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Clinicopathological features, treatment patterns, and prognosis of squamous cell carcinoma of the breast: an NCDB analysis

Clinicopathological features, treatment patterns, and prognosis of squamous cell carcinoma of the... Background: Squamous cell carcinoma (SCC) of the breast is a rare malignancy. The clinicopathological features, treatment patterns and prognosis of SCC of the breast is still unclear. Methods: In this study, we performed a 1:4 SCC-IDC (infiltrating ductal carcinoma) matching analysis of patients diagnosed between 2004 and 2014, using the data from the national cancer database. We used Chi-square test to compare the clinicopathological features and treatment patterns between SCC (n = 686) and IDC (n = 2744) patients. We used Kaplan-Meier analysis and Cox-regression to estimate the survival of SCC and IDC patients. Results: We observed that SCC patients are more likely to have T3–4, grade III, and ER negative diseases, when compared to IDC patients. Breast conserving surgery (BCS) (58.3% vs 65.4%, p = 0.048), as well as radiotherapy after BCS (65.3% vs. 83.0%, p < 0.001), was less performed in SCC patients. Among low-risk patients, chemotherapy was used more often for SCC patients (42.9%) than for IDC (18.7%) patients (p = 0.002). In HR-positive patients, endocrine therapy was used less often for SCC patients (51.6%) than for IDC patients (70.5%) (p < 0.001). SCC (vs. IDC) was associated with no responses to neoadjuvant chemotherapy (20% vs. 5.05%, p = 0.019). Adjusted analysis confirmed that SCC (vs. IDC) was associated with worse OS (HR = 1.40, 95%CI 1.17–1.67, P < 0.01), after a median follow- up of 58.3 months. In SCC patients, HR status is not prognostic of OS, but endocrine therapy was significantly associated with improved OS in HR-positive SCC patients. Conclusions: We conclude that SCC is associated with poorer clinicopathological features, no responses to neoadjuvant chemotherapy and worse clinical outcomes than IDC. The treatment patterns for SCC and IDC are different. Endocrine therapy is necessary for HR-positive SCC patients. Keywords: Breast cancer, Squamous cell carcinoma, Infiltrating ductal carcinoma, Survival, Endocrine therapy, Chemotherapy Background component is still an unanswered question. A recent Squamous cell carcinoma (SCC) of the breast is a rare study [3] showed that SCC and its adjacent infiltrating malignancy that accounts for < 0.2% of all breast cancers ductal carcinoma (IDC) component shared the same ori- [1]. Diagnosis of SCC can be made when a predomin- gin, but their transcription landscape [4] and driven- ance (> 90%) of areas with squamous cells is noticed at pathways [5] are different. Thus, whether the differing histology examinations [2]. The origin of the SCC histology of SCC may result in different biological be- havior, different treatment patterns and prognosis is * Correspondence: zhuliling@mail.sysu.edu.cn; liling.zhu@yale.edu; not clear. Most of the studies [1, 6] are limited sig- chenkai23@mail.sysu.edu.cn nificantly by their small sample size, due to its rarity. Department of Breast Surgery, Breast Tumor Center, Sun Yat-sen Memorial Therefore, a national cancer database remains as the Hospital, Sun Yat-sen University, 107 Yanjiang West. Road, Guangzhou 510120, People’s Republic of China only choice to provide adequate sample size to inves- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and tigate SCC of the breast. Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Zhu and Chen BMC Cancer (2019) 19:26 Page 2 of 9 The national cancer database (NCDB) is a hospital- estrogen receptor (ER) status, progesterone receptor (PR) based database that covers approximately 70% of cancer status, HER2 status, primary surgery categorization, radi- patients in the United States [7]. The participating cen- ation therapy (RT), chemotherapy, neoadjuvant chemother- ters are required to submit data to the database. In this apy, response to chemotherapy, endocrine therapy, survival study, we used the NCDB to compare the clinicopatho- month and OS status. Patients were categorized into three logical features, treatment patterns and prognoses of age groups based on their ages at diagnosis (≤50 yrs., 50– IDC and SCC patients. We hypothesized that SCC (vs. 60 yrs., > 60 yrs). We used this cut-off because the median IDC) was associated with poor clinicopathological char- age was close to 60 yrs. in our study population and be- acteristics, different treatment patterns, and worse sur- cause 50 yrs. is the usual cut-off age for premenopausal and vival. We also performed an exploratory analysis of the post-menopausal women. Histology was divided into two benefits of systemic therapies for SCC patients. categories, namely, IDC and SCC. Methods Statistical analysis We searched the NCDB for eligible patients using the We conducted a descriptive analysis of the baseline clin- inclusion and exclusion criteria below: icopathological features of the included patients and used the Chi-square test to compare the characteristics Inclusion of the patients with different histologies. The median follow-up time was calculated as the median observed 1) Female patients with pathologically confirmed survival time of the entire population. OS was measured breast cancer, as the time from diagnosis to death due to any cause. 2) Patients who were diagnosed between 2004 and The cumulative OS rates were estimated using Kaplan- 2014, and Meier analysis. We used a Cox regression model to 3) Diagnoses of SCC of the breast (code 8070–8078), screen for prognostic factors of OS. We tested the pro- and IDC (code 8500). portional hazards assumption by plotting the scaled Schoenfeld residuals of all coefficients over time and Exclusion criteria found no violations. All P-values were two-sided. P- values less than 0.05 were considered statistically signifi- 1) Patients with prior diagnoses of malignant tumors cant. Statistical analysis was performed using Stata/MP, and version 13.0 (StataCorp LP, College Station, TX, USA). 2) A number of follow-up months equal to 0. Results A total of 686 SCC patients and 1,211,403 IDC patients A total of 3430 patients (IDC: 2744; SCC: 686), with a me- were identified from the database. Given the huge discrep- dian age of 61 years, were included in this study. The clini- ancy of the amount of the SCC and IDC patients, we copathological features are listed in Table 1. In general, performed a 1:4 SCC-IDC matching on the following fac- SCC is associated with poorer clinicopathological features. tors: Year of diagnosis (2004–2014), Facility type (Commu- A total of 23.1% of the SCC patients had T3–4disease, nity Cancer Program, Comprehensive Community Cancer whereas only 4% of the IDC patients had T3–4disease. The Program, Academic/Research Program, Integrated Net- proportions of grade III disease were 61.06 and 39.10% for work Cancer Program, Unknown), Facility location (New the SCC and IDC patients, respectively. Additionally, the England, Middle Atlantic, South Atlantic, East North Cen- proportions of ER-negative tumors were 74.91 and 21.95% tral, East South Central, West North Central, West South for the SCC and IDC patients, respectively. The distribution Central, Mountain, Pacific), city type (Metropolitan, Non- of N-stage was similar between SCC and IDC patients. metropolitan/Unknown), type of insurance (Not insured, Private insurance, Medicaid, Medicare, other Government, Different treatment patterns between SCC and IDC patients Unknown.). There were 686 SCC and 2744 IDC patients In patients with T1–2 stages who did not received neoad- being selected as the final cohort for analysis. This study juvant chemotherapy, there were 58.3% (120/206) vs. was an epidemiological study using de-identified data 65.4% (890/1362) of the SCC and IDC patients received from the NCDB database. Therefore, consent for patient BCS (P = 0.048) respectively. Among the patients with participation and study publication was not required. The BCS (N = 1791, 16 patients with unknown RT status were study