Title of report: second primary ovarian carcinomas after breast cancer diagnosis- an analysis of a single cancer centre in China

Abstract

Objective:

We aimed to evaluate the clinicopathological characteristics and survival outcomes of patients with second primary ovarian carcinomas after a breast cancer diagnosis.

Materials and methods:

We reviewed the medical reports of 23 patients at Sichuan Cancer Hospital between May 2002 and October 2021. We analyzed demographic and clinicopathologic characteristics, the time interval between diagnoses, and survival time. Kaplan-Meier and Cox proportional hazards regression tests were used to determine survival outcomes.

Results:

The median age of patients at the time of diagnosis of breast cancer (BC) and ovarian cancer (OC) was 46 and 49 years, respectively. Among them were 6 cases of synchronous OC and 17 instances of metachronous OC. The average interval between diagnoses of the two cancers was 62.48 months. The median OS after the second primary OC diagnosis was 38 months. According to Kaplan-Meier’s analysis, the advanced stage at presentation of BC (p=0.023) resulted in a significantly shorter interval between BC and OC diagnosis. On univariate Cox regression analysis, only BC Scarff-Bloom-Richardson (SBR) 3 Grade resulted in a considerably worse PFS (HR 0.187, p=0.048) and OS (HR 0.190, p=0.048), respectively.

Conclusion:

We should strengthen the follow-up management of breast cancer patients.The later the stage of breast cancer, the shorter the time interval of diagnosis of OC was. Early control of ovarian tumors and active comprehensive treatment for synchronous and metachronous breast and ovarian cancer can achieve good results.

Highlights

• We should strengthen the follow-up management of breast cancer patients.

• The later the stage of breast cancer, the shorter the time interval of diagnosis of OC was.

• Early control of ovarian tumors and management throughout the treatment of BC and OC can yield good result.

1 Introduction

Multiple primary cancer (MPC) refers to the simultaneous or sequential occurrence of two or more primary cancers in the same patient’s single or multiple organs, with the same or different tissue types but no subordinate relationship between the tumors. Synchronous tumors are defined as the diagnosis of both primary tumors at the same time or second primary cancers detected within six months of primary tumor detection, while metachronous tumors have been defined as the diagnosis of both primary tumors more than six months apart.

In recent years, more and more patients with breast cancer have ovarian cancer many years later. Still, the diagnosis and treatment of some patients are often delayed due to a lack of attention. Lee et al. reported that the incidence of recurrent breast cancer second tumors in breast cancer was 2.02%, of which 0.34% were patients with ovarian cancer (1). Young women with a history of breast cancer were at high risk for ovarian cancer even 20 years after diagnosis (2). It is known that both breast and ovary are target organs of the sex hormone regulation axis, and they also have some common regulatory genes (3, 4), which may be the disease basis of breast cancer combined with ovarian cancer. Hereditary breast cancer ovarian cancer syndrome (HBOCS) is the most common underlying cause of hereditary breast cancer, with an incidence of 2%~7% in all breast cancer (5). BC and OC presenting as a synchronous or metachronous tumour often pose a diagnostic dilemma.There are many similarities between the primary ovarian cancer and the ovarian metastases from breast cancer but the treatment methods and prognosis between the two groups are different. So we should be focused on the differential diagnosis of metastatic disease and primary ovarian neoplasms.

There is little known regarding the time intervals between initial BC and OC diagnosis, as well as the prognosis of people with both cancers. So our study looked at the clinicopathological characteristics, time intervals between these two primary tumors, and survival outcomes of patients with second primary ovarian carcinomas after a breast cancer diagnosis.

2 Materials and methods

2.1 Patients

We reviewed medical reports of patients with second primary ovarian carcinomas after breast cancer diagnosis between January 2002 and December 2021 at Sichuan Cancer Hospital. The information includes demographic data, tumor stage (BC staging according to the 8th edition American Joint Committee on Cancer staging system while OC staging according to the 2018 International Federation of Gynecology and Obstetrics staging system), histological type, tumor grade, hormonal/HER2 receptors status (BC), surgical and medical treatment, the time intervals between double primary breast and ovarian cancers and disease-related outcomes, et al. were collected. The Institutional Review Board of Sichuan Cancer Hospital approved this study. The requirement for informed consent was waived because we analyzed de-identified data secondarily.

