Abstract
Currently, female breast cancer (BC) represents the highest incidence of cancer globally. This trend has raised significant attention regarding breast cancer young women (BCYW). With advancements in treatment technology, BCYW survivors are living longer; however, the risk of developing or succumbing to a second primary cancer (SPC) has greatly increased. In addition, several factors, including age, menstrual cycle, hormonal changes, obesity, pregnancy, and breastfeeding, interact to influence the development of SPC in BCYW and make its treatment more difficult. This study investigates the relationship between BCYW and SPC, focusing on morbidity trends, pathological genomics, recurrence rates, survival times, treatment modalities, and physiological fertility. Most BCYW involve BRCA pathogenic variants or fall under triple-negative and human epidermal growth factor receptor 2-overexpressing subtypes, increasing the risk of SPC. While there are regional variations in survival time following the diagnosis of an SPC, the long-term survival outcomes remain unfavorable. In addition, the choice of treatment for BCYW survivors has a prolonged cumulative toxic effect. The combination of endocrine therapy and chemotherapy is effective in treating BC, but it simultaneously increases the risk of developing an SPC, specifically endometrial cancer. Furthermore, radiotherapy is associated with a heightened risk of contralateral BC and lung cancer. We aim to address existing gaps in the literature and to enhance awareness of the risks associated with SPC in BCYW, thereby offering valuable insights for clinical diagnosis and treatment.
Introduction
Breast cancer (BC) has surpassed lung cancer to become the most common cancer worldwide and the fourth leading cause of cancer death. 1 Surprisingly, the rise in BC incidence is mostly observed in younger women. Studies show that BC rates in women <40 years old are steadily increasing,2,3 with nearly a 2% annual rise among those aged 20–29, and a 0.2% increase per year for women in their 30 years old. Fortunately, with the diversification of treatments and the maturity of imaging equipment, the proportion of BC survivors has increased.4,5 Nevertheless, it is important to recognize that while breast cancer survivors live longer, they face a significantly higher risk of developing or dying from a second cancer.4,6 In addition, the long-term nature of treatment and complications in younger patients significantly increase the risk of an SPC compared to older women with BC.7,8
Based on epidemiological data, approximately 12.30% of breast cancer in young women (BCYW) develop second primary cancer (SPC). 9 Among these, second primary breast cancer (SPBC) accounts for nearly one-third of all SPC, second only to the initial primary breast cancer (PBC). 10 Notably, contralateral breast cancer (CBC) is particularly common. 11 However, women with BC in Europe 12 and the United States 13 face a 20%–30% higher risk of developing a second non-breast primary cancer. Regarding the location of SPC, research from the Surveillance, Epidemiology, and End Results (SEER) database in the United States in 2019 indicates that the most common site for an SPC in female BC patients is the contralateral breast, 14 followed by uterine cancer, 15 ovarian cancer, 16 lung cancer, 17 stomach cancer, colorectal cancer, 18 thyroid cancer,15,19 and acute myeloid leukemia. 20 It is evident that with the long-term effects of BC treatment, the risk of developing SPC increases, 21 with contralateral second primary breast cancer being more common.
The rate of young-onset BC has been rising each year, along with the risk of SPC. Studies suggest this is linked to tumor size, germline pathogenic variants (PVs), 22 and family history. 23 Despite these risk factors, there is no systematic study describing the biological behavior and treatment-related risks of BCYW and SPC. This paper aims to comprehensively elaborate the incidence, pathological molecular subtypes, survival, susceptibility genes, treatment, and reproductive outcomes in BCYW with SPC, addressing gaps in current research. It highlights the importance of focusing on SPC in BCYW to provide valuable guidance for clinical diagnosis and treatment.