approval was waived by the ethical committee of excluded.), 65.3 and 83.0% of the SCC and IDC patients Yale University and Sun Yat-sen Memorial Hospital. received RT (P < 0.01), respectively. The use of RT in The following data were collected for each patient: the node-positive patients with mastectomies, were similar in year of diagnosis, age, race, Charlson-Deyo score, tumor SCC and IDC patients (42.1% (37/88) vs. 48.4%(166/343), grade, lymphovascular invasion, T-stage, N-stage, histology, P =0.287). Zhu and Chen BMC Cancer (2019) 19:26 Page 3 of 9 Table 1 Clinicopathological features of study population Histology P Infiltrating Ductal Carcinoma Squamous Cell Carcinoma a a N% N% Race White 2259 83.33 540 79.65 < 0.01 African American 343 12.65 119 17.55 Others 109 4.02 19 2.80 Unknown 33 8 Charlson-Deyo Score 0 2346 85.50 555 80.90 0.02 1 328 11.95 104 15.16 2 54 1.97 20 2.92 3 16 0.58 7 1.02 Grade I 476 18.90 62 11.33 < 0.01 II 1058 42.00 151 27.61 III 985 39.10 334 61.06 Unknown/IV 225 139 Lymphovascular Invasion Absence 768 79.67 185 85.65 0.04 Present 196 20.33 31 14.35 Not Applicable 1780 470 T-Stage T0-T1 1441 52.51 145 21.14 < 0.01 T2 502 18.29 178 25.95 T3 67 2.44 100 14.58 T4 45 1.64 58 8.45 Tx 689 25.11 205 29.88 N-Stage N0 1373 50.04 331 48.25 0.228 N1 381 13.88 85 12.39 N2 115 4.19 22 3.21 N3 56 2.04 16 2.33 Nx 819 29.85 232 33.82 M-Stage M0 2250 82.00 490 71.43 < 0.01 M1 49 1.79 23 3.35 Mx 445 16.22 173 25.22 Estrogen Receptor Negative 569 21.95 421 74.91 < 0.01 Positive 2023 78.05 141 25.09 Unknown 152 124 Progesterone Receptor Negative 843 32.69 491 87.84 < 0.01 Positive 1736 67.31 68 12.16 Zhu and Chen BMC Cancer (2019) 19:26 Page 4 of 9 Table 1 Clinicopathological features of study population (Continued) Histology P Infiltrating Ductal Carcinoma Squamous Cell Carcinoma a a N% N% Unknown 165 127 HER2 Negative 829 78.2 207 87.7 < 0.01 Borderline 31 2.9 2 0.9 Positive 200 18.9 27 11.4 Unknown 156 68 Breast Surgery No_Surgery 167 6.10 90 13.16 < 0.01 Breast-conserving surgery 1561 56.99 246 35.96 Mastectomy 1010 36.87 348 50.88 Surgery (Types_Unknown) 1 0.04 0 0.00 Unknown 5 2 Radiation Therapy No 1119 41.23 373 54.93 < 0.01 Yes 1595 58.77 306 45.07 Unknown 30 7 Chemotherapy None 1506 58.28 294 46.08 < 0.01 Single-Agent Chemotherapy 44 1.70 23 3.61 Multiagent Chemotherapy 1034 40.02 321 50.31 Unknown 160 48 Neoadjuvant chemotherapy No 1884 89.89 447 83.86 < 0.01 Yes 212 10.11 86 16.14 Unknown 91 14 Endocrine Therapy No 1110 42.53 567 85.91 < 0.01 Yes 1500 57.47 93 14.09 Unknown 134 26 Percentages were calculated based on the available data Only patients after 2010 were used for analysis of HER2 status In patients with favorable prognosis (hormone receptor Response to neoadjuvant chemotherapy (HR)-positive, HER2-negative and node-negative), chemo- In this study, there were 298 patients with known his- therapy was performed in 42.9% (12/28) and 18.7% tory of neoadjuvant chemotherapy, and 129 of them had (80/427) of the SCC and IDC patients, respectively clear information about treatment responses (CR, PR, (P = 0.002). In the HR-positive, node-negative patients CR/PR, No response). SCC (vs. IDC) was significantly who were diagnosed before 2010 (when the HER2 associated with no responses to neoadjuvant chemother- status was unknown), there were 51.6% (32/62) and apy (20% vs. 5.05%, P = 0.019) (Table 2). 24.9% (248/997) of the SCC and IDC patients who had received chemotherapy, respectively (P < 0.001). Survival analysis Among the patients with HR-positive disease, endo- With a median follow-up time of 58.3 months, the re- crine therapy was performed in 51.6% (79/153) and spective 5-yr and 10-yr OS were 62.1 and 50.6% for the 70.5% (1446/2050) of the SCC and IDC patients, re- SCC patients, and 83.0 and 69.5% for the IDC patients, spectively (P < 0.001). respectively (P < 0.001). SCC (vs. IDC) was associated Zhu and Chen BMC Cancer (2019) 19:26 Page 5 of 9 Table 2 Response to neoadjuvant chemotherapy by histology several important prognostic factors, and the information of adjuvant therapies were lacking in the SEER database. Category 1 In contrast, the NCDB database provides more prognostic Histology CR PR, CR/PR No response Total P* factors (e.g comorbidity score, HER2 status and LVI N% N% N % N % status), as well as the information of adjuvant therapies IDC 35 35.35 59 59.6 5 5.05 99 100 0.042 (chemotherapy and endocrine therapy), therefore allows a SCC 8 26.67 16 53.33 6 20 30 100 more accurate estimation with less bias. In this study, we Category 2 observed that the SCC patients had poorer clinicopatho- logical features (e.g., T3–4, grade III, HR-negative disease) Histology Response (CR, PR, CR/PR) No response Total P* than the IDC patients. The adjusted analysis demonstrated N% N % N% that the SCC patients had significantly worse clinical out- IDC 94 94.95 5 5.05 99 100 0.019 comes than the IDC patients in both the 2004–2014 and SCC 24 80 6 20 30 100 2010–2014 (HER2 status adjusted) cohorts. In consistent CR Complete Response, PR Partial Response, IDC Infiltrating Ductal Carcinoma, with previous studies, we confirmed that SCC (vs. IDC) is SCC Squamous Cell Carcinoma associated with poorer OS, after adjusting for more prog- *Fisher Exact test nostic factors and adjuvant therapies. with poorer OS in univariate analysis (HR = 2.39, 95%CI 2.06–2.77, P < 0.001), and in multivariate (HR = 1.40, SCC & systemic therapies 95%CI 1.17–1.67, P < 0.001) analysis after adjusting for The concept that SCC has worse clinical outcomes than age, race, comorbidity, T-stage, N-stage, M-stage, ER, PR, IDC is likely to affect the choice of treatments in the tumor grade, LVI, surgery, endocrine therapy, chemother- clinical practices. This is confirmed in our study that apy and RT (Table 3, & Additional file 1:FigureS1).Inpa- chemotherapy was more prevalent in low-risk (HR+/ tients who were diagnosed after 2010, SCC (vs. IDC) was HER2-/LN-) SCC (vs. IDC) patients (42.9% vs. 18.7%, still associated with poorer OS (HR = 1.57, 95%CI 1.11– P = 0.002). However, whether the SCC is responsive to 2.21, P = 0.011), after adjusting for the above variables, as chemotherapy is still unknown. Hennessy et al. [2] well as LVI and HER2 status. and Zhang et al. [6]reported thattheyused nore- We hypothesized that there was interaction between sponses were observed in their SCC patients after hormonal status (positive vs. negative) and the histology neoadjuvant chemotherapy. Only two case-reports [10, (SCC vs. IDC) in the analysis of OS. We performed a 11] have suggested that cisplatin-based chemotherapy is subgroup analysis and noticed that positive (vs. negative) able to achieve long-term control, but these results need hormonal status was significantly associated with im- further verification. In our study, we noticed that SCC (vs. proved OS in IDC (P < 0.01) patients, but not in the SCC IDC) was significantly associated with no responses to (P =0.042) patients (Fig. 1, Interaction test, P =0.023). neoadjuvant chemotherapy (20% vs. 5.05%, P =0.019). However, endocrine therapy was also associated with im- Therefore, the benefit of chemotherapy in SCC patients proved OS for the HR-positive IDC patients (HR = 0.61, remains unknown. 