiva, Colombia. Methods We performed a retrospective description from an outpatient care center in Huila, Colombia, a region with high breast cancer rates. This study included patients with both a breast cancer diagnosis and an incident genetic mutation for breast cancer (detected during a breast cancer consultation). We captured information from patient medical records. Descriptive analyses were performed. Results A total of 105 patients met the study’s inclusion criteria and were included patients with the BRCA1 mutation and three with BRCA2 mutations. They had a median age of 45 years (IQR, 36 to 51 years). Relatives with a breast cancer history were found in 74 carriers (70.5%). Most patients had a report of Breast Imaging-Reporting and Data System (BIRADS) ≥ 4. A TNM (tumor, node, metastasis) changed reclassification was observed in anatomical vs. prognostic classification. Median follow-up was of 74 months (IQR, 44 to 130), overall observed mortality was 22.9%, and specific mortality was 19.1%. Conclusion Women with breast cancer who carry a mutation related to breast cancer are usually younger than age 50 at diagnosis. Developing strategies and specific policies for this population is needed, and a prevalent BRCA1 c.3331_3334delCAAG mutation could be used as a cost-effective first approach. Among these patients, a risk-increased reclassification was observed.


Introduction
In Colombia, 15,509 new breast cancer cases were diagnosed in 2020 [1]. The average age for breast cancer diagnosis is 59.5 years [2]. Colombian women under age 40 have a higher risk for breast cancer when compared to women in the United States and Canada [1]. Colombian breast cancer patients younger than age 40 tend to have a higher proliferation index, a lower hormone reception expression, and genetic mutations, which are important factors concerning breast cancer [3,4].
Approximately 10% of all breast cancer cases are related to genetic factors [5,6]. These loss-of-function 1, 2, 3 4, 5, 6, 7, 8 9 10 10 11 10 germline mutations in tumor suppressor genes vary according to cancer susceptibility. These mutations can be classified as high-penetrance mutations (BRCA1, BRCA2, TP53, PTEN, STK11, and CDH1) and moderate penetrance variants (CHK2, ATM, RAD51C, BRIP1, and PALB2) [6]. Particularly regarding BRCA mutations, most patients are younger than 35 years old and have worse clinical manifestations, tumor features, and prognosis [7,8]. However, the risk gap between them is closing due to advancements in screening and treatments. Specific mutation factors in BRCA carriers, such as positive regional lymph nodes, increased primary tumor size, age, and negative receptor status, cause survival rates to vary [7]. Most of these factors correlated to a significant impact on later disease stages [8]. Given this consideration, early mutation detection is emerging as an area of focus for cost-effective care [9,10]. However, a recently published study of clinical genetic testing and outcomes among patients with breast and ovarian cancer in the US showed that nearly 25% of those with breast cancer had genetic test results of note with variation according to race or ethnicity and insurance [11]. The study included insured and uninsured out-of-pocket charges and elucidated testing disparities, limiting the interpretation of breast cancer patient's genetic results. Surveillance for familial breast cancer does not exist in Huila, Colombia. Patients with a very strong family history of breast or ovarian cancers are not screened routinely, which leads to preventable delays in diagnosis. Our main aim is to describe sociodemographic factors, clinical factors, and outcomes in patients with breast cancer and breast cancer-related mutations in Neiva, Huila, Colombia, over ten years from 2010 to 2019.

Patient population
We performed a retrospective observation and analytical cohort study at our specialized oncology outpatient care center in Huila, Colombia, a region with high reported breast cancer rates. Huila is a city of 1.1 million people and our specialized medical center diagnoses and treats ~70% of all breast cancer patients in the region. Patients included in the study were referred to our center and live in Colombia's southern regions. This study included patients with both a breast cancer diagnosis and an incident genetic mutation for breast cancer (detected during breast cancer consultation). We captured clinical and sociodemographic information from patient medical records, such as age at diagnosis and insurance, which delimited our population. Also, we collected participant clinical status at the diagnostic time, tumor features, the diagnostic process (imaging), management, and outcomes features.