Increasing incidence trends of BCYW and SPC
Globally, the incidence of BCYW is on the rise, 24 with approximately 25% of cases occurring in women under the age of 50. 25 Experts generally agree that BCYW should be defined as occurring in women under 40 based on clinical and biological characteristics. 26 A U.S. study of 134,518 women under 40 with BC across 42 states found the highest average annual percentage change (AAPC = 1.00%) in Asian Pacific American women, followed by non-Hispanic white women (AAPC = 0.50%) and non-Hispanic black women (AAPC = 0.30%; Table 1). 27 In a 20-year retrospective study of BCYW in China, the age-standardized percentage (ASP) of cases under 35 rose from 4% in 2000 to 5.9% in 2017, with incidence increasing by about 2% annually. 28 In France, the highest increase in incidence was seen in younger BC patients, with an AAPC of 2.10%. 29 In Iran, the rise in BC incidence primarily stems from the younger age group. The AAPC in the 20–29 age group (AAPC = 10.0) is twice as high as that in the 30–39 age group (AAPC = 5.10).30,31 In a study on young BC in West Africa (Gambia), the AAPC for women aged 50 and older was 1.30%, while the AAPC for women under 50 reached 7.6%. It is clear that the annual growth rate of BC incidence is higher in women aged 50 and under compared to those over 50. 32 Overall, the average annual increase in BCYW incidence is at least 2% (Figure 1), with the highest incidence observed in the 30–35 age group. Young BC is the primary concern for women under 40, and the issues of recurrence and the risk of SPC also pose urgent challenges.
Summary of partial characteristics of breast cancer in young women.
AAPC, average annual percentage change; APA women, Asian Pacific American women; ASP, annual standard percentage; BCSS, breast cancer-specific survival; BCYW, breast cancer in young women; CRR, cumulative relapse rate; CRRS, contralateral risk reduction surgery; DFS, disease-free survival; HER2−, human epidermal growth factor receptor 2 negative; HER2+, human epidermal growth factor receptor 2 positive; HR, hazard ratio; HR+, hormone receptor-positive; HR−, hormone receptor-negative; HR+ HER2−, hormone receptor-positive and human epidermal growth factor receptor 2 negative; MCRR, median cumulative recurrence rate; NHB women, non-Hispanic Blacks women; NHW women, non-Hispanic White women; OFS, ovarian function suppression; OS, overall survival; PVs, pathogenic variants; TNBC, triple-negative breast cancer.
High-risk factors for breast cancer in young women. Analysis and summary of high-risk factors in the incidence, molecular subtype, survival time, therapy, susceptibility genes, and physiological fertility in young breast cancer patients.
According to research, women younger than 40 years of age have a higher risk of local recurrence and distant metastasis than older women. 46 In a review of recurrence risk in BCYW, the median cumulative recurrence rate (MCRR) over 5–10 years of ipsilateral BC was 3.10%, and the 10-year MCRR was 7.90%. 33 Obviously, young BC has a higher risk of recurrence within 10 years; however, the occurrence of an SPC is often overlooked. In the United States, the 5-year cumulative incidence (CI) of an SPC in BC is 0.89% (Table 2). 47 Another study of BC patients found racial and ethnic differences in the risk of developing an SPC. Asian American, Native Hawaiian, or other Pacific Islander (standardized incidence ratio, SIR = 1.49), Black (SIR = 1.41), and Latino women (SIR = 1.45) had a 40%–49% higher risk of developing a second cancer, while white women had a lower but still 9% higher risk compared to the general population (SIR = 1.09). 48 SIR is a relative index obtained by comparing the actual incidence rate of a specific population with the expected incidence rate. The expected incidence rate is calculated based on the incidence rate of a standard population. The SIR can help assess whether the incidence of a specific population is higher or lower than that of the standard population.48,49 In a study of 53,783 female BC patients in Taiwan, the overall 5-year SIR of second primary non-breast cancer (SPNBC) was 1.09, with no increase in patients over 50 but a significant rise in those under 50 (SIR = 1.43). 50 Studies in northern Portugal found that patients with a first PBC had an SIR of 1.36 for all types of SPC and an SIR of 9.72 for SPC that occurred simultaneously, meaning those diagnosed within a short period (usually within 2 months) after the first PBC diagnosis. 51 The SIR of SNBC within 10 years in Korean breast cancer patients was 5.78. 52 Studies from the four regions mentioned above revealed that the 5-year SIR of SPC in BCYW ranged from 1.36 to 1.50 (Figure 2). The occurrence of SPC in BCYW was more prominent in the United States and South Korea. Several studies analyzed the interval times between the first BC and SPC; a Canadian study (2006–2016) found a median interval of 7.3 years. 53 Similar findings were observed in the Korean study, young BC patients developed a SPC within 7.61 years of their primary BC diagnosis. 52 In a U.S. cohort of 3223 women with BC, 719 SPC cases were detected over an average follow-up of 11.2 years. This indicates that most SPCs were diagnosed within 10 years.