95%CI 0.48–0.77, P < 0.001), as well as for the HR-positive In this study, we observed that the endocrine therapy SCC patients (HR = 0.30, 95%CI 0.15–0.59, P <0.001) was less performed in the HR-positive SCC (51.6%) pa- (Fig. 2), after adjusting for age, race, comorbidity score, tients, than in the HR-positive IDC (70.5%) patients. A grade, T-stage, N-stage, M-stage, and chemotherapy. contributing reason could be that endocrine therapy in the head & neck or esophageal SCC patients is not use- Discussion ful in clinical practices [12, 13], even if the in vitro evi- Prognosis of SCC patients dences [14, 15] had suggested the role of tamoxifen for Previous studies have shown that SCC of the breast is SCC of the oral cavity or esophagus. However, SCC of more likely to be HR-negative and is associated with the breast might possibly be different from the head & worse clinical outcomes [2, 8, 9]. Hennessy et al. [2]re- neck SCC. A recent study used whole-exome sequencing ported that the 5-year overall survival (OS) rates of 33 and to show that the SCC components have nearly identical 137 SCC patients selected from the M.D. Anderson Can- landscapes of somatic mutations to their adjacent IDC cer Center and the SEER database, respectively, were 40 component, suggesting that SCC may originate from the and 64%, respectively. In an update, Yadav et al [9]re- IDC [3]. Since the role of endocrine therapy had been ported a 5-year cancer-specific survival rate of 63.5% for established in IDC patients, it is possible the endocrine 445 SCC patients who were collected from the SEER data- therapy would also be beneficial in SCC patients. In the base. Due to the rarity of SCC, only the data from the analysis of prognostic factors of OS, we observed a sig- national cancer database is able to provide adequate statis- nificant interaction between the HR status and the hist- tical power to study the prognosis of SCC. However, ology (SCC vs. IDC). The HR status was prognostic only Zhu and Chen BMC Cancer (2019) 19:26 Page 6 of 9 Table 3 Univariate and multivariate analysis of prognostic factors of OS Variables Univariate analysis Multivariate analysis HR(95%CI) P HR(95%CI) P Age < =50 1 1 50–60 1.13 (0.89–1.44) 0.301 1.10 (0.86–1.40) 0.445 > 60 2.25 (1.86–2.74) < 0.001 2.11 (1.72–2.60) < 0.001 Race White 1 1 African American 1.51 (1.26–1.80) < 0.001 1.05 (0.87–1.27) 0.576 Others 0.43 (0.24–0.77) 0.004 0.48 (0.27–0.85) 0.012 Unknown 0.53 (0.24–1.19) 0.126 0.49 (0.22–1.10) 0.082 Comorbidity score Score 0 1 1 Score 1 2.17 (1.85–2.54) < 0.001 1.65 (1.40–1.95) < 0.001 Grade I1 1 II 1.20 (0.94–1.54) 0.149 0.98 (0.76–1.26) 0.877 III 2.05 (1.62–2.58) < 0.001 1.35 (1.05–1.74) 0.02 Unknown/IV 1.86 (1.39–2.49) < 0.001 1.05 (0.77–1.42) 0.767 T-stage T0-T1 1 1 T2 2.24 (1.86–2.69) < 0.001 1.65 (1.35–2.03) < 0.001 T3–4 5.63 (4.60–6.90) < 0.001 2.75 (2.14–3.55) < 0.001 Tx 1.25 (1.04–1.51) 0.017 0.62 (0.45–0.85) 0.003 N-stage N0 1 1 N1 1.82 (1.49–2.22) < 0.001 1.77 (1.43–2.18) < 0.001 N2–3 3.61 (2.90–4.49) < 0.001 2.18 (1.69–2.83) < 0.001 Nx 1.12 (0.94–1.32) 0.197 0.95 (0.70–1.30) 0.764 M-stage M0 1 1 M1 8.47 (6.42–11.17) < 0.001 4.50 (3.29–6.16) < 0.001 Mx 2.04 (1.74–2.39) < 0.001 1.90 (1.53–2.36) < 0.001 Histology Infiltrating Ductal Carcinoma 1 1 Squamous Cell Carcinoma 2.39 (2.06–2.77) < 0.001 1.37 (1.15–1.64) < 0.001 Lymphovascular invasion Absence 1 Not included Presence 1.91 (1.37–2.67) < 0.001 Not applicable/Unknown 2.18 (1.63–2.91) < 0.001 Estrogen Receptor Negative 1 1 Positive 0.53 (0.46–0.61) < 0.001 0.86 (0.67–1.10) 0.218 Unknown 0.85 (0.67–1.08) 0.195 2.46 (0.60–10.15) 0.212 Progesterone Receptor Zhu and Chen BMC Cancer (2019) 19:26 Page 7 of 9 Table 3 Univariate and multivariate analysis of prognostic factors of OS (Continued) Variables Univariate analysis Multivariate analysis HR(95%CI) P HR(95%CI) P Negative 1 1 Positive 0.56 (0.48–0.65) < 0.001 0.96 (0.76–1.20) 0.724 Unknown 0.92 (0.73–1.16) 0.484 0.31 (0.08–1.27) 0.103 HER2 Negative 1 Not included Positive 0.83 (0.57–1.22) 0.347 Borderline/Unknown 1.20 (0.87–1.66) 0.266 Surgery Breast-conserving surgery 1 1 Mastectomy 2.22 (1.90–2.59) < 0.001 1.26 (1.04–1.54) 0.02 Others/Unknown 7.05 (5.77–8.62) < 0.001 6.57 (5.04–8.55) < 0.001 Radiation therapy No 1 1 Yes 0.54 (0.47–0.62) < 0.001 0.92 (0.77–1.10) 0.351 Unknown 0.50 (0.24–1.05) 0.067 0.54 (0.25–1.17) 0.12 Chemotherapy No 1 1 Yes 0.89 (0.77–1.03) 0.116 0.67 (0.55–0.80) < 0.001 Unknown 0.72 (0.53–0.99) 0.043 0.61 (0.43–0.85) 0.004 Endocrine therapy No 1 1 Yes 0.44 (0.38–0.51) < 0.001 0.60 (0.50–0.73) < 0.001 Unknown 0.56 (0.40–0.78) < 0.001 0.77 (0.54–1.09) 0.145 HR Hazard ratio, CI confidence interval Only patients diagnosed after 2010 were included for IDC patients, but not for SCC patients. Despite of this, alterations of SCC and reported that TP53(78%) and we still observed that the endocrine therapy significantly PI3KCA(44%) are the most frequently mutated genes in improves the OS in HR-positive IDC and SCC patients. SCC. They proposed that the mutation affecting genes Taken together, we suggested that endocrine therapy should might result in the Wnt and mTOR pathway activation. Fu- remain as the standard treatment for HR-positive SCC pa- ture studies are warranted to investigate whether relevant tients. Ng et al. [5] studied the landscape of somatic genetic pathway inhibitors could be used for SCC patients. ab Fig. 1 Kaplan-Meier survival analysis stratified by HR status in (a) IDC and (b) SCC patients Zhu and Chen BMC Cancer (2019) 19:26 Page 8 of 9 ab Fig. 2 Kaplan-Meier survival analysis stratified by endocrine therapy in (a) HR-positive IDC patients, and (b) HR-positive SCC patients SCC & local therapy survival benefit of chemotherapy, as patients with more We assessed the influence of the SCC component on the advanced diseases are prone to receive chemotherapy. local therapy. SCC patients had a slightly lower rate of However, estimation of the survival benefit of endocrine BCS, when compared to IDC patients (58.3% vs. 65.4%, therapy in HR-positive patients is less likely to be affected P = 0.048). The underlying reason could be that the SCC by the “treatment-by-indication” bias. HR-positive is the patients had larger tumor than IDC patients (T3–4: only indication for endocrine therapy. In addition, the de- 23.1% vs. 4%). Among patients with BCS, RT was used cision to implement the endocrine therapy is less likely to in 65.3 and 83.0% of the SCC and IDC patients, respect- be influenced by the comorbidity status. Thus, estimation ively. Currently, evidence that support the use of RT for of the survival benefit of endocrine therapy using observa- SCC is lacking. Hennessy et al. [2] reported that 4 out of tional data is reasonable. Due to the rarity of SCC of the 19 SCC patients treated with RT had locoregional breast, a prospective, randomized study for SCC cannot relapse within the irradiated field, suggesting that SCC be realistically implemented. Third, the NCDB did not might be radioresistant. Two studies [16, 17] reported have information regarding trastuzumab therapy. Whether no benefit of RT on OS, but the small sample sizes in trastuzumab would be appropriate for HER2-positive SCC these studies limited their statistical power. Using the patients remains unclear. The lack of information regard- SEER database, Wu et al. [18] reported that RT was ing local relapse, metastatic relapse and cancer-specific significantly associated with improved OS but not survival is also one of the limitations. Fourth, there is a cancer-specific survival, which is difficult to explain. Fur- growing awareness of an association between SCC of the thermore, they reported that RT was significantly associ- breast and implants. But the significance of the association ated with improved CSS in stage II SCC patients, but is unclear due to the rarity of this situation [20–22]. The the analysis was not adjusted for ER, PR or HER2. Thus, NCDB database does not have the information about the the role of RT as an adjuvant local control therapy after history of breast implants augmentation before the diag- surgery remains controversial. nosis of SCC, therefore limits our understanding about this issue. Limitations First, it is possible that the IDC patients may have a small Conclusions proportion of SCC component area. Without pathological In this study, we show that compared with IDC, SCC is confirmation, grouping the cases into IDC, and SCC associated with poorer clinicopathological outcomes. might not be always accurate. However, a detailed histo- The treatment patterns differ between IDC and SCC. pathology examination is impossible in mining large data- Radiotherapy after BCS is used less often for SCC (vs. base, such as NCDB. The large sample size of this study IDC) patients. Chemotherapy is used more often for population is able to compensate this limitation. Second, low-risk (HR+/HER2-, node-negative) SCC (vs. IDC) nonrandomized comparisons of treatment effects are patients. Endocrine therapy is used less often in HR- prone to providing misleading estimations. One study [19] positive SCC (vs. IDC) patients. In addition, SCC is less showed that the treatment effect of RT in breast cancer likely to response to chemotherapy, and is associated was over-estimated in observational data compared with with worse clinical outcomes. Although the HR status randomized clinical trial data. This effect is reasonable as is not prognostic in SCC patients, endocrine therapy is the “treatment-by-indication” bias can never be eliminated still associated with improved OS in HR-positive SCC in observational data. Therefore, we did not estimate the patients. Zhu and Chen BMC Cancer (2019) 19:26 Page 9 of 9 Additional file 2. Hennessy BT, Krishnamurthy S, Giordano S, Buchholz TA, Kau SW, Duan Z, Valero V, Hortobagyi GN. Squamous cell carcinoma of the breast. J Clin Oncol. 