Long-term survival of screen-detected synchronous and metachronous bilateral non-palpable breast cancer among Chinese women: a hospital-based study (2003–2017)

The growing awareness, prolonged lifetime, advancements in diagnostic imaging, and improvements in detection rate from diversified screening had resulted in increased incidence of BBC and SBBC [2, 3, 12, 13]. Studies on survival of screen-detected BBC are difficult to conduct because there are several issues bringing complexity: (1) the heterogeneity of contralateral BC: for ipsilateral NPBC, the contralateral BC could be screen-detected NPBC, screen-detected symptomatic BC or interval BC; (2) the parameter of diagnostic interval: the contralateral BC could be synchronous or metachronous; (3) the parameter of diagnostic sequence: for ipsilateral NPBC with contralateral palpable or interval BC, would it be different whether the ipsilateral NPBC comes first or after the contralateral BC?

To our knowledge, our study was the first to investigate the long-term prognosis of screen-detected synchronous and metachronous BBC with the concern of contralateral palpable or non-palpable BC among Chinese women. The BC screening in China is quite diversified [3, 7, 12, 14, 15] so the screen-detected symptomatic BC and interval BC were usually difficult to differentiate and both documented as contralateral palpable BC in our study. The long-term follow-up of median 91 months was to ensure accurate evaluation of personalized prognosis and sufficient detection of metachronous BBC. To decipher the complexity of prognosis of screen-detected BBC, we choose interval of 6 months between detection of bilateral cancers as the criteria to differentiate SBBC versus MBBC to minimize the confounding effects on comparison of survival [8]. As for the third issue mentioned above, there were only 9 NPBC diagnosed before contralateral palpable BC, whereas 8 NPBC came after, which was too small case number for survival comparison. Studies suggested that risk of third primary cancers of non‐breast origin among women with BBC would also increase, indicating that BBC might be genetically susceptible to develop cancer [16]. Hence we chose RFS in addition to OS as prognostic endpoint so that the relapse events were breast cancer specific and diseases such as third primary cancers including thyroid, lung, pancreas, or cardiovascular diseases, etc. would be excluded as RFS events.

In our study, the development of contralateral BC in MBBC would also be taken as a relapse event. Otherwise, the survival outcome of the first tumor (ipsilateral BC) of MBBC would be over-estimated. For example, the contralateral BC showed different histology or subtype from ipsilateral BC, and then recurrence arose years later from the contralateral BC, if the development of contralateral BC was not taken as a relapse event, it was also unreasonable to take this recurrence from contralateral BC as a relapse event of the ipsilateral BC, then the RFS of the first tumor (ipsilateral BC) would be largely biased and over-estimated too much.

As for the clinicopathological features, study suggested that index cancers of bilateral screen-detected cancers and bilateral interval cancers show significant differences in tumor size, whereas nodal status, receptor status, and final surgical treatment are comparable [17]. Our study showed that the clinicopathological characteristics of screen-detected NPBC in those (N + Contra) PBC patients were similar to those of BiNPBC (Table 2). Taken together, it implied that screen-detected NPBC, either bilateral or ipsilateral, might be different clinical entities with contralateral palpable interval BC, even in the same patient and regardless of synchrony or metachrony.

There were controversies about whether adjuvant therapy for BBC should base on the higher risk tumor or the index tumor [18] and adjuvant chemotherapy might paradoxically both reduce the risk and worsen the prognosis of MBBC [13]. For screen-detected BBC, this paradox also included escalation or de-escalation of the treatment. Our study showed (N + Contra) PBC received more chemotherapy than BiNPBC due to existence of contralateral palpable BC (Table 2), however (N + Contra) PBC still showed worsened survival than BiNPBC, suggesting that the treatment of (N + Contra) PBC should be escalated. Similar to reports from other studies that majority of BBC patients (69.0–76.2%) would usually choose bilateral mastectomy even with young age [9, 19, 20], (N + AnyContra) PBC patients in our study also received more mastectomy compared to UniNPBC (79.3% vs. 67.6%, Table 1).

Study implied that women were more likely to have small breast cancer that was detected in screening than to have earlier detection of a tumor that was destined to become large [5]. In other words, early BC including NPBC could be detected small because they were good in biological behavior rather than they were good in prognosis because they were detected small. Our study results were highly coincided with this. Bilateral NPBC (BiNPBC) was actually screen-detected low-risk BC with similar prognosis as unilateral NPBC (UniNPBC) (Table 3, Fig. 2). Thus, the therapy of BiNPBC could be tailored according to UniNPBC and should not be intensified as those symptomatic SBBC. On the contrary, if the contralateral BC was palpable [(N + Contra) PBC], then it was in essence bilateral symptomatic interval BC with compromised survival (Table 3, Figs. 2, 3). The 10-year OS 70.1% of Syn(N + Contra)PBC (Table 4, Fig. 3) was close to the 10-year OS 71–77% of SBBC reported in our previous study [8]. Hence the treatment of Syn(N + Contra)PBC should be intensified as symptomatic SBBC and the therapy of Meta(N + Contra)PBC should be similar as unilateral symptomatic interval BC. Syn(N + Contra)PBC and SynBiNPBC belonged to distinct clinical entities with different prognoses and thus should be treated differently (Table 4, Figs. 2, 3). Taken together, these results implied that the survival ordered from poor to favorable might be like: Syn(N + Contra)PBC ≤ (N + Contra)PBC ≤ Meta (N + Contra) PBC ≌ symptomatic unilateral BC (UBC) < MetaBiNPBC ≤ SynBiNPBC ≌ BiNPBC ≌ UniNPBC.

The key strength of this study was that the clinicopathological features and survival outcomes were compared between both UniNPBC vs BBC and among subgroups of BBC with long follow-up time of 48–227 (median 91) months. There are several limitations in our study. Firstly, although majority of BBC could not fully be explained by BRCA carriership [18, 21], there was limited germline mutation data about BRCA1/2 and other BC related genes in the current study. Several studies suggest that BBC is one of the related clinical factors that increases the probability of BRCA mutations [9, 22] and remains one of the criteria for recommendation of genetic testing [23]. BRCA mutation rate was about 24% among Chinese women with BBC [22]. Interval breast cancers among BRCA mutation carriers have worse clinicopathologic features than screen-detected tumors, and require more aggressive medical and surgical therapy [6]. Association between BRCA mutation and survival of BBC and screen-detected BBC would be further studied in our future research. Secondly, due to the BC screening conditions in China [3, 7, 12, 14, 15], there was no clear-cut documentation of whether the contralateral palpable BC was screen-detected symptomatic or interval BC between regular screenings, which had overlap but were not identical clinical entities [24]. So they were both regarded as ContraPBC in this study. Thirdly, it was a retrospective single-center study based on hospital population with limited case number. Thus comparison between NPBC as first cancer and NPBC as second cancer among Meta(N + Contra)PBC could not be performed. Last but not the least, the patients enrolled in this study were collected over 15 years (2013.01–2017.12), although the follow-up time was long enough to identify the metachronous BBC with long interval, the improvement of neo/adjuvant therapy would inevitably bring bias to prognosis of BBC due to the heterogeneity in BC treatment over decades.

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