Summary of partial characteristics of breast cancer in second primary cancer.
CIR, cumulative incidence rate; CR, cumulative risk; CRRS, contralateral risk reduction surgery; HR, hazard ratio; OS, overall survival; PVs, pathogenic variants; SHR, sub-hazard ratio; SIR, standardized incidence rate; SPC, second primary cancer; SPNBC, second primary non-breast cancer; TNBC, triple-negative breast cancer; UM, unilateral mastectomy.
Risk factors and solutions for the development of a second primary cancer. Summary of the highest risk factors of young breast cancer survivors and preventive measures, based on six areas, incidence, molecular subtype, survival time, therapy, susceptibility gene, and physiological fertility.
In summary, the incidence of young BC is high, and the risk of recurrence within 10 years is also elevated. While there is no significant variation in the 5-year SIR of SPC among BCYW across different countries, all rates are increasing. Most SPCs occur within 10 years after the first diagnosis.
Molecular subtypes impact BCYW and SPC
Across various studies, 34%–54% of women diagnosed with BCYW have been found to have TNBC. 40 In a study, very young BC patients exhibited a higher incidence of TNBC subtypes (18.10% vs a mean of 8.60%), and an increased rate of HER2 overexpression (8.00% vs a mean of 6.40%). 34 Furthermore, a study on molecular subtyping of BCYW in Mexico found that the incidence of TNBC and Luminal A was the highest, both at 37.14%. By contrast, the incidence of the HER2 subtype was lower at 13.47%, and Luminal B occurred at a rate of 12.24%. 35 Nonetheless, a study in Switzerland found that most patients were diagnosed with the molecular subtypes Luminal A and Luminal B, at 32.8% and 37.5% respectively. By contrast, TNBC comprised only 10.40% of tumors, making it the least prevalent subtype. 36 The above studies fully confirmed that the molecular subtypes of BCYW are mostly TNBC or HER2 overexpression types, and the other types also exist but account for a relatively small and uncommon proportion.
BCYW are more likely to develop SPC because their molecular subtypes are often TNBC, HER2 overexpression, or HR–. For young patients with TNBC, a study conducted in Korea revealed that this subtype was linked to the highest incidence of CBC. Specifically, the 10-year CI of CBC was 12.40% in the TNBC group and the 10-year CI of CBC associated with HER2 overexpression was 6.10%. The incidence of HR+ BC was notably lower than that of the first two molecular subtypes, with rates of 4.80% and 2.70%, respectively (p = 0.002). 54 Similarly, multiple studies in the United States have found that TNBC significantly increased the risk of CBC (HR = 1.77, 95% CI = 1.46–2.15).55,69 HER2 overexpression in the first BC was strongly associated with an increased risk of CBC (HR = 1.37, 95% CI = 0.99–1.89). This finding suggests that HER2 overexpression and TNBC in young women in the United States carry a high risk of developing an SPBC. 55 In the British HER2-positive study, the results were inconsistent. Young patients with HER2+ BC exhibited a 7% lower risk of developing an SPNBC (HR = 0.93, 95% CI = 0.89–0.97). 56 In summary, the molecular subtypes TNBC, HER2 overexpression, and HR-negative are closely associated with the occurrence of SPC.