Statistical analyses
Statistical analyses were performed using Stata, version 15 (StataCorp LLC, College Station, Texas, USA). A descriptive statistic was performed, using categorical variables' absolute (n) and relative (%) frequencies.
Median (Med) and interquartile range (IQR) were employed for continuous variables. Survival analyses were assessed using the Kaplan-Meier test. The center's institutional review board approved this study.

Demographics
A total of 1,378 female patients were screened, and 105 met the inclusion criteria of having both a breast cancer diagnosis and breast cancer-related genetic mutation.

Related familiar breast cancer record
Relatives with a breast cancer history were found in 74 carriers (70.5%). One family member with breast cancer was reported in 36 patients (34.3%), two family members with breast cancer were reported in 29 patients (26.7%), and three family members with breast cancer were reported in eight patients (7.6%). One carrier had four relatives with a history of breast cancer. Commonly reported relatives were aunts, cousins, and mothers (

Pathology and immunohistochemical markers
All patients' biopsy analyses found ductal carcinoma except one patient with lobular carcinoma. Positive estrogen receptors were reported in 32 patients (30.5%), positive progesterone receptors were reported in 24 patients (22.9%), and positive Her2neu was reported in seven patients (6.7%). Sixty-six patients had triplenegative markers (62.9%). Fifty-six patients had a positive ki-67 index (data were only available for this variable in 58 carriers).

Breast cancer genetic mutations
BRCA1 was the most frequent mutation, found in 102 carriers (97.1%). Three patients had BRCA2 mutations. Genetic sequences are listed in Table 4.

Clinical and prognostic staging
According to clinical tumor-node-metastasis (TNM) staging, locally advanced disease (TNM staging ≥ IIb and <IV) was found in 83 patients (79.0%); just one carrier had evidence of distant disease. Locally advanced disease (TNM staging ≥ IIb and <IV) was found in 85 patients (81.7%), and one carrier had evidence of distant disease. The TNM IIIb stage was the most common among study participants. TNM distributions are listed in Table 5.

Follow-up
After a median follow-up of 74 months (IQR, 44 to 130 months), overall observed mortality was 22.9% (24 patients) and specific mortality was 19.1% (20 patients). The median time to death was 46 months (IQR, 14 to 69 months). By the end of the follow-up, two patients had active breast cancer disease. Twenty-six patients had other malignancy diagnoses (Figure 1, Figure 2).

