Breast cancer as the first primary malignancy: clinical pathological characteristics of common cancer combinations

Abstract

With the continuous rise in breast cancer incidence and significant improvement in patient survival, the risk of developing Multiple Primary Malignancies (MPMs) has garnered increasing attention. As the most common malignant tumor in women, breast cancer has a complex pathogenesis involving multiple factors such as genetic predisposition, treatment exposure, and interactions between hormonal pathways. These tumors are often difficult to distinguish from metastases or recurrences in clinical practice, frequently leading to delays in diagnosis and treatment, thereby affecting patient prognosis. Therefore, predicting the occurrence of second primary cancer (SPC) in cancer survivors is important in clinical diagnosis and treatment. This review synthesizes evidence from global cohorts, with an emphasis on Asian populations where relevant, to provide a narrative review of the research progress on Breast Cancer First Primary Malignancy (BCFPM). It focuses on the epidemiological characteristics, mechanisms (including the field cancerization theory and multifocal origin theory), and clinicopathological features of common cancer combinations. The aim is to identify high-risk populations for breast cancer and propose follow-up strategies, providing a scientific basis for the development of clinical prevention and intervention strategies, as well as early diagnosis and treatment.

Introduction

Multiple Primary Malignancies (MPMs) refer to the occurrence of two or more independent primary malignant tumors in the same individual, which can develop in different organs or tissues simultaneously or at different times. Based on the time interval between the diagnoses of these tumors, MPMs are classified into two categories: synchronous (interval ≤ 6 months) and metachronous (interval > 6 months). With advancements in cancer diagnosis and treatment, as well as the prolonged survival of cancer patients, the incidence of MPMs has shown a significant upward trend, increasing from 7.3% in 2004 to 12.2% in 2007 [1]. Globally, breast cancer remains the most frequently diagnosed malignancy in women, with GLOBOCAN 2022 reporting over 2.3 million new cases annually [2]. In China [3, 4], it constitutes 15.6% of newly diagnosed female cancer cases, while the American Cancer Society notes [5] it accounts for 31% of newly diagnosed cancers in US women, with increasing incidence trends observed worldwide. The survival rate of breast cancer patients has significantly improved, but this also increases their risk of developing a Second Primary Cancer (SPC). Studies show that the risk of SPC in breast cancer patients is significantly higher than in the general population, with a hazard ratio (HR) ranging from 1.14 to 2.14 [1, 6]. Common SPCs in breast cancer patients include contralateral breast cancer, thyroid cancer, female reproductive system tumors, colorectal cancer, and lung cancer [7–9]. The occurrence of SPC significantly worsens the prognosis of breast cancer patients. This article narrative reviews global evidence on the epidemiological characteristics, pathogenesis, common cancer combinations, and clinicopathological features and treatment of Breast Cancer First Primary Malignancy (BCFPM), aiming to identify high-risk populations and propose follow up high-risk populations with breast cancer, thereby providing assistance for clinical preventive interventions and early diagnosis and treatment, and optimizing the long-term quality of life for patients.

Summary of BCFPM

Epidemiological characteristics

The risk of SPC in breast cancer patients is significantly higher than in the general population [1, 10], with notable differences observed across various races and age groups [6, 11]. Brandt et al.‘s SEER analysis [11] identified significant racial variations in SPC risk using standardized incidence ratios (SIR). Compared with non-Hispanic White women (reference SIR = 1.09, 95%CI = 1.08–1.10), elevated risks were observed in: Non-Hispanic Asian American/Native Hawaiian/Pacific Islander (AANHPI): SIR = 1.49 (1.44–1.54), Non-Hispanic/Latina Black: SIR = 1.41 (1.37–1.45), Hispanic/Latina: SIR = 1.45 (1.41–1.49) (P-heterogeneity < 0.001). Beyond well-documented socioeconomic and lifestyle disparities—such as higher obesity prevalence, along with differences in dietary habits [12, 13] and physical activity levels—emerging molecular research has uncovered critical race-associated biomarkers: (1) Genetic variations: Pathogenic BRCA1/2 variants are notably prevalent in Ashkenazi Jewish populations (2.5%) compared to other ethnic groups (< 0.5%) [14]. (2) Hormonal regulation: Black women demonstrate lower estrogen receptor (ER)-positive tumor rates (74.8%) than White women (78.5%) [15, 16], which difference may lead to variations in clinical outcomes via modulation of the estrogen metabolism pathway. Inequities in healthcare access further exacerbate these biological disparities, compounding their clinical impact. The risk of SPC in multiple primary tumors shows a significant age-related trend, increasing with advancing age [1]; the median age for the occurrence of SPC in breast cancer patients is 63.4 years, with an incidence rate of approximately 6.28% in patients over 60 years old, significantly higher than that in patients under 60 years old (3.47%) [6]. This age-related increase in risk may be attributed to immune suppression and cumulative environmental exposure with advancing age. Regarding gender differences, statistics from Taiwan [17] indicated that male patients exhibited a significantly higher risk of SPC (SIR: 2.17; 95% CI: 1.70–2.73) than female patients (SIR: 1.50; 95% CI: 1.44–1.55). According to a study by Allen et al. [18], pathogenic BRCA2 mutations were detected at a markedly higher rate in male breast cancer patients compared to females (8.1% vs. 1.5%, respectively), with BRCA2 mutations accounting for the vast majority of cases in males (74 BRCA2 carriers vs. only 7 BRCA1 carriers in the cohort). Male BRCA2 carriers were particularly prone to developing SPCs, including contralateral breast cancer (CBC) (SIR = 431), prostate cancer (SIR = 4.46), and pancreatic cancer (SIR = 20.2) [19, 20]. Male breast cancer patients are more frequently ER-positive than females [21], suggesting that this gender disparity may also be linked to sex hormone receptor signaling pathways [22]. Current research on SPC in male breast cancer remains limited, and larger-scale studies are required in the future to elucidate its epidemiological characteristics further.