Poor survival of SPCs in long-term survivors of BCYW
Survival time of BCYW
The survival time of BCYW and the prognosis of the SPC have become the focus of attention. The high tumor burden, advanced stage, and greater aggressiveness in BCYW increase the risk of SPC and impact patient survival. 38 Two studies compared survival outcomes between young Chinese women and white American women with BC (Figure 1). The results showed that the white American women had lower 5-year overall survival (OS; 90.00% vs 93.90%, p < 0.001) and breast cancer-specific survival (BCSS; 91.20% vs 94.20%, p < 0.001). 37 Similarly, it was observed that the 5-year BCSS in young Chinese women was significantly higher than in young white women for both HR+/HER2-and TNBC (96.30% vs 92.90%, p < 0.001; 88.00% vs 81.70%, p = 0.006). 37 However, a study conducted in Switzerland reported longer survival times. The 10-year OS for young BC patients was approximately 68%, with a 10-year disease-free survival (DFS) rate of 68% (95% CI = 0.66–0.71). After 20 years, the DFS rate dropped to 60% (95% CI = 0.57–0.63). 36 In a similar study, it was found that the 10-year OS rate for BC patients aged 35 and younger was 73%, while the 10-year DFS rate for this age group was 48%. 38 For BCYW, the 10-year OS is about 70%, and young Chinese women have better survival benefits than American women in both OS and BCSS.
Further molecular subtype studies have found that Luminal B and HR+ subtypes offer better survival benefits. In the HER2-negative group, Luminal B demonstrated the most favorable prognosis, with an 8-year DFS of 69% (95% CI = 64%–73%), compared to 62% (95% CI = 54%–69%) for Luminal A and 63% (95% CI = 60%–66%) for TNBC, respectively. 23 Another study showed that HR+ patients have a better prognosis than HR–, in terms of OS, recurrence, or progression time. HR+ patients 8-year DFS rate was 65.80% (95% CI = 63.40%–68.20%), compared to 63.40% (95% CI = 61.20%–65.60%) for HR– patients. The 8-year OS rate was 88.10% (95% CI = 86.30%–89.70%) for HR+ patients, while for HR– patients, it was 87.10% (95% CI = 85.50%–88.50%). 40 In a global multicenter retrospective study that evaluated the 8-year OS, BCSS, and PFS across different molecular subtypes, the 8-year DFS rates were as follows: Luminal A: 60.80% (95% CI = 55.70%–65.40%), Luminal B: 69.7% (95% CI = 66.20%–72.80%), TNBC: 63.5% (95% CI = 61.10%–65.70%), and HER2+: 65.50% (95% CI = 59.10%–71.10%). In addition, the 8-year OS rates were as follows: Luminal A at 87.80% (95% CI = 83.90%–90.80%), Luminal B at 90.10% (95% CI = 87.70%–92.00%), TNBC at 87% (95% CI = 85.40%–88.50%), and HER2+ at 87.20% (95% CI = 82.10%–90.90%). These findings suggest that BCYW with the Luminal B subtype tend to have better prognoses, with similar outcomes observed among BRCA mutation carriers. 40 The study indicated that shorter survival times in BCYW were linked to a higher risk of recurrence or progression. Among these patients, those with Luminal B or HR+ subtypes had better OS, PFS, and BCSS. In the long-term treatment of BCYW, it is crucial not only to actively manage the primary tumor but also to remain vigilant about the impact of SPC on subsequent survival.
