1203 Original Article The prognostic and predictive significance of cytokeratin 5/6 and epidermal growth factor receptor in metastatic triple-negative breast cancer treated with maintenance capecitabine Yiping Zhu1#^, Kai Li2#, Jieling Zhang2#, Lu Wang1, Lili Sheng1, Liang Yan2 1Department of Oncology, The First Affiliated Hospital of Wannan Medical College, Wuhu, China; 2Wannan Medical College, Wuhu, China Contributions: (I) Conception and design: Y Zhu, L Yan; (II) Administrative support: L Sheng; (III) Provision of study materials or patients: Y Zhu, L Wang, L Sheng; (IV) Collection and assembly of data: K Li, J Zhang; (V) Data analysis and interpretation: Y Zhu, K Li, J Zhang; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. #These authors contributed equally to this work. Correspondence to: Lili Sheng. Department of Oncology, The First Affiliated Hospital of Wannan Medical College, No. 2 Zheshan West Road, Jinghu District, Wuhu 241000, China. Email: [email protected]; Liang Yan. Department of Biochemistry, Wannan Medical College, No. 22 Wenchang West Road, Yijiang District, Wuhu 241000, China. Email: [email protected]. Background: Capecitabine is the most widely used agent for maintenance chemotherapy in patients with metastatic triple-negative breast cancer (mTNBC). However, there are no biomarkers for identifying mTNBC patients who could benefit from capecitabine maintenance. Methods: The prognostic roles of cytokeratin 5/6 (CK5/6), epidermal growth factor receptor (EGFR), and maintenance therapy were evaluated in mTNBC patients. Both CK5/6 and EGFR were detected using immunohistochemistry. Of 115 patients who achieved disease control, 56 received capecitabine maintenance therapy and 59 underwent observation. The progression-free survival (PFS) and overall survival (OS) of the patients were evaluated. Results: The median PFS and OS were longer in the maintenance group than that in the observation group (7.3 versus 5.7 months, P=0.0016; 22.4 versus 17.9 months, P=0.0055). Patients with basal-like TNBC had a poorer survival times than in those with non-basal-like TNBC (P=0.0062). Capecitabine maintenance significantly prolonged the OS of non-basal-like TNBC patients (P=0.0257), while in the basal-like TNBC patients, the difference was not significant (P=0.0541). Multivariate analysis revealed that the prolonged OS was related to age >50 years (P=0.005), presence of visceral metastases (P=0.035), response to initial therapy (P=0.017), maintenance therapy (P=0.033), and CK5/6 and EGFR status (P=0.032). Compared with the observation group, toxicities of all grades were more frequently observed in the maintenance group, including neutropenia, 85.71% vs. 25.87%, P<0.001; thrombocytopenia, 55.36% vs. 11.86%, P<0.001; anemia, 82.14% vs. 52.54%, P= 0.001; nausea 83.47% vs. 11.86%, P<0.001; vomiting 69.64% vs. 8.47%, P<0.001; and hand-foot syndrome (HFS) 32.14% vs. 1.69%, P<0.001. Conclusions: Our study revealed that patients with non-basal-like TNBC had a better clinical outcome than those with basal-like TNBC, and capecitabine maintenance treatment significantly prolonged PFS and OS in patients with TNBC. Patients with non-basal-like TNBC could benefit from maintenance therapy with capecitabine and CK5/6 and EGFR are biomarkers for TNBC prognosis. Keywords: Maintenance chemotherapy; capecitabine; triple-negative breast cancer (TNBC) Submitted Apr 03, 2020. Accepted for publication Jan 27, 2021. doi: 10.21037/tcr-20-1760 View this article at: http://dx.doi.org/10.21037/tcr-20-1760 ^ ORCID: 0000-0002-4738-1125. © Translational Cancer Research. All rights reserved. Transl Cancer Res 2021;10(3):1193-1203 | http://dx.doi.org/10.21037/tcr-20-1760 1194 Zhu et al. CK5/6 and EGFR predict mTNBC prognosis Introduction (EGFR)-positive patients had more BRCA1 mutations, more distant metastases, and a poor prognosis compared Breast cancer is the most common female malignancy with CK5/6- and EGFR-negative patients. worldwide. In approximately 5% of cases, the breast cancer Capecitabine is widely used in the treatment of breast has metastasized by the time of initial diagnosis. Despite cancer. The FinXX study (13) and the CSCSG-010 most operable patients receiving surgery and adjuvant study (14) showed that capecitabine-based adjuvant chemotherapy, the rate of recurrence or metastasis reaches chemotherapy significantly prolonged the recurrence-free 20–35% (1). Metastatic breast cancer (MBC) is an incurable survival and OS of TNBC patients, while the GEICAM/ disease, and the major goal of treatment is to relieve and 2003-11 (15) study showed that patients with a non-basal- control patients’ symptoms, improve their quality of life, like phenotype could benefit from the addition of extended and prolong their survival time (2). capecitabine treatment