2.2 Pathology

Synchronous and Metachronous Breast and Ovarian Cancer was confirmed using a panel of IHC markers, PAX8, WT1, P53, CA125, and P16 for OC, and estrogen receptor (ER), progesterone receptor (PR), HER2, mammaglobin, GCDFP-15, GATA3 for BC. Additional markers such as CK7, CK20, and Vimentin were performed to rule out metastatic disease from the gastrointestinal tract and when required. These markers were used to approximately classify patients into four breast cancer subtypes: luminal A (ER + or PR +, and HER2 -); luminal B (ER + or PR +, and HER2 +); HER2 enhanced (ER -, PR- and HER2 +); and triple negative (ER -, PR - and HER2-).

2.3 Statistical analysis

Statistical analysis was conducted using SPSS statistical software version 27 (IBM Corp.). The association between variables was evaluated using the χ2 or t-test, as appropriate. Overall survival (OS) was calculated as the interval between each cancer diagnosis and death or last follow-up. We also evaluated the progression-free survival (PFS) after the OC diagnosis, calculated from the time of OC diagnosis to progression or last follow-up. Survival curves were estimated using the Kaplan–Meier model and the hazard ratio (HR) and 95% confidence interval (95% CI) were calculated with the Cox regression model. Level of significance was set at 0.05. The data cut-off for the survival events was March 2024.

3 Results

3.1 Clinico-pathological characteristics

A total of 23 patients were included in the study, and the median age at BC or OC diagnosis was 46 years (32-62 years)and 49 years (40-71 years), respectively. Among them were 6 synchronous OC and 17 cases of metachronous OC. Only one patient has a family history of tumors; her mother suffers from rectal cancer, and her brother suffers from lung cancer. Approximately 56.5% of OC cases occurred during the first 60 months after the BC diagnosis. The most common histological subtype of OC was high-grade serous carcinoma (19/24, 82.6%), other 4 patients was endometrioid adenocarcinoma. At the time of diagnosis of OC, the median serum CA-125 levels were 448.7 U/mL (16.4-3578 U/mL) (Table 1).

All patients were treated following discussion in a multidisciplinary team. Surgery for BC comprised modified radical mastectomy (MRM) and breast conservation surgery (BCS), followed by chemo-endocrine therapy and radiotherapy as per institutional protocols depending on the stage and immunophenotype of breast cancer. For patients with OC, 3 patients received chemotherapy alone due to extensive lesions or refusal of surgery. Among 6 cases of synchronous OC who were all diagnosed at the same time with BC, five patients underwent PDS and one patient underwent IDS; considering that the prognosis of ovarian cancer is worse than that of breast cancer, all patients firstly underwent surgery for ovarian cancer and adjuvant chemotherapy then obtained breast cancer surgery (Table 2).

3.2 Long-term outcome

Five patients (21.7%) was lost to follow-up, 8 patients (34.8%) died due to progression of OC. The average interval between BC and OC diagnosis was 62.48 months (Table 2). The median PFS and OS after OC diagnosis was 15 months and 38 months, respectively.

On Kaplan-Meier analysis, the advanced stage at presentation of BC (p=0.023) resulted in a significantly shorter interval time between BC and OC diagnosis (Figure 1). On the univariate Cox regression analysis, it was also found that the later the BC stage was, the shorter interval time between the diagnosis of BC and OC was (HR 8.047, p = 0.055), although it was not statistically significant (Table 3). On univariate Cox regression analysis, only BC SBR Grade 3 resulted in a significantly worse PFS (HR 0.187, p=0.048) and OS (HR 0.190, p=0.048), respectively (Table 4).

Figure 1

4 Discussion

In this article, the average age of BC was 45.78 years and 73.9% of them were under 50 years old. 78.3% patients were in premenopausal. Tong et al. (6) reported that MPC patients onset 10-20 years earlier than primary epithelial ovarian cancer (average age 56-60 years) and are more common in premenopausal women. Berkowitz et al. (2) found that for women diagnosed with BC at an age younger than 50, the relative risk (RR) of OC diagnosed within two months to 5 years was 2.5 [95% confidence interval (CI): 2.1 -2.9]. Thus, it can be seen that the risk of postoperative OC in young patients with BC is significantly higher, which is similar to the results of this study.