Survival time of SPC
Chinese research data show that the incidence of SPC in BCYW is 2.20% at 5 years and 4.40% at 10 years. 38 There was a notable difference in OS between patients with and without SPC (10 years: 85.77% with SPC vs 86.37% without; 15 years: 66.16% vs 74.39%; 20 years: 49.21% vs 74.39%). Patients with a SPC had much worse long-term survival compared to those without. 55 In addition, the survival time of patients with a SPC varies in different regions. In a small sample study of 163 cases in Shanghai, China, it was found that the 5-year, 10-year, and 15-year OS rates of BCYW with an SPC were 88.34%, 64.42%, and 56.44%, respectively. 52 Similarly, in a study of 53,783 BCYW in Taiwan, 1-year, 5-year, 10-year, and 15-year survival rates for patients with a SPC were 71%, 40%, 30%, and 23%, respectively. 50 By contrast, in a Korean study of 52,506 women with BC, the 5-year OS rate for BCYW with an SPC was significantly higher than in Taiwan, China, at 62.28% (95% CI = 65.53–69.02). 52 In patients with SPC, the 5-year OS is highest for thyroid cancer (5-year OS = 89.6%), followed by cervical cancer (5-year OS = 75.3%) and colorectal cancer (5-year OS = 73.9%). However, the lowest 5-year OS among second primary cancers is observed in lung cancer (5-year OS = 21.5%). 70 Although survival time after developing an SPC in BCYW varies by region, long-term survival outcomes are generally poor. This makes SPC the second leading cause of death for BCYW, after the primary cancer itself.
Genetic susceptibility implies the risk of BCYW and SPC
BRCA1/2 PVs are the most common individual mutations in familial breast cancer, increasing the risk of developing BC by 3–5 times. 71 BCYW <50 years tend to be more aggressive and advanced, often linked to inherited PVs, such as those in the BRCA gene.59,69 One study found that approximately 12% of BCYW < 40 years of age are associated with germline PVs in the BC susceptibility genes BRCA1/2.41,72 Even in another study, very young BC (age ⩽ 35) were found to have a 9.4% chance of having a detectable BRCA1/2 PVs.42,73 Compared to older women (⩾ 40 years), HR+ HER2− early BC in younger women shows distinct genomic characteristics. These include a higher frequency of GATA3 PVs (19% vs 16%) and copy number amplifications (47% vs 26%), but a lower frequency of PIK3CA (32% vs 47%), CDH1 (3% vs 9%), and MAP3K1 (7% vs 12%) PVs. However, most BC carry pathogenic mutations in only one gene, and the co-occurrence of germline PVs in both BRCA1 and BRCA2 is rare. 39
Similarly, studies on SPBC are more common in carriers of BRCA1 or BRCA2 PVs. 41 Several studies have shown that BRCA1 PV carriers have a cumulative risk of CBC of 15% at 5 years, rising to 27% at 10 years. In BRCA2 PV carriers, the cumulative risk of CBC is 9% at 5 years, increasing to 19% at 10 years. The 5-year cumulative risk of developing an SPC is approximately five times higher in women with BRCA1 mutations and three times higher in those with BRCA2 PVs compared to non-carriers. Moreover, Peking University Cancer Hospital conducted a study on the 10-year cumulative risk of CBC in BC patients with BRCA PVs. The 10-year cumulative CBC risk was 15.5% (95% CI = 9.99–24.20) for BRCA1 PVs carriers, 17.5% (95% CI = 10.90–28.00) for BRCA2 carriers, and 3.20% (95% CI = 2.50–4.10) for non-carriers. In addition, BRCA1 PV carriers first diagnosed with BC at or before age 40 had a significantly higher 10-year cumulative risk of CBC (21.50% vs 11.90%; p = 0.044). 59 Similarly, a recent 10-year study in the United States found that the 5-year risk of SPBC in germline PV carriers was 5.50% (95% CI 1.60%–19.60%), and the 10-year risk was 8.90% (95% CI = 2.60%–30.30%). These rates were significantly higher compared to non-carriers, whose 5-year risk was 1.30% (95% CI = 0.70%–2.60%) and 10-year risk was 2.20% (95% CI = 1.20%–4.00%). 61 Thus, approximately 12% of BCYW cases are linked to germline PVs in BRCA1 or BRCA2. Moreover, the cumulative risk of developing a SPC increases almost exponentially every 5 years.