In breast cancer patients, common sites for SPC include contralateral breast cancer, thyroid cancer, female reproductive system tumors, colorectal cancer, and lung cancer. Among these, contralateral breast cancer is the most common, and its occurrence is related to genetic susceptibility (such as BRCA mutations) [18] and hormone therapy [23]. Thyroid cancer follows, which may be linked to shared hormone-related pathways between breast and thyroid cancers [24], and this occurrence is more common in Asian populations. Endometrial cancer and ovarian cancer are also common SPCs in breast cancer patients, especially in those with BRCA1/2 gene mutations, where the risk is significantly increased [25]. The occurrence of lung cancer [26] and gastrointestinal tumors may be closely associated with the long-term side effects of breast cancer treatments such as radiotherapy and chemotherapy [27]. Table 1 summarizes the common cancers and their incidences after breast cancer in recent years. Understanding the common cancer combinations in breast cancer patients with MPMs is helpful for early identification and effective follow-up of high-risk individuals.

Table 1.

Incidence and common sites of multiple primary malignancies after the first primary breast cancer

Authors	Years	Country	People count	Incidence rate(%)	Common sites
Ramin et al. [6]	2023	USA	16,004	9.7	Peritoneal cancer (SIR = 3.44), soft tissue sarcoma (SIR = 3.32), contralateral breast cancer (SIR = 3.44), myelodysplastic syndrome (SIR = 3.25), acute myeloid leukemia (SIR = 2.11)
Macq et al. [1]	2023	Belgium	149,530	10.1	Contralateral breast cancer (SIR = 2.14), esophageal cancer (SIR = 1.87), colorectal cancer (SIR = 1.4), lung cancer (SIR = 1.37), and renal cancer (SIR = 1.34)
Li et al. [8]	2020	USA	250 764	12	Contralateral breast cancer (5.2%), gastrointestinal tumors (1.7%), lung cancer (1.3%), female reproductive tract tumors (1.2%), and skin cancer (0.6%)
Parhizgar et al. [28]	2022	22 countries	91,678	NA*	Non-melanoma skin cancer (SIR = 2.87), bone and soft tissue sarcoma (SIR = 2.25), uterus (SIR = 1.98), ovary (SIR = 1.64), and thyroid (SIR = 1.56)
Zheng et al. [9]	2018	Sweden	87,752	17	Contralateral breast cancer (9.9%), colorectal cancer (1.8%), lung cancer (1.0%), endometrial cancer (0.8%), and melanoma (0.5%)
Baos et al. [7]	2021	USA	8616	NA*	Contralateral breast cancer (30%), lung cancer (13.4%), uterine corpus cancer (5.8%), thyroid cancer (5.6%), and cutaneous melanoma (4.5%)
Qian et al. [29]	2020	USA	208,474	8.9%	Contralateral breast cancer (3.0%), lung and bronchial cancer (1.2%), uterine corpus cancer (0.5%), cutaneous melanoma (0.4%), and thyroid cancer (0.3%)
Allen et al. [20]	2023	Global	NA**	NA*	Thyroid cancer (SIR = 1.89), endometrial cancer (SIR = 1.84), ovarian cancer (SIR = 1.53), kidney cancer (SIR = 1.43), and cutaneous melanoma (SIR = 1.34)