Patients with double primary BC and OC are sporadic. Suppose women have a history of unmarried and childless, family inheritance, triple-negative breast cancer, postoperative oral selective estrogen antagonist, and BRCA1/BRCA2 gene mutation. In that case, they should be particularly alert to the possibility of the occurrence of OC after breast cancer surgery. The most important risk factors are the family history of the tumor (especially the medical history of first-degree relatives) and BRCA1/2 gene mutations (7). The estimated risk of developing ovarian cancer is increased approximately 2-fold for patients with a history of breast cancer (8). Metcalfe et al. reported a 10-year actuarial risk of developing EOC after BC of 12.7% for BRCA1 and 6.8% for BRCA2 mutation carriers (p=0.03) (9). In our study, due to the lack of widespread testing technology and high testing costs in earlier years, the vast majority of patients had not undergone BRCA gene mutation testing. Five patients had BRCA germline mutation. Thus, it can be seen that BRCA1/2 gene screening is essential for the prevention and early detection of hereditary breast cancer/ovarian cancer. By accurately stratifying patients’ risk and guiding targeted screening and preventative interventions, development of a novel prediction model for carriage of BRCA1/2 pathogenic variant in patients with breast cancer will contribute to improved management and outcomes of HBOC (10). In this article, only one patient has a family history of tumors, which suggesting that double primary breast and ovarian tumors can also appear in those without prior relevant clinical or family histories and other common etiological factors such as hormonal and reproductive aspects and mutation of different genes involved in tumor suppression may also induce cancer to occur (11–13).Other relevant genes are related to HBOC syndrome diagnosis, prognosis, and treatment, including TP53, PALB2, CHEK2, ATM, etc. Multi-gene testing implementation improves the detection of often overlooked genes related to HBOC pathogenesis and treatment (14). The majority of cases of breast cancer were initial (IA - IIA), luminals and treated with radical mastectomy in our study,Generally, this type of breast cancer has a good prognosis, but the simultaneous occurrence of ovarian cancer in this type of patients indirectly proves that genetic factors such as BRCA mutations may lead to secondary ovarian cancer rather than metastasis.In our study, 5 patients had BRCA mutations, and 18 patients had unknown BRCA detection status. The study showed that the mutation status of BRCA did not affect the survival of the patients.As several reports suggested (15–17), the initial survival advantage among EOC patients with BRCA mutations may reflect a higher initial sensitivity of BRCA carriers to chemotherapy and short-term survival but this response does not predict long-term survival. The strongest predictor of long-term survival is the status of no residual disease at resection. Though BRCA mutations appear to be associated with improved OS and PFS in patients with ovarian cancer, there has no difference in the surgical resection rate between participants in the two groups (18). Another study also proves that BRCA-status is not a prognostic factor in early ovarian cancer regarding PFS (19). It should emphasize the major impact of achieving complete surgery on the prognosis of HRD EOCs with or without BRCA1/2 mutation, whether in primary surgery or interval surgery, despite a better sensitivity to chemotherapy and maintenance treatments with PARP inhibitors (20).

In our study, the average interval between BC and OC diagnosis was 62.48 months, and approximately 43.5% of second primary OC cases occurred after the first 60 months of the BC diagnosis, suggesting that breast cancer patients who have achieved long-term survival should also be alert to the occurrence of ovarian cancer. Metcalfe et al. (9) found a mean time of 8.1 years (range 0.1–25.5 years) from BC to OC. In this article, the Kaplan-Meier approach revealed that the later the stage of breast cancer, the shorter the time interval of diagnosis of OC was. It reminds doctor to strengthen the follow-up management of breast cancer patients, especially the screening management of high-risk patients with ovarian cancer. During the follow-up of breast cancer, attention should be paid to gynecological examination and gynecological ultrasound examination. If the patient is taking tamoxifen and the uterus and ovary are not removed surgically, they should be examined every 3-6 months. If patients with BRCA mutations are recommended to undergo prophylactic bilateral adnexectomy to reduce the risk of ovarian cancer. One meta-analysis revealed that prophylactic interventions significantly reduced cancer risk and mortality. Risk-reducing surgeries (RRS) were more effective than chemoprevention, with RRS notably reducing cancer risk by 56% compared to 39% for chemoprevention (21). Joshi S suggested timing prophylactic oophorectomy 5–6 years after diagnosis of first BC based on the median time interval before development of second cancer to be 77 months after diagnosis of OC (22). Our study found that approximately 56.5% of OC cases occurred during the first 60 months after the BC diagnosis, therefore, prophylactic oophorectomy should be performed more earliar.