Therapy associated with BCYW and SPC
Surgery and SPC risk
BC treatment options include surgery, radiotherapy (RT), chemotherapy (CT), endocrine therapy (ET), and targeted therapy. Younger patients or those with large, aggressive tumors are more likely to undergo mastectomy and contralateral risk reduction surgery (CRRS).74,75 A U.S. study found a rapid increase in the rate of CRRS, rising from 10% in 2004 to 33% in 2012 among women aged 20–44, and from 4% to 10% in women aged 45 and older during the same period. This indicates that younger women with BC are increasingly opting for mastectomy combined with CRRS to reduce the risk of future recurrence. 44 A Korean study found that surgery for PBC at age ⩽ 35 (hazard ratios, HR = 2.49) doubled the risk of developing CBC. 54 Ten years after BC surgery, the incidence of an SPC was 0.93% in the CRRS group, compared to 4.44% in the unilateral mastectomy (UM) group, with bilateral Mastectomy (BM) reducing the risk by approximately 78.50%. After 15 years, the incidence increased to 1.15% in CRRS patients and 7.77% in UM patients. 61 While BM reduces the risk of recurrence and SPC, patients still face a certain level of risk. Within the first 10 years, this approach provides better outcomes compared to UM, benefiting both the primary cancer and SPC. However, after 15 years, the risk of developing a SPC following BM becomes more pronounced.
Endocrine therapy and SPC risk
Furthermore, elevated estrogen levels in women can also result in the abnormal proliferation of breast ducts, which may ultimately lead to BC. 76 Therefore, approximately 70% of patients with HR+ BC can achieve antitumor effects by reducing estrogen levels through ET.77,78 Similarly, a 2023 EBCTCG meta-analysis further confirmed that OFS or ovarian ablation significantly reduced the 15-year recurrence risk, breast cancer-specific mortality, and overall mortality. 45 In patients aged ⩽ 35 years, the combination of aromatase inhibitors and OFS resulted in better 12-year DFS and it may also provide an OS benefit. 79 However, multiple studies have indicated that the use of AIs in postmenopausal BC patients may not sufficiently suppress estradiol and estrone levels.80,81 Consequently, this inadequacy can lead to an increased risk of SPBC events, particularly among tamoxifen-treated patients with a history of uterine cancer. 82 A study in the UK showed that women with BC with HT (SIR = 2.30, 95% CI = 2.21–2.40) had a higher SIR than those without HT (SIR = 1.95, 95% CI = 1.86–2.04). In the era of widespread use of ET, the incidence of second primary endometrial cancer in BC patients receiving HT has significantly increased. 56 ET has varying effects depending on the site of action. Studies have demonstrated that the incidence of CBC in patients treated with tamoxifen for 5 years progressively decreases over a 30-year follow-up period. Patients who received tamoxifen for 5 years experienced an increased incidence of endometrial cancer. Conversely, the incidence of lung cancer, especially small-cell and squamous-cell lung cancers, was reduced in this treatment group. 83 Indeed, ET has a dual effect on patients with early-stage BC. On one hand, it can inhibit estrogen resistance in PBC, and on the other hand, it helps reduce the risk of an SPBC, providing a protective role against secondary tumors. 84
Radiotherapy and SPC risk
RT has the potential to lead to the development of SPC through ionizing radiation. Therefore, it is considered a risk factor for tumor occurrence and progression. Survivors with RT have a higher risk of developing SPC (SHR = 1.161, 95% CI = 1.109–1.217, p < 0.001). By contrast, patients only with CT have a slightly reduced risk of developing SPC (SHR = 0.880, 95% CI = 0.832–0.931, p < 0.001). 62 However, when chest RT is added to CT, the adverse effects of radiation gradually appear. In addition to the risk of leukemia and myelodysplastic syndromes,85,86 the risk of developing SPC in irradiated areas is significantly increased.52,87 Studies show that RT patients have an elevated risk of any SPC, with specific risks for LC (SHR = 1.109; 95% CI = 1.033–1.192; p = 0.045), BC (SHR = 1.389; 95% CI = 1.34–1.44; p < 0.001), and acute myeloid leukemia (SHR = 1.298; 95% CI = 1.01–1.67; p = 0.045), particularly for LC, esophageal cancer, and CBC.63–65 According to a study conducted in the United States, the CI of NBC SPC >25 years is higher in the RT group compared to the non-RT group for patients of all ages. 88 Patients with rare missense mutations in the ATM gene receive RT and have a higher risk of CBC. Specifically, the 10-year cumulative risk of CBC in these patients is 16% (95% CI = 7.00%–36.50%). By contrast, similar patients not receiving RT have a 10-year cumulative risk of only 2.20% (95% CI = 0.50%–9.00%). This indicates that the risk of CBC increases by approximately seven times for patients carrying rare missense mutations in ATM after receiving RT. 67 The use of RT can indeed lead to the development of SPC. RT kills tumor cells by inducing DNA damage. However, it also harms normal tissues and leads to the development of SPC.