*NA: not explicitly mentioned in the literature

**NA: the paper is a meta-analysis with a wide range of inclusion

Etiology and risk factors

The etiology of MPMs in breast cancer patients is complex, encompassing genetic predisposition, treatment-related factors, and environmental exposure. Among these, genetic factors, particularly pathogenic variants (PVs) in the BRCA1/2 genes, play a significant role. Research has identified a notable association between BRCA2 and the DNA-binding domain (DBD) of MPMs, with 55.6% of BRCA2 patients carrying pathogenic variants in the DBD region experiencing breast cancer as SPC [25]. Furthermore, familial cancer syndromes, such as Lynch syndrome and Li-Fraumeni syndrome, are critical risk factors for MPMs, highlighting the importance of genetic background in their development. Table 2 summarizes the hereditary tumor syndromes currently known to be associated with breast cancer.

Table 2.

Hereditary tumor syndromes associated with breast cancer

Hereditary cancer syndrome	Susceptibility gene	Inheritance pattern	Affected site
Hereditary breast-ovarian cancer syndrome [30]	BRCA1、BRCA2	Autosomal dominant inheritance	Breast cancer, ovarian cancer
Cowden syndrome [31]	PTEN、MMAC1、TEP1	Autosomal dominant inheritance	Multiple colonic hamartomas, breast cancer, thyroid cancer
Li-Fraumeni syndrome [32]	TP53	Autosomal dominant inheritance	Breast cancer, soft tissue sarcoma, osteosarcoma, brain tumor, leukemia, adrenocortical carcinoma
Lynch syndrome [33]	MLH1、MSH2、MSH6、PMS2、EPCAM	Autosomal dominant inheritance	Susceptibility to colon cancer, endometrial cancer, and rarer cancers such as those of the urinary tract, ovaries, small intestine, stomach, liver, and biliary tract
Hereditary diffuse gastric cancer	CDH1 [34]、CTNNA1 [35]	Autosomal dominant inheritance	Diffuse gastric cancer, lobular breast cancer
Peutz–Jeghers syndrome [36]	LKB1/STK11	Autosomal dominant inheritance	Gastric cancer, breast cancer, pancreatic cancer

Secondly, treatment-related factors also play a significant role in the occurrence of MPMs. Although radiotherapy and chemotherapy improve the survival rate of breast cancer patients, they may also increase the risk of SPC. Specifically, radiation exposure is associated with an increased risk of soft tissue sarcomas, lung cancer, esophageal cancer, etc [6]. Chemotherapy drugs such as anthracyclines and alkylating agents induce DNA damage and are closely related to the development of hematologic malignancies, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) [37–39]. The study by Lee et al. demonstrated that anthracycline-containing regimens were associated with substantially elevated risks of therapy-related AML (HR 9.531) and MDS (HR 2.559) compared to chemotherapy-naïve patients. Furthermore, although endocrine therapeutic agents such as tamoxifen effectively reduce breast cancer recurrence rates, evidence indicates they concomitantly elevate endometrial cancer risk in postmenopausal populations [40]. Longitudinal data reveal that women undergoing tamoxifen therapy for > 2 years exhibit a 2.3-fold increased incidence of endometrial carcinoma relative to untreated controls, with risk escalation demonstrating a strong temporal correlation to treatment duration [41]. Age and hormonal status are also risk factors for SPC. Studies show that the 20-year cumulative incidence rate in young breast cancer patients (≤ 30 years) reaches 20.08%, which may be closely related to the patients’ longer survival and exposure time. Compared to estrogen receptor-positive (ER+) breast cancer patients, estrogen receptor-negative (ER-) patients are more likely to develop hematologic tumors and lung cancer [8].

Environmental exposure and lifestyle factors also influence the occurrence of MPMs. Obesity increases the risk of contralateral breast cancer and colorectal cancer in breast cancer patients through chronic inflammation and hormonal metabolic disorders. Smoking and alcohol consumption elevate the risk of SPC by 2.2-fold and 1.9-fold, respectively, through mechanisms of carcinogen exposure and DNA repair inhibition [42]. In summary, the etiology and risk factors for MPMs in breast cancer patients involve multiple dimensions, including genetics, treatment, and lifestyle. This suggests that genetic counseling should be strengthened in clinical practice, optimized treatment options should be implemented, and lifestyle interventions should be introduced to effectively reduce the risk of SPC.