2005;23(31):7827–35. Additional file 1: Figure S1. Kaplan-Meier survival analysis stratified by 3. Avigdor BE, Beierl K, Gocke CD, Zabransky DJ, Cravero K, Kyker-Snowman K, histology (IDC vs. SCC) and nodal status in a) HR-positive and b) HR- Button B, Chu D, Croessmann S, Cochran RL, et al. Whole-exome sequencing negative patients. (PDF 62 kb) of Metaplastic breast carcinoma indicates Monoclonality with associated ductal carcinoma component. Clin Cancer Res. 2017;23(16):4875–84. 4. Piscuoglio S, CKY N, Geyer FC, Burke KA, Cowell CF, Martelotto LG, Natrajan Abbreviations R, Popova T, Maher CA, Lim RS, et al. Genomic and transcriptomic BCS: Breast-conserving surgery; ER: Estrogen receptor; HR: Hormonal receptor; heterogeneity in metaplastic carcinomas of the breast. NPJ Breast Cancer. IDC: Infiltrating ductal carcinoma; LN: Lymph node; LVI: Lymphovascular 2017;3:48. invasion; NCDB: National cancer database; OS: Overall survival; PR: Progesterone 5. Ng CKY, Piscuoglio S, Geyer FC, Burke KA, Pareja F, Eberle CA, Lim RS, receptor; RT: Radiation therapy; SCC: Squamous cell carcinoma Natrajan R, Riaz N, Mariani O, et al. The landscape of somatic genetic alterations in Metaplastic breast carcinomas. Clin Cancer Res. 2017;23(14): Acknowledgements 3859–70. The NCDB is a joint project of the Commission on Cancer of the American 6. Zhang X-M, Zhang B, Zang F, Zhao L, Yuan Z, Wang P. Clinical features and College of Surgeons and the American Cancer Society. The data used in the treatment of squamous cell carcinoma of the breast. Onco Targets Ther. study are derived from a de-identified NCDB file. The American College of 2016;9:3181–5. https://doi.org/10.2147/OTT.S95128. eCollection 2016. Surgeons and the Commission on Cancer have not verified and are not 7. Bilimoria KY, Stewart AK, Winchester DP, Ko CY. The National Cancer Data responsible for the analytic or statistical methodology employed or the Base: a powerful initiative to improve cancer care in the United States. Ann conclusions drawn from these data by the investigator. We appreciated Surg Oncol. 2008;15(3):683–90. Qian Ouyang for her assistance in the analysis of the study. 8. Behranwala KA, Nasiri N, Abdullah N, Trott PA, Gui GP. Squamous cell carcinoma of the breast: clinico-pathologic implications and outcome. Eur J Funding Surg Oncol. 2003;29(4):386–9. This study was supported by Guangdong Science and Technology Department 9. Yadav S, Yadav D, Zakalik D. Squamous cell carcinoma of the breast in the (2017B030314026). The role of the funding body was to provide financial support United States: incidence, demographics, tumor characteristics, and survival. for the cost of language editing service, as well as the publication charges. Breast Cancer Res Treat. 2017;164(1):201–8. 10. Bhatt L, Fernando I. Primary squamous cell carcinoma of the breast: Availability of data and materials achieving long-term control with cisplatin-based chemotherapy. Clin Breast The data is available to all readers upon the readers’ request. Cancer. 2009;9(3):187–8. 11. Dejager D, Redlich PN, Dayer AM, Davis HL, Komorowski RA. Primary Authors’ contributions squamous cell carcinoma of the breast: sensitivity to cisplatinum-based LZ: Designed the study, collected and analyzed the data, wrote the manuscript, chemotherapy. J Surg Oncol. 1995;59(3):199–203. and approved it for final publication. KC: Designed the study, wrote and revised 12. Esophageal and Esophagogastric Junction Cancers. www.nccn.org. the manuscript, and approved it for final publication. Both of the authors agree Accessed 4 July 2018. to be accountable for all aspects of the work in ensuring that questions related 13. Head and Neck Cancers. www.nccn.org. Accessed 4 July 2018. to the accuracy or integrity of any part of the work are appropriately 14. Nelson K, Helmstaedter V, Lage H. The influence of tamoxifen on growth investigated and resolved. behavior and cell-cell adhesion in OSCC in vitro. Oral Oncol. 2007;43(7):720–7. 15. Sukocheva OA, Wee C, Ansar A, Hussey DJ, Watson DI. Effect of estrogen on Ethics approval and consent to participate growth and apoptosis in esophageal adenocarcinoma cells. Dis Esophagus. This study was an epidemiological study using de-identified data from the NCDB 2013;26(6):628–35. database. Therefore, consent for patient participation and study publication was 16. Liu J, Yu Y, Sun JY, He SS, Wang X, Yin J, Cao XC. Clinicopathologic not required. The study approval was waived by the ethical committee of Yale characteristics and prognosis of primary squamous cell carcinoma of the University and Sun Yat-sen Memorial Hospital. breast. Breast Cancer Res Treat. 2015;149(1):133–40. 17. Wang J, Zhang X, He J, Yang M, Tang J, Li X, Tang H, Xie X. Co-expression Consent for publication of EGFR and CK5/6 in primary squamous cell carcinoma of the breast. Med Not applicable. Oncol. 2014;31(9):172. 18. Wu SG, Sun JY, Liu WM, Li FY, Lin HX, He ZY. Effect of postoperative Competing interests radiotherapy for squamous cell cancer of the breast in a surveillance The authors declare that they have no competing interests. epidemiology and end results population-based study. Oncotarget. 2016; 7(9):10684–93. 19. Henson KE, Jagsi R, Cutter D, McGale P, Taylor C, Darby SC. Inferring the Publisher’sNote effects of Cancer treatment: divergent results from early breast Cancer Springer Nature remains neutral with regard to jurisdictional claims in published Trialists' collaborative group meta-analyses of randomized trials and maps and institutional affiliations. observational data from SEER registries. J Clin Oncol. 2016;34(8):803–9. 20. Buchanan PJ, Chopra VK, Walker KL, Rudolph R, Greco RJ. Primary squamous Author details cell carcinoma arising from a breast implant capsule: a case report and Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and review of the literature. Aesthet Surg J. 2018;38(7):97–102. Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 21. Olsen DL, Keeney GL, Chen B, Visscher DW, Carter JM. Breast implant Guangzhou, Guangdong, China. Department of Breast Surgery, Breast capsule-associated squamous cell carcinoma: a report of 2 cases. Hum Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 107 Pathol. 2017;67:94–100. Yanjiang West. Road, Guangzhou 510120, People’s Republic of China. 22. Zomerlei TA, Samarghandi A, Terando AM. Primary squamous cell Department of Biostatistics, School of Public Health, Yale University, 300 carcinoma arising from a breast implant capsule. Plast Reconstr Surg Glob George Suit 503, New Haven, CT 06511, USA. Open. 2015;3(12):e586. Received: 7 August 2018 Accepted: 12 December 2018 References 1. Nayak A, Wu Y, Gilcrease MZ. Primary squamous cell carcinoma of the breast: predictors of locoregional recurrence and overall survival. Am J Surg Pathol. 2013;37(6):867–73. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png BMC Cancer Springer Journals

Clinicopathological features, treatment patterns, and prognosis of squamous cell carcinoma of the breast: an NCDB analysis

Zhu, Liling; Chen, Kai
BMC Cancer , Volume 19 (1) – Jan 8, 2019
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Springer Journals
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Copyright © 2019 by The Author(s).