Chemotherapy and SPC risk
In studies related to CT for BC, the results are inconsistent, and there is currently no definitive conclusion. Research indicates that patients undergoing CT experience a diminished likelihood of developing SPC. Specifically, the risk of LC is reduced (SHR = 0.895; 95% CI = 0.818–0.979; p = 0.015), and the risk of BC is also lowered (SHR = 0.891; 95% CI = 0.854–0.930; p < 0.001). Nonetheless, some studies have reported that the use of CT drugs can damage DNA, leading to an increased incidence of SPC. 68 A study on young women with BC in the UK found differences in the (SIRs for myeloid leukemia related to CT: for those who received CT, the SIR = 2.71 (95% CI = 2.36–3.08), while for those who did not receive CT, the SIR = 1.32 (95% CI = 1.20–1.44). 56 Surprisingly, two other studies showed different results. CT was significantly associated with a reduced BCSS in patients with ER deficiency (HR = 0.51, 95% CI = 0.29–0.90, p = 0.020) or PR deficiency (HR = 0.47, 95% CI = 0.28–0.79, p = 0.004). 89 In addition, the use of adjuvant CT and ET was associated with a lower risk of CBC. 90
In summary, questions remain regarding the therapy increase the risk of SPC. BC patients developing SPC after treatment may have a poorer prognosis than those with only BC. As a result, these patients may be unable to tolerate treatment for secondary tumors, and their options for medication are very limited, significantly reducing the effectiveness of treatment for SPC. Future studies in this area need to be strengthened to explore potential risk factors and effective treatment strategies in depth. 70 Based on the above research findings, clinical physicians should take a comprehensive approach when making treatment decisions.
Physiological and reproductive risk factors
The diagnosis of BCYW can be comprehensively analyzed and considered from physiological, reproductive, and psychosocial perspectives. Recent studies indicate that a short duration or lack of breastfeeding (BF), as well as abruptly stopping BF, can increase the risk of BC in young women. 91 The occurrence of BC is closely related to advanced maternal age at first childbirth. Multiple studies have shown that having a first pregnancy at age 35 or older increases the risk of BC.92,93 Similarly, the postpartum period is a high-risk window with an increased likelihood of developing new cancers and rapidly progressing subclinical metastatic phenotypes. 94 Postpartum breast cancer (PPBC) patients often have a poorer survival prognosis. In a study, the overall mortality risk increased by 1.7 times in the PPBC group with a duration of 5 to less than 10 years (HR = 1.72, 95% CI = 1.17–2.52, p = 0.006). 95 In summary, giving birth for the first time after the age of 35, having interrupted or short BF, and being within 10 years postpartum are all associated with the risk of developing a SPC.