Pathogenesis

Field cancerization

Field cancerization refers to the phenomenon where the same organ or adjacent tissues, due to long-term exposure to common carcinogenic factors (such as radiotherapy, chemotherapy, or environmental toxins), develop varying degrees of genetic mutations in the tissue of that region, leading to precancerous lesions. Due to differences in the sensitivity of various tissue cell types and the intensity of carcinogenic stimuli, epithelial tissues exposed to the same stimulus may undergo cancerous transformation at different times, resulting in multifocal, independent primary tumors. Slaughter et al. [43] first proposed this theory, discovering that multifocal carcinogenesis in oral squamous epithelium arises from widespread epithelial abnormalities caused by long-term carcinogen exposure. Bedi et al. [44] confirmed through X-chromosome inactivation and microsatellite analysis that MPMs in the head and neck region may originate from the same clone, providing support for the “monoclonal spread” hypothesis in field cancerization. Recent studies suggest that the simultaneous occurrence of colorectal cancer in esophageal cancer patients may be related to carcinogen-induced multi-organ field cancerization, further supporting this theory [45].

Multifocal origin theory

In the normal human body, multiple susceptibility centers exist for tumorigenesis. Upon exposure to different carcinogenic factors, the timing, location, and type of carcinogenesis may vary significantly, ultimately leading to the development of primary cancers at different sites, times, and types. The multifocal origin theory emphasizes that different tumors independently arise from genetically heterogeneous cell clones. Cavazos et al. [46], through whole-exome sequencing, identified 22 gene variants in patients with multiple primary cancers, including 10 novel variants, providing robust evidence for the genetic heterogeneity of multiclonal origins. Burr et al. [47] discovered developmental mosaicism in EGFR-mutant lung cancer, where embryonic gene mutations led to the independent formation of multifocal tumors, a process unrelated to environmental factors such as smoking. This mechanism can explain the etiology of patients without environmental exposure.

Other mechanisms

Epigenetic dysregulation: Genome-wide hypomethylation or hypermethylation of specific genes (e.g., CDKN2A) may simultaneously affect both breast and colorectal tissues, promoting the occurrence of MPMs [48]. Clonal hematopoiesis: Acquired mutations in DNMT3A or Tet Methylcytosine Dioxygenase 2 gene(TET2) post-chemotherapy can lead to myelodysplastic changes and eventually progress to leukemia [49]. Immune surveillance escape: Prolonged immunosuppression induced by radiotherapy and chemotherapy may impair the body’s ability to eliminate precancerous lesions [50, 51]. For instance, radiotherapy-induced depletion of CD8 + T cells is associated with an increased risk of second primary lung cancer [51].

Biomarkers

In addition to the biomarkers previously mentioned, such as BRCA1 and BRCA2 PVs, genome-wide hypomethylation and hypermethylation of specific genes (e.g., CDKN2A, BRCA1), DNMT3A or TET2 mutations, TP53 mutations, and CD8 + T cell exhaustion markers (e.g., TIM-3, LAG-3), there are several other approaches to predict the risk of subsequent primary cancers in breast cancer patients. The study by Wang et al. [52] demonstrated that in triple-negative breast cancer (TNBC), patients with gBRCA1 mutations have a significantly increased risk of developing SPC (particularly CBC) due to systemic DNA repair deficiency (sHR = 4.04, 95% CI 2.29–7.13). Tumor-infiltrating lymphocytes(sTILs) reflect antitumor immunity: higher sTILs (≥ 50%) are associated with improved survival rates (a 16% increase in overall survival(OS) per 10% increment). Therefore, the combination of BRCA1 PVs and tumor-infiltrating lymphocyte counts can predict SPC risk and survival outcomes. Patients with gBRCA1 mutations and low sTILs (< 50%) tend to have a poorer prognosis and are more prone to developing SPC. Glenn et al. suggest that combining imaging and circulating tumor DNA (e.g., Human Papillomavirus (HPV) ctDNA) monitoring in head and neck tumors can improve the early detection rate of SPCs. However, its clinical application requires support from individualized risk assessment [53]. Among emerging biomarkers, the overexpression of satellite α transcripts (SAT) (SAT > 1.5) can serve as an independent predictor of MPMs by inducing chromosomal instability [54]. These findings provide new directions for early identification and targeted intervention but require clinical validation to optimize their application.

Clinicopathological characteristics of common disease combinations

Bilateral primary breast cancer

The most common recurrent malignancy in breast cancer patients is contralateral breast cancer, including synchronous bilateral breast cancer (SBBC) and metachronous bilateral breast cancer (MBBC). They have distinct clinicopathological characteristics, as detailed in Table 3.

Table 3.