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Biomedicine; Cancer Research; Oncology; Surgical Oncology; Health Promotion and Disease Prevention; Biomedicine, general; Medicine/Public Health, general
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1471-2407
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10.1186/s12885-018-5212-x
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Abstract

Background: Squamous cell carcinoma (SCC) of the breast is a rare malignancy. The clinicopathological features, treatment patterns and prognosis of SCC of the breast is still unclear. Methods: In this study, we performed a 1:4 SCC-IDC (infiltrating ductal carcinoma) matching analysis of patients diagnosed between 2004 and 2014, using the data from the national cancer database. We used Chi-square test to compare the clinicopathological features and treatment patterns between SCC (n = 686) and IDC (n = 2744) patients. We used Kaplan-Meier analysis and Cox-regression to estimate the survival of SCC and IDC patients. Results: We observed that SCC patients are more likely to have T3–4, grade III, and ER negative diseases, when compared to IDC patients. Breast conserving surgery (BCS) (58.3% vs 65.4%, p = 0.048), as well as radiotherapy after BCS (65.3% vs. 83.0%, p < 0.001), was less performed in SCC patients. Among low-risk patients, chemotherapy was used more often for SCC patients (42.9%) than for IDC (18.7%) patients (p = 0.002). In HR-positive patients, endocrine therapy was used less often for SCC patients (51.6%) than for IDC patients (70.5%) (p < 0.001). SCC (vs. IDC) was associated with no responses to neoadjuvant chemotherapy (20% vs. 5.05%, p = 0.019). Adjusted analysis confirmed that SCC (vs. IDC) was associated with worse OS (HR = 1.40, 95%CI 1.17–1.67, P < 0.01), after a median follow- up of 58.3 months. In SCC patients, HR status is not prognostic of OS, but endocrine therapy was significantly associated with improved OS in HR-positive SCC patients. Conclusions: We conclude that SCC is associated with poorer clinicopathological features, no responses to neoadjuvant chemotherapy and worse clinical outcomes than IDC. The treatment patterns for SCC and IDC are different. Endocrine therapy is necessary for HR-positive SCC patients. Keywords: Breast cancer, Squamous cell carcinoma, Infiltrating ductal carcinoma, Survival, Endocrine therapy, Chemotherapy Background component is still an unanswered question. A recent Squamous cell carcinoma (SCC) of the breast is a rare study [3] showed that SCC and its adjacent infiltrating malignancy that accounts for < 0.2% of all breast cancers ductal carcinoma (IDC) component shared the same ori- [1]. Diagnosis of SCC can be made when a predomin- gin, but their transcription landscape [4] and driven- ance (> 90%) of areas with squamous cells is noticed at pathways [5] are different. Thus, whether the differing histology examinations [2]. The origin of the SCC histology of SCC may result in different biological be- havior, different treatment patterns and prognosis is * Correspondence: zhuliling@mail.sysu.edu.cn; liling.zhu@yale.edu; not clear. Most of the studies [1, 6] are limited sig- chenkai23@mail.sysu.edu.cn nificantly by their small sample size, due to its rarity. Department of Breast Surgery, Breast Tumor Center, Sun Yat-sen Memorial Therefore, a national cancer database remains as the Hospital, Sun Yat-sen University, 107 Yanjiang West. Road, Guangzhou 510120, People’s Republic of China only choice to provide adequate sample size to inves- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and tigate SCC of the breast. Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Zhu and Chen BMC Cancer (2019) 19:26 Page 2 of 9 The national cancer database (NCDB) is a hospital- estrogen receptor (ER) status, progesterone receptor (PR) based database that covers approximately 70% of cancer status, HER2 status, primary surgery categorization, radi- patients in the United States [7]. The participating cen- ation therapy (RT), chemotherapy, neoadjuvant chemother- ters are required to submit data to the database. In this apy, response to chemotherapy, endocrine therapy, survival study, we used the NCDB to compare the clinicopatho- month and OS status. Patients were categorized into three logical features, treatment patterns and prognoses of age groups based on their ages at diagnosis (≤50 yrs., 50– IDC and SCC patients. We hypothesized that SCC (vs. 60 yrs., > 60 yrs). We used this cut-off because the median IDC) was associated with poor clinicopathological char- age was close to 60 yrs. in our study population and be- acteristics, different treatment patterns, and worse sur- cause 50 yrs. is the usual cut-off age for premenopausal and vival. We also performed an exploratory analysis of the post-menopausal women. Histology was divided into two benefits of systemic therapies for SCC patients. categories, namely, IDC and SCC. Methods Statistical analysis We searched the NCDB for eligible patients using the We conducted a descriptive analysis of the baseline clin- inclusion and exclusion criteria below: icopathological features of the included patients and used the Chi-square test to compare the characteristics Inclusion of the patients with different histologies. The median follow-up time was calculated as the median observed 1) Female patients with pathologically confirmed survival time of the entire population. OS was measured breast cancer, as the time from diagnosis to death due to any cause. 2) Patients who were diagnosed between 2004 and The cumulative OS rates were estimated using Kaplan- 2014, and Meier analysis. We used a Cox regression model to 3) Diagnoses of SCC of the breast (code 8070–8078), screen for prognostic factors of OS. We tested the pro- and IDC (code 8500). portional hazards assumption by plotting the scaled Schoenfeld residuals of all coefficients over time and Exclusion criteria found no violations. All P-values were two-sided. P- values less than 0.05 were considered statistically signifi- 1) Patients with prior diagnoses of malignant tumors cant. Statistical analysis was performed using Stata/MP, and version 13.0 (StataCorp LP, College Station, TX, USA). 2) A number of follow-up months equal to 0. Results A total of 686 SCC patients and 1,211,403 IDC patients A total of 3430 patients (IDC: 2744; SCC: 686), with a me- were identified from the database. Given the huge discrep- dian age of 61 years, were included in this study. The clini- ancy of the amount of the SCC and IDC patients, we copathological features are listed in Table 1. In general, performed a 1:4 SCC-IDC matching on the following fac- SCC is associated with poorer clinicopathological features. tors: Year of diagnosis (2004–2014), Facility type (Commu- A total of 23.1% of the SCC patients had T3–4disease, nity Cancer Program, Comprehensive Community Cancer whereas only 4% of the IDC patients had T3–4disease. The Program, Academic/Research Program, Integrated Net- proportions of grade III disease were 61.06 and 39.10% for work Cancer Program, Unknown), Facility location (New the SCC and IDC patients, respectively. Additionally, the England, Middle Atlantic, South Atlantic, East North Cen- proportions of ER-negative tumors were 74.91 and 21.95% tral, East South Central, West North Central, West South for the SCC and IDC patients, respectively. The distribution Central, Mountain, Pacific), city type (Metropolitan, Non- of N-stage was similar between SCC and IDC patients. metropolitan/Unknown), type of insurance (Not insured, Private