In our study, most of the patients were bilateral tumors (65.2%), ovarian tumors’ size was >5cm (73.9%), the pathological types of ovarian cancer were mostly serous papillary carcinoma and endometrioid carcinoma, and the ovarian tumor was located in the epithelium. The main emphasis should be to differentiate BC from primary OC and vice versa for subsequent best management of these patients to decide curative or palliative approach. The clinicopathological characteristics of breast cancer with ovarian metastasis are as follows: most of them have no obvious symptoms, and a few of them have symptoms, such as abdominal distention, ascites, abnormal vaginal bleeding, etc (14).Breast metastases to the ovary most frequently are bilateral solid masses at ultrasonographic (US) with small tumor size, multiple nodules and involvement of the surface (17, 23–26), while patients with primary OC had predominantly cystic images at US (27). Previous tumor history is an important factor to assist in the differential diagnosis of primary or metastatic ovarian cancer. It is reported that patients with BC are 3-7 times more likely to develop primary ovarian cancer (POC) than ovarian metastases (OM) (28). A single imaging or CA125 examination is not meaningful in distinguishing between primary and metastatic ovarian tumors. Many ovarian metastatic adenocarcinoma and primary ovarian cancer have extremely similar pathological morphology and clinical pathological types, requiring careful pathological identification. Immunohistochemistry has a pivotal role in differentiating primary and secondary ovarian adenocarcinoma. In our study, ovarian tumor cell immunohistochemistry showed positive expression of P53, WT-1, PAX8, Ck7, P16, ER, and CA125, while GCDFP-15, mammaglobin, GATA3, CK20, Vimentin expression were negative. WT1 and PAX8 appear to have utility in differentiating primary OC from metastatic BC due to their higher sensitivity and low potential for aberrant expression (29). GATA3 is a very specific marker for breast cancer (and urothelial carcinomas) (30). Wick et al. reported that the overall sensitivity of GCDFP 15 in the diagnosis of breast cancer is 74%, the specificity is 95%, and the negative predictive value is 95% (31). Monteagudo et al.found that GCDFP-15 was positive in 71% of breast cancer metastatic to the ovary, while none of the primary ovarian cancer was positive (32). Mammaglobin, GCDFP-15, CK7, and GATA-3 are the most commonly used markers to confirm breast origin. Because none of these markers is completely specific and/or sensitive, ovarian markers should be included to obtain the differential diagnosis (33).

In our study, there were 6 cases of synchronous OC. Among them, 5 patients underwent PDS and one patient underwent IDS. All of them firstly underwent surgery for ovarian cancer and adjuvant chemotherapy then obtained breast cancer surgery. Primary BC and OC in the same patient must be treated following the best evidence available for each tumor, considering disease stage, pathology findings and molecular characteristics. Currently, there is no standard treatment of patients with synchronous OC and BC. Neoadjuvant chemotherapy was effective in both breast and ovarian cancer. We used platinum drugs, taxanes, and anthracycline agents, which were active in both diseases. In the context of advanced disease, treatment may be tailored according to prognosis, patient´s performance status and preferences. According to research reports, early control of ovarian tumors with poorer prognosis can avoid distant metastasis and widespread implantation metastasis as early as possible (34–36). In our study, all of patients were died of OC progression. Studies reported that OS survival was dominated by the stage of disease (37, 38) and the most virulent of the synchronous tumors defined mortality rates, while the mortality rate of individuals with metachronous tumors was determined by second malignancies after the first neoplasm was cured (39).

As we known,PARP inhibitors (olaparib, niraparib) are effective targeted therapies in BRCAm ovarian cancer in first-line treatment as well as in maintenance therapy after platinum based chemotherapy for ovarian cancer recurrence (40–43). In our study,the vast majority of patients did not receive maintenance treatment with PARPi due to economic reasons and the fact that PARPi was only approved for ovarian cancer in China after 2018. Only 6 patients received PARP inhibitor maintenance treatment, among them, four patients receiving first-line maintenance therapy, including two BRCA mutation patients receiving olaparib maintenance therapy, two patients with unknown genetic testing status receiving nirapali maintenance therapy, and two second-line maintenance therapy patients with BRCA mutations receiving olaparib maintenance therapy. PARP inhibitors reduced the risk of disease progression and death (HR=0.024) and (HR= 0.029), respectively, although it was not statistically significant, which may be related to only a few patients in our study had received PARPi maintenance treatment.

To the best of our knowledge, this is one of the few study to investigate the time intervals and prognosis of individuals with both primary BC and OC. But it also has several shortcomings. Firstly, It was retrospective study and the sample size was relatively small which limits the generalizability of the conclusions. Secondly, there were a limited number of patients who underwent BRCA1/2 gene testing and maintenance therapy. Thirdly, the analysis did not include the assessment of treatment after OC recurrence. Future studies with larger sample sizes and more rigorous research designs are necessary to further elucidate the prognostic value of variables such as age, disease characteristics, mutation type, targeted therapy, intervention, surveillance and prophylactic surgery and to identify the appropriate management strategies for this specific population.

In conclusion, patients with breast cancer may have ovarian cancer later,it reminds doctor to strengthen the follow-up management of breast cancer patients, especially the screening management of high-risk patients with ovarian cancer. Early control of ovarian tumors and active comprehensive treatment for synchronous and metachronous breast and ovarian cancer can achieve good results.

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