Comparison of clinicopathological characteristics between synchronous and metachronous bilateral breast cancer

Characteristics	SBBC	MBBC
Incidence rate [55,56]	0.7%-1.4%	0.91%-2.5%
Average age [56]	53.5 years old	44 years old, Median interval for SPC: 67.9 months [57]1
TNM2 staging [58]	Stage III accounts for 50.5%	T1 accounts for 68.9%
Imaging findings	Multifocality/Multicentricity [59]	Often accompanied by axillary lymph node enlargement [60]
Molecular subtype	ER+(60%-75%), HER-2 + 315%-20% [25, 61]	ER+(50%-65%), TNBC20%-25% [62]
Pathological type	Invasive ductal carcinoma(80%-90%) [63]	Invasive ductal carcinoma(75%-85%), the proportion of invasive pathology is higher in second cancers [8]
Histological grade	Mainly Grade 2(60.8%) [58]	The second cancer may be of a higher grade [64]
5-year OS	74.6%-82% [28, 65]	63.2%-70%, if the interval is > 5 years, it increases to 75% [1, 66]

¹Mruthyunjayappa et al. analyzed 52 cases in a U.S. cohort and found that the median interval time for MBBC was 67.9 months

²TNM staging: The TNM staging system (Tumor, Node, Metastasis) classifies cancer progression based on primary tumor extent (T), lymph node involvement (N), and distant metastasis presence (M)

³HER-2 + indicates HER-2 expression++/+++, and FISH staining is positive

Thyroid cancer as a SPC

Thyroid cancer is one of the most common SPCs after breast cancer. A retrospective cohort study based on Dutch cancer registry data showed that the SIR for thyroid cancer after breast cancer was 1.86, and the SIR for breast cancer after thyroid cancer was 1.46 [67]. Mendelian randomization studies also support a causal relationship between ER + breast cancer and thyroid cancer [68], indicating an association between the two. The median age of breast cancer patients who subsequently developed thyroid cancer was 54 years, younger than those with only breast cancer (median age 59), and they had smaller tumor volumes, more invasive ductal carcinoma, and more hormone receptor positivity. However, these differences did not reach statistical significance [69]. Jiang et al. [70] analyzed 20,98 Chinese patients and found that the median interval between breast cancer and subsequent thyroid cancer diagnosis was 69 months.

The risk of thyroid cancer development in breast cancer survivors involves multifactorial mechanisms: (1) Genetic predisposition, particularly BRCA1/2 pathogenic variants and PARP4 germline mutations [71] ; (2) Radiation exposure history from prior treatments; (3) Hormonal pathways where estrogen demonstrates dual carcinogenic effects - both directly through thyroid cell interaction [72, 73] and indirectly via thyroid-stimulating hormone (TSH) secretion stimulation [74];. The most common pathological type of thyroid cancer occurring after breast cancer is papillary carcinoma, accounting for over 80% of all cases, and it often presents at an early stage (TNM stage I) and is asymptomatic [67]. Pathologically, thyroid cancer usually exhibits low invasiveness, but it is noteworthy that shared molecular pathways with breast cancer (e.g., PI3K/AKT/Bcl-2 pathway activation) may accelerate its progression [75].

Subsequent thyroid cancer typically presents with a mass or nodule in the thyroid region, and some patients may experience neck discomfort, difficulty swallowing, or hoarseness. Due to the insidious nature of early thyroid cancer symptoms, most patients are diagnosed during routine follow-ups or imaging examinations. Ultrasound is the primary method for thyroid cancer detection in breast cancer survivors, showing hypoechoic nodules with irregular margins and microcalcifications. Elastography helps evaluate stiffness. CT/MRI assesses tumor extent, while PET-CT aids in differentiating primary from metastatic lesions. All thyroid nodules require fine-needle aspiration biopsy(FNA) confirmation [6, 63, 76]. Breast cancer survivors should receive thyroid cancer surveillance with ultrasound at 6- to 12-month intervals.

SEER database analysis reveals that when breast cancer serves as an SPC, thyroid cancer patients exhibit significantly improved cancer-specific survival rates, likely attributable to early screening and timely intervention, whereas when breast cancer is the first primary cancer (FPC), thyroid cancer patients have poorer OS, possibly related to the side effects of systemic therapy or differences in tumor biology [77]. Overall, the prognosis of secondary thyroid cancer is favorable, with its 5-year survival rate showing no significant difference compared to solitary thyroid cancer [67].

Female reproductive system tumors as SPC

The risk of developing female reproductive system tumors after breast cancer is significantly higher than in the general population, with pathogenesis involving genetic susceptibility (see Table 2), overactivation of hormone receptor (ER/Progesterone Receptor(PR)) signaling pathways [78], and treatment factors (such as tamoxifen use). A longitudinal cohort study based on Korean national health insurance data revealed that premenopausal breast cancer patients treated with tamoxifen had a 3.77-fold higher incidence of endometrial cancer compared to those not receiving endocrine therapy, along with significantly increased risks of endometrial hyperplasia and polyps [79]. A high-fat diet can also contribute to the development of female reproductive system tumors by inducing fluctuations in estrogen levels [80]. Additionally, HPV and EBV infections have been shown to facilitate the development and progression of cervical cancer and breast cancer [81].