insurance, Medicaid, Medicare, other Government, Different treatment patterns between SCC and IDC patients Unknown.). There were 686 SCC and 2744 IDC patients In patients with T1–2 stages who did not received neoad- being selected as the final cohort for analysis. This study juvant chemotherapy, there were 58.3% (120/206) vs. was an epidemiological study using de-identified data 65.4% (890/1362) of the SCC and IDC patients received from the NCDB database. Therefore, consent for patient BCS (P = 0.048) respectively. Among the patients with participation and study publication was not required. The BCS (N = 1791, 16 patients with unknown RT status were study approval was waived by the ethical committee of excluded.), 65.3 and 83.0% of the SCC and IDC patients Yale University and Sun Yat-sen Memorial Hospital. received RT (P < 0.01), respectively. The use of RT in The following data were collected for each patient: the node-positive patients with mastectomies, were similar in year of diagnosis, age, race, Charlson-Deyo score, tumor SCC and IDC patients (42.1% (37/88) vs. 48.4%(166/343), grade, lymphovascular invasion, T-stage, N-stage, histology, P =0.287). Zhu and Chen BMC Cancer (2019) 19:26 Page 3 of 9 Table 1 Clinicopathological features of study population Histology P Infiltrating Ductal Carcinoma Squamous Cell Carcinoma a a N% N% Race White 2259 83.33 540 79.65 < 0.01 African American 343 12.65 119 17.55 Others 109 4.02 19 2.80 Unknown 33 8 Charlson-Deyo Score 0 2346 85.50 555 80.90 0.02 1 328 11.95 104 15.16 2 54 1.97 20 2.92 3 16 0.58 7 1.02 Grade I 476 18.90 62 11.33 < 0.01 II 1058 42.00 151 27.61 III 985 39.10 334 61.06 Unknown/IV 225 139 Lymphovascular Invasion Absence 768 79.67 185 85.65 0.04 Present 196 20.33 31 14.35 Not Applicable 1780 470 T-Stage T0-T1 1441 52.51 145 21.14 < 0.01 T2 502 18.29 178 25.95 T3 67 2.44 100 14.58 T4 45 1.64 58 8.45 Tx 689 25.11 205 29.88 N-Stage N0 1373 50.04 331 48.25 0.228 N1 381 13.88 85 12.39 N2 115 4.19 22 3.21 N3 56 2.04 16 2.33 Nx 819 29.85 232 33.82 M-Stage M0 2250 82.00 490 71.43 < 0.01 M1 49 1.79 23 3.35 Mx 445 16.22 173 25.22 Estrogen Receptor Negative 569 21.95 421 74.91 < 0.01 Positive 2023 78.05 141 25.09 Unknown 152 124 Progesterone Receptor Negative 843 32.69 491 87.84 < 0.01 Positive 1736 67.31 68 12.16 Zhu and Chen BMC Cancer (2019) 19:26 Page 4 of 9 Table 1 Clinicopathological features of study population (Continued) Histology P Infiltrating Ductal Carcinoma Squamous Cell Carcinoma a a N% N% Unknown 165 127 HER2 Negative 829 78.2 207 87.7 < 0.01 Borderline 31 2.9 2 0.9 Positive 200 18.9 27 11.4 Unknown 156 68 Breast Surgery No_Surgery 167 6.10 90 13.16 < 0.01 Breast-conserving surgery 1561 56.99 246 35.96 Mastectomy 1010 36.87 348 50.88 Surgery (Types_Unknown) 1 0.04 0 0.00 Unknown 5 2 Radiation Therapy No 1119 41.23 373 54.93 < 0.01 Yes 1595 58.77 306 45.07 Unknown 30 7 Chemotherapy None 1506 58.28 294 46.08 < 0.01 Single-Agent Chemotherapy 44 1.70 23 3.61 Multiagent Chemotherapy 1034 40.02 321 50.31 Unknown 160 48 Neoadjuvant chemotherapy No 1884 89.89 447 83.86 < 0.01 Yes 212 10.11 86 16.14 Unknown 91 14 Endocrine Therapy No 1110 42.53 567 85.91 < 0.01 Yes 1500 57.47 93 14.09 Unknown 134 26 Percentages were calculated based on the available data Only patients after 2010 were used for analysis of HER2 status In patients with favorable prognosis (hormone receptor Response to neoadjuvant chemotherapy (HR)-positive, HER2-negative and node-negative), chemo- In this study, there were 298 patients with known his- therapy was performed in 42.9% (12/28) and 18.7% tory of neoadjuvant chemotherapy, and 129 of them had (80/427) of the SCC and IDC patients, respectively clear information about treatment responses (CR, PR, (P = 0.002). In the HR-positive, node-negative patients CR/PR, No response). SCC (vs. IDC) was significantly who were diagnosed before 2010 (when the HER2 associated with no responses to neoadjuvant chemother- status was unknown), there were 51.6% (32/62) and apy (20% vs. 5.05%, P = 0.019) (Table 2). 24.9% (248/997) of the SCC and IDC patients who had received chemotherapy, respectively (P < 0.001). Survival analysis Among the patients with HR-positive disease, endo- With a median follow-up time of 58.3 months, the re- crine therapy was performed in 51.6% (79/153) and spective 5-yr and 10-yr OS were 62.1 and 50.6% for the 70.5% (1446/2050) of the SCC and IDC patients, re- SCC patients, and 83.0 and 69.5% for the IDC patients, spectively (P < 0.001). respectively (P < 0.001). SCC (vs. IDC) was associated Zhu and Chen BMC Cancer (2019) 19:26 Page 5 of 9 Table 2 Response to neoadjuvant chemotherapy by histology several important prognostic factors, and the information of adjuvant therapies were lacking in the SEER database. Category 1 In contrast, the NCDB database provides more prognostic Histology CR PR, CR/PR No response Total P* factors (e.g comorbidity score, HER2 status and LVI N% N% N % N % status), as well as the information of adjuvant therapies IDC 35 35.35 59 59.6 5 5.05 99 100 0.042 (chemotherapy and endocrine therapy), therefore allows a SCC 8 26.67 16 53.33 6 20 30 100 more accurate estimation with less bias. In this study, we Category 2 observed that the SCC patients had poorer clinicopatho- logical features (e.g., T3–4, grade III, HR-negative disease) Histology Response (CR, PR, CR/PR) No response Total P* than the IDC patients. The adjusted analysis demonstrated N% N % N% that the SCC patients had significantly worse clinical out- IDC 94 94.95 5 5.05 99 100 0.019 comes than the IDC patients in both the 2004–2014 and SCC 24 80 6 20 30 100 2010–2014 (HER2 status adjusted) cohorts. In consistent CR Complete Response, PR Partial Response, IDC Infiltrating Ductal Carcinoma, with previous studies, we confirmed that SCC (vs. IDC) is SCC Squamous Cell Carcinoma associated with poorer OS, after adjusting for more prog- *Fisher Exact test nostic factors and adjuvant therapies. with poorer OS in univariate analysis (HR = 2.39, 95%CI 2.06–2.77, P < 0.001), and in multivariate (HR = 1.40, SCC & systemic therapies 95%CI 1.17–1.67, P < 0.001) analysis after adjusting for The concept that SCC has worse clinical outcomes than age, race, comorbidity, T-stage, N-stage, M-stage, ER, PR, IDC is likely to affect the choice of treatments in the tumor grade, LVI, surgery, endocrine therapy, chemother- clinical practices. This is confirmed in our study that apy and RT (Table 3, & Additional file 1:FigureS1).Inpa- chemotherapy was more prevalent in low-risk (HR+/ tients who were diagnosed after 2010, SCC (vs. IDC) was HER2-/LN-) SCC (vs. IDC) patients (42.9% vs. 18.7%, still associated with poorer OS (HR = 1.57, 95%CI 1.11– P = 0.002). However, whether the SCC is responsive to 2.21, P = 0.011), after adjusting for the above variables, as chemotherapy is still unknown. Hennessy et al. [2] well as LVI and HER2 status. and Zhang et al. [6]reported thattheyused nore- We hypothesized that there was interaction between sponses were observed in their SCC patients after hormonal status (positive vs. negative) and the histology neoadjuvant chemotherapy. Only two case-reports [10, (SCC vs. IDC) in the analysis of OS. We performed a 11] have suggested that cisplatin-based chemotherapy is subgroup analysis and noticed that positive (vs. negative) able to achieve long-term control, but these results need hormonal status was significantly associated with im- further verification. In our study, we noticed that SCC (vs. proved OS in IDC (P < 0.01) patients, but not in the SCC IDC) was significantly associated with no responses to (P =0.042) patients (Fig. 1, Interaction test, P =0.023). neoadjuvant chemotherapy (20% vs. 5.05%, P =0.019). However, endocrine therapy was also associated with im- Therefore, the benefit of chemotherapy in SCC patients proved OS for the HR-positive IDC patients (HR = 0.61, remains unknown. 