In addition, the occurrence of BC is influenced by various factors, including its physiological structure, hormonal changes, unhealthy lifestyle habits, and social psychological stress. The earlier the onset of menstruation, the higher the lifetime risk of BC, increasing by 5% for each year earlier. Similarly, each year, the menopause is delayed, the risk of BC rises by 2.8%–3.5%. 96 Being overweight or obese, consuming alcohol, having lower fertility rates, experiencing irregular menstruation, and having high social-psychological stress can also contribute to the occurrence and development of BC.97,98 A study on menstrual cycle irregularity found that women aged 29–46 with irregular menstruation have an 11% higher overall cancer risk than those with regular cycles. 99 As mentioned above, factors such as late age at first pregnancy, short or sudden interruption of BF, early age at menarche, late menopause, a high-risk period postpartum (5–10 years), obesity, alcohol consumption, lower fertility rates, irregular menstruation, and increased social psychological stress contribute to a higher incidence of BCYW. Through the research outlined above, young women can implement control measures or interventions to reduce the risk of developing BC.
Summary and outlook
It is becoming increasingly clear that there is a complex relationship between BCYW and SPC. This study provides a comprehensive analysis of the epidemiology, molecular subtypes, genetic mutations, survival times, treatment methods, and reproductive factors related to both conditions. This article provides the relationship between BCYW and SPC, offering valuable insights for personalized treatment plans, risk assessment, and long-term follow-up in clinical practice.
The occurrence of SPC in BCYW remains a significant global health challenge for women. Despite advances in medical technology, the trend of increasing incidence of BC in younger populations continues to elevate the risk of developing SPC. There are still many gaps in research regarding this issue. To better identify BCYW and avoid late-stage diagnoses due to delayed detection, women <40 years should be included in a comprehensive screening and treatment program (Figure 2). Young women should be aware of whether any direct relatives have a history of BC. They should also conduct self-examinations of both breasts for any lumps, nodules, skin changes resembling orange peel, or nipple discharge and retraction. In addition, young women should complete BC screenings regularly and on schedule. For those with a family history of BC, it is advisable to undergo genetic testing to determine whether they carry PVs in the BRCA1/2 genes. If young BC is diagnosed, the patient’s prognosis and the risk of SPC should be estimated based on the molecular subtype of the BC and the type of PVs. Clinicians should explain the benefits and risks of treatment to patients. For surgical options, it is important to be vigilant about the risk of SPC occurring 10–15 years later. For HR+ patients, it is essential to closely monitor and actively prevent the development of endometrial cancer while undergoing ET. RT carries a high risk for the occurrence of SPC in the chest, and patients should be fully informed about the dual nature of these treatments. Young women can also take relevant intervention measures to reduce the occurrence of high-risk factors. For example, it is advisable to have the first pregnancy between the ages of 25 and 30. In addition, maintaining regular menstrual cycles and a healthy body weight, providing self-encouragement and stress reduction, and avoiding harmful habits such as smoking and drinking are all important steps.
Of course, the above represents an ideal situation, and many current studies still cannot fully explain the underlying mechanisms. First, the mechanisms leading to precancerous and tumor phenotypes are still unclear, and the changes in cancer tissue or the surrounding stromal components remain unknown. This makes it difficult to identify causal signals and their targets. For example, what causes the development of the TNBC, and whether pathogenic genetic mutations have corresponding therapeutic targets. Second, the field of BCYW still lacks strong predictive biomarkers and risk assessment screening tools. Factors related to BC, such as age, hormone levels, menstrual cycles, menopausal status, pregnancy, number of pregnancies, and BF, need to be evaluated as potential independent predictors of SPC in young BC survivors. Therefore, more predictive models are needed for further validation. Third, to better understand the risk of SPC in BCYW and the potential cellular basis, it is essential to describe the details of the hormonal interactions and feedback regulation between the breast and its stroma, as well as the hypothalamic–pituitary–gonadal axis. In addition, we need to explore how these signals affect breast development and the occurrence of SPC during cyclical reproduction. Thus, a comprehensive understanding and research into the occurrence of SPC in BCYW is necessary and aligns with current research trends.
In summary, this review emphasizes the occurrence of SPC, particularly among young BC survivors. Consequently, regular monitoring and screening, along with appropriate treatment plans that weigh the benefits and risks, are crucial for BC survivors to enable early detection and intervention of potential SPC.