Endometrial cancer as a SPC

Endometrial cancer occurring after breast cancer is predominantly of the serous type, which is highly aggressive [82]. A multicenter retrospective study revealed that when endometrial cancer is an SPC following breast cancer, serous carcinoma accounts for 44%, significantly higher than in primary endometrial cancer [82]. The analysis by Stern et al. [82] of 42 Israeli patients with endometrial cancer following breast cancer revealed that the mean interval for developing this second primary cancer was 144.5 months (approximately 12 years). These tumors are often associated with the loss of PTEN protein expression and high-frequency somatic mutations (e.g., TP53), suggesting potential defects in DNA repair mechanisms [83]. In terms of prognosis, patients with serous carcinoma have significantly lower 5-year survival rates compared to those with endometrioid carcinoma, and BRCA1 mutation carriers face higher overall survival risks [84]. However, a UK cohort study showed that the risk of endometrial cancer in general BRCA mutation carriers does not significantly differ from that in the general population, suggesting the need for a comprehensive assessment incorporating molecular subtypes [85].

Ovarian cancer and cervical cancer as SPC

Kryzhanivska et al. [86] found that ovarian cancer usually develops 5–10 years post-breast cancer treatment. The pathological type of ovarian cancer is predominantly high-grade serous carcinoma, a subtype known for its high aggressiveness and poor prognosis [87]. Current preventive measures for ovarian cancer, in addition to testing for cancer antigen 125 every six months, include the use of oral contraceptives and prophylactic salpingo-oophorectomy, which can also reduce the risk of ovarian cancer [88].

The risk of cervical cancer following breast cancer is relatively low, but previous studies have shown an increasing trend in its incidence, particularly among younger patients. George et al. found that the average interval between breast cancer and subsequent cervical cancer is 5 years [89]. The pathological type of cervical cancer is predominantly squamous cell carcinoma, with some patients presenting as adenocarcinoma or other rare types. In terms of prognosis, cervical cancer patients are often diagnosed at advanced stages, with poor outcomes and a 5-year survival rate of only 61.9% [90], lower than other SPCs of breast cancer, which may be related to immunosuppression or insufficient monitoring after breast cancer treatment [91]. Studies have shown that FGD3 mRNA expression levels have prognostic value in breast and cervical squamous cell carcinoma [92]. However, in recent years, there have been fewer studies on the relationship between cervical cancer and breast cancer, and the data need further updating and refinement.

Colorectal cancer as a SPC

Bao et al. [7] conducted a SEER database analysis of 8,616 patients with second primary cancers (SPCs) and found that the median interval between breast cancer diagnosis and subsequent colorectal cancer development was 20–26 months. Genetic factors, such as germline variants in DNA damage repair genes (e.g., MLH1, MUTYH), are significant risk factors, and patients carrying these variants have an increased risk of developing both breast and colorectal cancer [93]. Additionally, patients with Li-Fraumeni syndrome have a significantly higher risk of secondary colorectal cancer due to radiation exposure [94]. Endocrine therapies such as tamoxifen may indirectly increase the risk of colorectal cancer through non-estrogen receptor-dependent pathways [95].

Colorectal cancer following breast cancer often presents as mucinous adenocarcinoma or adenocarcinoma and is frequently located in the left colon (e.g., descending colon, sigmoid colon) [96]. Pathologically, colorectal cancer is often associated with microsatellite stability (MSS), but patients with BRCA1/2 or PTEN mutations may exhibit high-frequency somatic mutations [93]. In terms of prognosis, the 5-year survival rate for colorectal cancer patients diagnosed early can exceed 70%. Still, overall survival is significantly reduced if accompanied by breast cancer metastases (e.g., to the lungs or bones) [97]. Additionally, second primary colorectal cancer in patients with hereditary cancer syndromes (e.g., Li-Fraumeni syndrome) tends to be more aggressive, necessitating enhanced monitoring [98].

The imaging manifestations of second primary colorectal cancer following breast cancer are similar to those of primary colorectal cancer. They can be detected through abdominopelvic CT, MRI, PET-CT, and colonoscopy. Among these modalities, 18 F-FDG PET-CT demonstrates high sensitivity and specificity in detecting second primary malignancies, particularly showing advantages in evaluating tumor metabolic activity [99].