95%CI 0.48–0.77, P < 0.001), as well as for the HR-positive In this study, we observed that the endocrine therapy SCC patients (HR = 0.30, 95%CI 0.15–0.59, P <0.001) was less performed in the HR-positive SCC (51.6%) pa- (Fig. 2), after adjusting for age, race, comorbidity score, tients, than in the HR-positive IDC (70.5%) patients. A grade, T-stage, N-stage, M-stage, and chemotherapy. contributing reason could be that endocrine therapy in the head & neck or esophageal SCC patients is not use- Discussion ful in clinical practices [12, 13], even if the in vitro evi- Prognosis of SCC patients dences [14, 15] had suggested the role of tamoxifen for Previous studies have shown that SCC of the breast is SCC of the oral cavity or esophagus. However, SCC of more likely to be HR-negative and is associated with the breast might possibly be different from the head & worse clinical outcomes [2, 8, 9]. Hennessy et al. [2]re- neck SCC. A recent study used whole-exome sequencing ported that the 5-year overall survival (OS) rates of 33 and to show that the SCC components have nearly identical 137 SCC patients selected from the M.D. Anderson Can- landscapes of somatic mutations to their adjacent IDC cer Center and the SEER database, respectively, were 40 component, suggesting that SCC may originate from the and 64%, respectively. In an update, Yadav et al [9]re- IDC [3]. Since the role of endocrine therapy had been ported a 5-year cancer-specific survival rate of 63.5% for established in IDC patients, it is possible the endocrine 445 SCC patients who were collected from the SEER data- therapy would also be beneficial in SCC patients. In the base. Due to the rarity of SCC, only the data from the analysis of prognostic factors of OS, we observed a sig- national cancer database is able to provide adequate statis- nificant interaction between the HR status and the hist- tical power to study the prognosis of SCC. However, ology (SCC vs. IDC). The HR status was prognostic only Zhu and Chen BMC Cancer (2019) 19:26 Page 6 of 9 Table 3 Univariate and multivariate analysis of prognostic factors of OS Variables Univariate analysis Multivariate analysis HR(95%CI) P HR(95%CI) P Age < =50 1 1 50–60 1.13 (0.89–1.44) 0.301 1.10 (0.86–1.40) 0.445 > 60 2.25 (1.86–2.74) < 0.001 2.11 (1.72–2.60) < 0.001 Race White 1 1 African American 1.51 (1.26–1.80) < 0.001 1.05 (0.87–1.27) 0.576 Others 0.43 (0.24–0.77) 0.004 0.48 (0.27–0.85) 0.012 Unknown 0.53 (0.24–1.19) 0.126 0.49 (0.22–1.10) 0.082 Comorbidity score Score 0 1 1 Score 1 2.17 (1.85–2.54) < 0.001 1.65 (1.40–1.95) < 0.001 Grade I1 1 II 1.20 (0.94–1.54) 0.149 0.98 (0.76–1.26) 0.877 III 2.05 (1.62–2.58) < 0.001 1.35 (1.05–1.74) 0.02 Unknown/IV 1.86 (1.39–2.49) < 0.001 1.05 (0.77–1.42) 0.767 T-stage T0-T1 1 1 T2 2.24 (1.86–2.69) < 0.001 1.65 (1.35–2.03) < 0.001 T3–4 5.63 (4.60–6.90) < 0.001 2.75 (2.14–3.55) < 0.001 Tx 1.25 (1.04–1.51) 0.017 0.62 (0.45–0.85) 0.003 N-stage N0 1 1 N1 1.82 (1.49–2.22) < 0.001 1.77 (1.43–2.18) < 0.001 N2–3 3.61 (2.90–4.49) < 0.001 2.18 (1.69–2.83) < 0.001 Nx 1.12 (0.94–1.32) 0.197 0.95 (0.70–1.30) 0.764 M-stage M0 1 1 M1 8.47 (6.42–11.17) < 0.001 4.50 (3.29–6.16) < 0.001 Mx 2.04 (1.74–2.39) < 0.001 1.90 (1.53–2.36) < 0.001 Histology Infiltrating Ductal Carcinoma 1 1 Squamous Cell Carcinoma 2.39 (2.06–2.77) < 0.001 1.37 (1.15–1.64) < 0.001 Lymphovascular invasion Absence 1 Not included Presence 1.91 (1.37–2.67) < 0.001 Not applicable/Unknown 2.18 (1.63–2.91) < 0.001 Estrogen Receptor Negative 1 1 Positive 0.53 (0.46–0.61) < 0.001 0.86 (0.67–1.10) 0.218 Unknown 0.85 (0.67–1.08) 0.195 2.46 (0.60–10.15) 0.212 Progesterone Receptor Zhu and Chen BMC Cancer (2019) 19:26 Page 7 of 9 Table 3 Univariate and multivariate analysis of prognostic factors of OS (Continued) Variables Univariate analysis Multivariate analysis HR(95%CI) P HR(95%CI) P Negative 1 1 Positive 0.56 (0.48–0.65) < 0.001 0.96 (0.76–1.20) 0.724 Unknown 0.92 (0.73–1.16) 0.484 0.31 (0.08–1.27) 0.103 HER2 Negative 1 Not included Positive 0.83 (0.57–1.22) 0.347 Borderline/Unknown 1.20 (0.87–1.66) 0.266 Surgery Breast-conserving surgery 1 1 Mastectomy 2.22 (1.90–2.59) < 0.001 1.26 (1.04–1.54) 0.02 Others/Unknown 7.05 (5.77–8.62) < 0.001 6.57 (5.04–8.55) < 0.001 Radiation therapy No 1 1 Yes 0.54 (0.47–0.62) < 0.001 0.92 (0.77–1.10) 0.351 Unknown 0.50 (0.24–1.05) 0.067 0.54 (0.25–1.17) 0.12 Chemotherapy No 1 1 Yes 0.89 (0.77–1.03) 0.116 0.67 (0.55–0.80) < 0.001 Unknown 0.72 (0.53–0.99) 0.043 0.61 (0.43–0.85) 0.004 Endocrine therapy No 1 1 Yes 0.44 (0.38–0.51) < 0.001 0.60 (0.50–0.73) < 0.001 Unknown 0.56 (0.40–0.78) < 0.001 0.77 (0.54–1.09) 0.145 HR Hazard ratio, CI confidence interval Only patients diagnosed after 2010 were included for IDC patients, but not for SCC patients. Despite of this, alterations of SCC and reported that TP53(78%) and we still observed that the endocrine therapy significantly PI3KCA(44%) are the most frequently mutated genes in improves the OS in HR-positive IDC and SCC patients. SCC. They proposed that the mutation affecting genes Taken together, we suggested that endocrine therapy should might result in the Wnt and mTOR pathway activation. Fu- remain as the standard treatment for HR-positive SCC pa- ture studies are warranted to investigate whether relevant tients. Ng et al. [5] studied the landscape of somatic genetic pathway inhibitors could be used for SCC patients. ab Fig. 1 Kaplan-Meier survival analysis stratified by HR status in (a) IDC and (b) SCC patients Zhu and Chen BMC Cancer (2019) 19:26 Page 8 of 9 ab Fig. 2 Kaplan-Meier survival analysis stratified by endocrine therapy in (a) HR-positive IDC patients, and (b) HR-positive SCC patients SCC & local therapy survival benefit of chemotherapy, as patients with more We assessed the influence of the SCC component on the advanced diseases are prone to receive chemotherapy. local therapy. SCC patients had a slightly lower rate of However, estimation of the survival benefit of endocrine BCS, when compared to IDC patients (58.3% vs. 65.4%, therapy in HR-positive patients is less likely to be affected P = 0.048). The underlying reason could be that the SCC by the “treatment-by-indication” bias. HR-positive is the patients had larger tumor than IDC patients (T3–4: only indication for endocrine therapy. In addition, the de- 23.1% vs. 4%). Among patients with BCS, RT was used cision to implement the endocrine therapy is less likely to in 65.3 and 83.0% of the SCC and IDC patients, respect- be influenced by the comorbidity status. Thus, estimation ively. Currently, evidence that support the use of RT for of the survival benefit of endocrine therapy using observa- SCC is lacking. Hennessy et al. [2] reported that 4 out of tional data is reasonable. Due to the rarity of SCC of the 19 SCC patients treated with RT had locoregional breast, a prospective, randomized study for SCC cannot relapse within the irradiated field, suggesting that SCC be realistically implemented. Third, the NCDB did not might be radioresistant. Two studies [16, 17] reported have information regarding trastuzumab therapy. Whether no benefit of RT on OS, but the small sample sizes in trastuzumab would be appropriate for HER2-positive SCC these studies limited their statistical power. Using the patients remains