Discussion
BRCA-positive cancer has a differential risk and clinical features associated with poor prognoses such as sporadic cancer [7,8]. Results from various studies of patient characteristics and outcomes highlight that knowledge of the population's variability allows for a better understanding of this disease and improved strategies for its assessment [11]. Identifying relevant characteristics in a large population (especially in a high-risk region) is important for assessing cost-effectiveness strategies such as screening methods and early mutation staging [9][10][11]. Breast cancer data in Colombia are based on institutional experiences, limiting the understanding of breast cancer and breast cancer-related mutations at the population level [12][13][14]. Our institution is a referral center for oncology patient management in Southwestern Colombia. Our goal was to understand and describe breast cancer and its related mutation in a large population. Our results help assess the impact of strategies such as screening methods and mutation detection.
We performed a retrospective data analysis of patients with breast cancer and breast cancer-related mutations in Neiva, Huila, Colombia, over 10 years. Our report included population-risk patients with higher incidence rates than the rest of the country and a previously described screening experience [2,15]. Age at the time of breast cancer diagnosis was a relevant finding in our study. More than half of the patients included in our study are outside the national screening strategies [16], making their diagnosis a challenging event, thus compromising the possibility of a diagnosis at an early stage of the disease. Another important finding is the tendency to reclassify according to prognostic staging; this may be related to the immunohistochemical profile of carriers of a genetic mutation [17]. Another interesting trend relates to better survival in patients who underwent breast-conserving therapy (BCT) rather than mastectomy [18]. These findings suggest a variation in outcomes and characteristics in a group with a differential risk.
For patients with a genetic mutation, age at the time of diagnosis might be influenced by several factors, especially the diagnosis, screening approach, and genetic testing [19,20]. In our national guidance, the optimal selection of individuals for BRCA mutation testing is guided by Adelaide's criteria, which consider patient age, family breast cancer history, ovarian cancer, and a known genetic mutation [16,21]. Our observed age distribution suggests that most patients are not included in population screening methods. This age distribution is similar to other national and international reports, indicating that screening techniques may have a small contribution to detecting a mutation carrier [12][13][14]17,20,22,23]. Otherwise, genetic testing is linked to health information relevant to blood relatives; disseminating this information with family members (uncles, cousins, nephew/nieces) affects the probabilities for the diagnostic approach, which might explain our findings concerning consanguinity [24].
Surgical management in carriers has been controversial in the literature, specifically, the outcomes concerning the performance of BCT compared to mastectomy. Overall survival from studies with small sample sizes favors BTC over mastectomy [19]. While our findings align with this, additional studies are needed to explore the impact of other variables and surgical approach planning [17]. While BRCA1 carriers tend to have poorer survival than those with BRCA2 germline mutation, other variables influence the prognosis (e.g., clinical staging). Locally advanced breast cancer is frequently related to BRCA mutation carriers and ductal invasive tumor type but not a hormone and Her2-neu expressions [8,17]. Recently, in Colombia, Cervera et al. described the prognostic upstaging and downstaging, compared to the anatomic staging in a large Colombian breast cancer cohort. They reported that prognostic staging decreases were more frequent than those of staging increases [25]. We observed a higher frequency in the increased staging than a descent when comparing anatomical to prognostic staging. This represents the lower rates in the expression of factors that improve the prognosis in patients with breast cancer related to a genetic mutation [8,17].
According to Torres et al., "two founder BRCA1 mutations accounted for 100% of all BRCA1 mutations, and the identified founder BRCA2 mutation represented 40% of all BRCA2 mutations" [26]. In our study, most of the patients were BRCA1 and categorized as small-range BRCA1/2 founder mutations in unselected breast cancer patients. This information would improve Colombian patients' risk assessment and carrier detection [26]. This 3450del4-BIC (or c.3331_3334del-NCBI) was described as a founding mutation in Colombia in a previous study by Torres et al. [26]. In our experience, this mutation was mainly in the center municipalities of Huila, followed by 4523G>A, which was more frequent in the southern municipalities [12]. These findings may contribute to genetic screening test strategies, support efforts to understand uncertain clinically significant variants, and involve laboratories, clinicians, patients, and relatives [27]. The European origin of the mutation was introduced early in the country's colonization, resulting in a high mutation prevalence in the population, mainly in the department of Huila (Southern Colombia) [28]. In our study cohort, 105 BRCA1/2 P/LP mutation carriers were identified. The prevalence of the BRCA1 c.3331_3334delCAAG mutation was 87% (92 of 105), suggesting that specific genetic risk assessment strategies for this geographical area from Colombia need to be developed.
Our study has one of the larger sample sizes reported in the region and at the national level, including breast cancer patients associated with a genetic mutation. Our findings might represent a south Colombian region population, and it is not generalizable to other regions. A study of these patients at the national level would be of value.

Conclusions
Women with breast cancer who carry a mutation related to breast cancer are usually younger than age 50 at diagnosis. The diagnostic approach and early detection efforts in these patients remain a challenge, given that they are not included in national strategies for breast cancer screening. This highlights the need to continue developing strategies and policies for this population. Additionally, when using the anatomical vs. prognostic system, these patients represent a risk-increased reclassification due to a higher frequency of triple-negative tumors. Surveillance for familial breast cancer does not exist in Huila. Patients with a strong family history of breast or ovarian cancers are not screened routinely, which causes preventable delays in diagnosis. The scrutiny of the prevalent BRCA1 c.3331_3334delCAAG mutation could be used as a costeffective first approach. Patients from this region might undergo preventive measures to reduce morbidity and mortality and improve their quality of life.

Additional Information Disclosures
Human subjects: Consent was obtained or waived by all participants in this study. Hospital Universitario Hernando Moncaleano Perdomo issued approval 005-002. Our research uses a retrospective methodology. We requested approval from the institutional ethics committee. Given the essence of its methodology, the act of informed consent didn't apply. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.