Lung primary cancer as a SPC

A retrospective study conducted at Jiangsu Provincial People’s Hospital in China revealed that among 9,179 breast cancer patients, 0.8% developed primary lung cancer subsequently, with a SIR of 1.4 (95% CI: 1.25–1.55) and an EGFR mutation rate as high as 78.5% [100]. The expression status of ER and PR was significantly associated with the risk of lung cancer after breast cancer (ER: RR = 0.93, 95% CI: 0.87–0.99, p = 0.014; PR: RR = 0.86, 95% CI: 0.82–0.91, P < 0.001), with patients who were ER-/PR- being more likely to develop lung cancer [101]. Additionally, the risk of lung cancer in breast cancer patients is significantly associated with radiotherapy (RR = 1.40, with a higher risk for ipsilateral lung cancer) and smoking (OR = 9.73), while chemotherapy (RR = 0.69) and hormone receptor-positive status (RR = 0.93) may reduce the risk [102]. Traditional radiotherapy techniques (e.g., high-dose chest wall irradiation) significantly increase the risk of ipsilateral lung cancer, while modern precision radiotherapy techniques may reduce this risk.

Nobel et al. [103] conducted a statistical analysis of 331 U.S. patients who developed primary lung cancer following breast cancer, revealing a median interval of 110 months (approximately 9.2 years) between cancer diagnoses, with a higher median age at lung cancer diagnosis (70 years). The predominant pathological type is adenocarcinoma, often presenting as ground-glass nodules, with a significantly higher EGFR mutation rate compared to the general lung cancer population, usually accompanied by a lower Ki67 index and absence of lymph node metastasis [100]. Approximately 58% of cases can be detected early through breast cancer follow-up imaging, mostly at stages I-II, often presenting as solitary pulmonary nodules or masses, which can be confirmed by lung biopsy. Their 5-year overall survival rate is comparable to that of general lung cancer patients (both at 73.3%) [103].

Treatment

Currently, there is no unified standard for selecting MPMs treatment plans. The efficacy of MPMs patients is often better than that of patients with recurrent and metastatic cancer. For the treatment of MPC, different tumor stages, tumor behavior, patient age, life expectancy, and comorbidities usually need to be considered. At present, the most consistent plan in most literature is that whether it is patients with simultaneous or metachronous MPMs, the treatment principle is based on the treatment principles of each primary tumor: Determine the order of treatment according to the biological behavior and stage of each primary tumor; Priority should be given to treating tumors with higher histological grades (e.g., G3) or advanced stages (e.g., TNM stage III-IV) [104]; MPMs should try to clarify the primary lesions of each metastatic lesion. In addition, treating MPMs requires sufficient age and organ functional tolerance evaluation.

Multidisciplinary collaboration and personalized treatment

Breast cancer treatment requires a multidisciplinary team (MDT) approach, considering molecular subtypes, staging, and the patient’s overall condition to formulate a plan. For patients with MPMs, priority should be given to treating the more aggressive tumors, and sequential therapy should be used to reduce risks [105]. Breast-conserving surgery combined with precision radiotherapy (e.g., intensity-modulated radiotherapy) is the preferred option for early-stage breast cancer, reducing the risk of ipsilateral lung cancer caused by traditional radiotherapy [106]. Hormone receptor-positive patients undergoing endocrine therapy require regular screening for endometrial cancer and thyroid cancer [107].

Systemic therapy and long-term monitoring

Systemic therapy requires individualized customization: HER2-positive patients may benefit from trastuzumab, while those with triple-negative breast cancer could consider immunotherapy [107]. In long-term follow-up, imaging surveillance (e.g., breast MRI, low-dose CT) combined with tumor markers can enable early detection of recurrence or second primary cancers. Breast cancer survivors require regular screening for colorectal and thyroid cancers via colonoscopy and thyroid ultrasound, particularly those who have undergone radiotherapy or endocrine therapy [108]. Genetic counseling (e.g., BRCA1/2 testing) is also crucial for managing high-risk populations [105]. In addition, it is also vital to improve patients’ self-monitoring awareness of SPC symptoms (such as abnormal bleeding and persistent cough).

Summary and outlook

This paper reviews the research progress of BCFPM patients and reveals key issues in their epidemiological characteristics, molecular mechanisms, and clinical management strategies. The incidence of MPMs is significantly associated with prolonged survival in patients with breast cancer and has increased significantly with age. In terms of molecular mechanisms, the Field cancerization theory and the multifocal origin theory explain the occurrence of MPMs from the perspective of carcinogenic exposure accumulation and genetic heterogeneity, respectively; epigenetic disorders, clonal hematopoiesis, and imbalance in the immune microenvironment further explain the relevant mechanisms. Contralateral breast cancer, thyroid cancer, and female reproductive system tumors are common types of SPC. Understanding their common clinical pathological characteristics can help identify early-stage high-risk individuals.