unclear. The lack of information regard- SEER database, Wu et al. [18] reported that RT was ing local relapse, metastatic relapse and cancer-specific significantly associated with improved OS but not survival is also one of the limitations. Fourth, there is a cancer-specific survival, which is difficult to explain. Fur- growing awareness of an association between SCC of the thermore, they reported that RT was significantly associ- breast and implants. But the significance of the association ated with improved CSS in stage II SCC patients, but is unclear due to the rarity of this situation [20–22]. The the analysis was not adjusted for ER, PR or HER2. Thus, NCDB database does not have the information about the the role of RT as an adjuvant local control therapy after history of breast implants augmentation before the diag- surgery remains controversial. nosis of SCC, therefore limits our understanding about this issue. Limitations First, it is possible that the IDC patients may have a small Conclusions proportion of SCC component area. Without pathological In this study, we show that compared with IDC, SCC is confirmation, grouping the cases into IDC, and SCC associated with poorer clinicopathological outcomes. might not be always accurate. However, a detailed histo- The treatment patterns differ between IDC and SCC. pathology examination is impossible in mining large data- Radiotherapy after BCS is used less often for SCC (vs. base, such as NCDB. The large sample size of this study IDC) patients. Chemotherapy is used more often for population is able to compensate this limitation. Second, low-risk (HR+/HER2-, node-negative) SCC (vs. IDC) nonrandomized comparisons of treatment effects are patients. Endocrine therapy is used less often in HR- prone to providing misleading estimations. One study [19] positive SCC (vs. IDC) patients. In addition, SCC is less showed that the treatment effect of RT in breast cancer likely to response to chemotherapy, and is associated was over-estimated in observational data compared with with worse clinical outcomes. Although the HR status randomized clinical trial data. This effect is reasonable as is not prognostic in SCC patients, endocrine therapy is the “treatment-by-indication” bias can never be eliminated still associated with improved OS in HR-positive SCC in observational data. Therefore, we did not estimate the patients. Zhu and Chen BMC Cancer (2019) 19:26 Page 9 of 9 Additional file 2. Hennessy BT, Krishnamurthy S, Giordano S, Buchholz TA, Kau SW, Duan Z, Valero V, Hortobagyi GN. Squamous cell carcinoma of the breast. J Clin Oncol. 2005;23(31):7827–35. Additional file 1: Figure S1. Kaplan-Meier survival analysis stratified by 3. Avigdor BE, Beierl K, Gocke CD, Zabransky DJ, Cravero K, Kyker-Snowman K, histology (IDC vs. SCC) and nodal status in a) HR-positive and b) HR- Button B, Chu D, Croessmann S, Cochran RL, et al. Whole-exome sequencing negative patients. (PDF 62 kb) of Metaplastic breast carcinoma indicates Monoclonality with associated ductal carcinoma component. Clin Cancer Res. 2017;23(16):4875–84. 4. Piscuoglio S, CKY N, Geyer FC, Burke KA, Cowell CF, Martelotto LG, Natrajan Abbreviations R, Popova T, Maher CA, Lim RS, et al. Genomic and transcriptomic BCS: Breast-conserving surgery; ER: Estrogen receptor; HR: Hormonal receptor; heterogeneity in metaplastic carcinomas of the breast. NPJ Breast Cancer. IDC: Infiltrating ductal carcinoma; LN: Lymph node; LVI: Lymphovascular 2017;3:48. invasion; NCDB: National cancer database; OS: Overall survival; PR: Progesterone 5. Ng CKY, Piscuoglio S, Geyer FC, Burke KA, Pareja F, Eberle CA, Lim RS, receptor; RT: Radiation therapy; SCC: Squamous cell carcinoma Natrajan R, Riaz N, Mariani O, et al. The landscape of somatic genetic alterations in Metaplastic breast carcinomas. Clin Cancer Res. 2017;23(14): Acknowledgements 3859–70. The NCDB is a joint project of the Commission on Cancer of the American 6. Zhang X-M, Zhang B, Zang F, Zhao L, Yuan Z, Wang P. Clinical features and College of Surgeons and the American Cancer Society. The data used in the treatment of squamous cell carcinoma of the breast. Onco Targets Ther. study are derived from a de-identified NCDB file. The American College of 2016;9:3181–5. https://doi.org/10.2147/OTT.S95128. eCollection 2016. Surgeons and the Commission on Cancer have not verified and are not 7. Bilimoria KY, Stewart AK, Winchester DP, Ko CY. The National Cancer Data responsible for the analytic or statistical methodology employed or the Base: a powerful initiative to improve cancer care in the United States. Ann conclusions drawn from these data by the investigator. We appreciated Surg Oncol. 2008;15(3):683–90. Qian Ouyang for her assistance in the analysis of the study. 8. Behranwala KA, Nasiri N, Abdullah N, Trott PA, Gui GP. Squamous cell carcinoma of the breast: clinico-pathologic implications and outcome. Eur J Funding Surg Oncol. 2003;29(4):386–9. This study was supported by Guangdong Science and Technology Department 9. Yadav S, Yadav D, Zakalik D. Squamous cell carcinoma of the breast in the (2017B030314026). The role of the funding body was to provide financial support United States: incidence, demographics, tumor characteristics, and survival. for the cost of language editing service, as well as the publication charges. Breast Cancer Res Treat. 2017;164(1):201–8. 10. Bhatt L, Fernando I. 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Accessed 4 July 2018. to the accuracy or integrity of any part of the work are appropriately 14. Nelson K, Helmstaedter V, Lage H. The influence of tamoxifen on growth investigated and resolved. behavior and cell-cell adhesion in OSCC in vitro. Oral Oncol. 2007;43(7):720–7. 15. Sukocheva OA, Wee C, Ansar A, Hussey DJ, Watson DI. Effect of estrogen on Ethics approval and consent to participate growth and apoptosis in esophageal adenocarcinoma cells. Dis Esophagus. This study was an epidemiological study using de-identified data from the NCDB 2013;26(6):628–35. database. Therefore, consent for patient participation and study publication was 16. Liu J, Yu Y, Sun JY, He SS, Wang X, Yin J, Cao XC. Clinicopathologic not required. The study approval was waived by the ethical committee of Yale characteristics and prognosis of primary squamous cell carcinoma of the University and Sun Yat-sen Memorial Hospital. breast. Breast Cancer Res Treat. 2015;149(1):133–40. 17. 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Buchanan PJ, Chopra VK, Walker KL, Rudolph R, Greco RJ. Primary squamous Author details cell carcinoma arising from a breast implant capsule: a case report and Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and review of the literature. Aesthet Surg J. 2018;38(7):97–102. Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 21. Olsen DL, Keeney GL, Chen B, Visscher DW, Carter JM. Breast implant Guangzhou, Guangdong, China. Department of Breast Surgery, Breast capsule-associated squamous cell carcinoma: a report of 2 cases. Hum Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 107 Pathol. 2017;67:94–100. Yanjiang West. Road, Guangzhou 510120, People’s Republic of China. 22. Zomerlei TA, Samarghandi A, Terando AM. Primary squamous cell Department of Biostatistics, School of Public Health, Yale University, 300 carcinoma arising from a breast implant capsule. Plast Reconstr Surg Glob George Suit 503, New Haven, CT 06511, USA. 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BMC Cancer – Springer Journals

Published: Jan 8, 2019

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