The identification of middle-to-high-risk groups for breast cancer patients can be based on gene testing and family history evaluation, such as BRCA1/2 and TP53. Genetic consultations are carried out to screen correspondingly for areas where tumors may occur, such as contralateral breast ultrasound/MRI (annual examination), thyroid ultrasound (every 1–2 years), gynecological examination combined with CA125 (BRCA mutations), low-dose CT (radiotherapy history or smokers), and lifestyle interventions: controlling obesity, quitting smoking and limiting alcohol, reducing inflammation and hormone metabolic disorders can also help early prevention.

In terms of treatment, it emphasizes the refinement of radiotherapy and uses intensity-modulated radiotherapy (IMRT) or proton therapy to reduce radiation exposure in the lungs, esophagus, and other organs; the selection of chemotherapy drugs requires avoiding excessive use of alkylating agents and monitoring hematologic toxicity; patients receiving tamoxifen therapy should undergo annual gynecological examinations [109], with endometrial biopsy recommended when endometrial thickness exceeds 8 mm, abnormal uterine bleeding occurs, or suspicious endometrial findings are detected on ultrasound, and consideration should be given to switching to aromatase inhibitors if necessary.

Enhancing health literacy is increasingly recognized as a pivotal preventive strategy and prognostic modifier, demonstrating significant potential to improve quality of life and clinical outcomes [110]. Primary care providers require targeted training to strengthen their competency in patient education and counseling, ensuring timely follow-up and personalized risk communication [111]. Furthermore, a systematic evaluation of cost-effectiveness between advanced diagnostic modalities (e.g., imaging surveillance) and genetic counseling is imperative, as early intervention through these approaches may substantially reduce long-term treatment burdens while optimizing resource allocation [112, 113].

In the future, we can integrate multi-omics data, including genomics, transcriptomics, epigenomics, clinicopathological features (such as hormone receptor status and treatment history), and long-term follow-up results to construct dynamic risk stratification models [52]. This will enable early screening for high-risk breast cancer patients. Additionally, AI-driven predictive algorithms can identify high-risk populations, and real-time monitoring technologies based on liquid biopsies (e.g., ctDNA methylation markers) can be developed, combined with regular imaging screenings (such as low-dose CT or PET-CT), to facilitate early detection [6]. In terms of treatment, centralized patient care is implemented, and decision-making tools based on quality of life are designed to balance treatment benefits with SPC risks and optimize long-term survival outcomes. For the subsequent treatment of breast cancer patients, exploring cross-cancer molecular pathways (such as BRCA1-related DNA repair defects and ER/PR signaling abnormalities) can provide targets for the joint prevention and control of MPMs to achieve precise treatment [114].In the future, we hope to establish a global MPMs registration database, promote large-scale cohort research, and clarify the mechanism of the impact of ethnic and regional differences on SPC risks.

The management of MPMs in breast cancer patients needs to follow the entire cycle of “prevention, screening, treatment, and follow-up.” In the future, through the integration of technological innovation and multidisciplinary disciplines, more accurate risk stratification and personalized intervention are expected to achieve more precise results, ultimately improving patients’ quality of life and reducing medical burden.

Abbreviations

MPM

Multiple Primary Malignancies

SPC

Second Primary Cancer

BCFPM

Breast Cancer First Primary Malignancy

SIR

Standardized Incidence Ratio

gPV

Pathogenic variants

ER

Estrogen receptor

ER-

Estrogen receptor-negative

ER-

Estrogen receptor-positive

PR

Progesterone receptor

SBBC

Synchronous bilateral breast cancer

MBBC

Metachronous bilateral breast cancer

FPC

First primary cancer

HPV

Human Papillomavirus

TNM

Human Papillomavirus

MDS

Myelodysplastic syndrome

TET2

Tet Methylcytosine Dioxygenase 2 gene

FNA

Fine-needle aspiration biopsy

sTIL

Tumor-infiltrating lymphocytes

OS

Overall survival

HR

Hazard ratio

Author contributions

Conceptualization: B.S., data curation: Y.H., H.G., writing-original draft: Y.M., visualization: Y.M., supervision: B.S., writing-review, and editing: all authors

Funding

The authors declare that no funds, Grants, or other support were received during the preparation of this manuscript.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

The authors affirm that human research participants provided informed consent for publication of this article and the corresponding form.

Competing interests

The authors declare no competing interests.