in early TNBC. In mTNBC, Based on gene and immunohistochemistry analyses, capecitabine maintenance therapy has been reported to breast cancers can be divided into different subtypes. demonstrate high activity and manageable safety (16,17). Biological characteristics and clinical outcomes differ among Clinical biomarkers to predict the efficacy of capecitabine patients with different subtypes, and the treatment strategies are extremely important in TNBC, although studies in this also vary. Expert consensus recommends endocrine therapy area are relatively limited. as the treatment of choice for hormone receptor (HR)- This retrospective cohort study focused on the positive tumors. Trastuzumab is also used in combination correlations between CK5/6 and EGFR expression, the with chemotherapy and then maintained on its own in prognosis of TNBC, and the efficacy of capecitabine HER2-positive patients. Triple-negative breast cancer maintenance in patients with different TNBC subtypes. (TNBC), which is defined as HER2-negative and HR- We present the following article in accordance with the negative, accounts for nearly 12–17% of all breast cancers REMARK reporting checklist (available at http://dx.doi. (3). TNBC progresses rapidly and is life threatening, and org/10.21037/tcr-20-1760). chemotherapy is recommended as treatment (4-6). Compared with HER2/HR-positive breast cancers, TNBC is more prone to recurrence and metastasis, even Methods with similar treatments, and is associated with shorter Patients progression-free survival (PFS) and overall survival (OS). The median time to recurrence for metastatic Between January 2012 and December 2016, 164 mTNBC triple-negative breast cancer (mTNBC) patients is 1–2 patients received first-line combination chemotherapy in years, and the median OS (mOS) is almost 1 year (7,8). the Oncology Department of the First Affiliated Hospital Lehmann et al. compiled the gene expression profiles of of Wannan Medical College, Anhui, China. Table 1 shows 587 TNBC patients from 21 independent studies and the baseline characteristics of the patients. All patients were identified 6 different TNBC subtypes using cluster analysis aged 18 years or above, and all had confirmed recurrent or (9). These subtypes consist of basal-like 1, basal-like 2, metastatic TNBC. Of 115 patients who achieved disease immunomodulatory (IM), mesenchymal (M), mesenchymal control after first-line combination chemotherapy, 93 stem cell-like (MSL), and lumen androgen receptor (LAR) had received an anthracycline-containing regimen, and breast cancer. Different subtypes present with unique 85 had received a taxane-containing regimen as adjuvant/ gene expression profiles and are associated with different neoadjuvant therapy. All patients had a good Eastern signaling pathways. Of the 6 subtypes, basal-like breast Cooperative Oncology Group (ECOG) score and a life cancer (BLBC) has attracted the most attention. The expectancy of ≥3 months, along with at least 1 measurable majority of BLBCs exhibit a triple-negative phenotype metastatic lesion detected by computed tomography or and have a poor prognosis (10). Nielsen et al. examined magnetic resonance imaging examination, and adequate the protein expression patterns in various basal-like breast organ function. tumors (11). They reported that the detection of cytokeratin Patients with clinically detectable meningeal and/or brain 5/6 (CK5/6) in TNBC could accurately identify BLBC parenchyma metastases, congestive heart failure, or reduced and showed high specificity. Rakha et al. (12) reported hepatic or renal function were excluded, as were those with that CK5/6-positive and epidermal growth factor receptor HER2- or HR-positive cancers. We also excluded patients © Translational Cancer Research. All rights reserved. Transl Cancer Res 2021;10(3):1193-1203 | http://dx.doi.org/10.21037/tcr-20-1760 Translational Cancer Research, Vol 10, No 3 March 2021 1195 Table 1 Characteristics of 115 mTNBC patients treated with gemcitabine combined with cisplatin Maintenance (n=56) Observation (n=59) Characteristic P value n % n % Age (years) 0.896 Median 56 54 Range 31–74 30–76 ECOG performance status 0.161 0 32 57.14 26 44.07 1 24 42.86 33 55.93 Menopausal status 0.555 Premenopausal 39 69.64 44 74.58 Postmenopausal 17 30.36 15 25.42 Lymph nodes number 0.426 0–3 38 67.86 44 74.58 >3 18 32.14 15 25.42 Metastatic site Liver 20 35.71 18 30.51 0.553 Lung 29 51.79 26 44.07 0.408 Bone 30 53.57 29 49.15 0.636 Brain 4 7.14 5 8.47 0.790 Soft tissue 34 60.71 37 62.71 0.826 Number of metastatic site 0.272 1 19 33.91 18 30.51 2 16 28.57 25 42.37 ≥3 21 37.50 16 27.12 Prior chemotherapy Taxane 44 78.57 41 69.49 0.268 Anthracycline 47 83.93 46 77.97 0.416 Prior adjuvant/neoadjuvant therapy 0.309 Yes 41 73.21 38 64.41 No 15 26.79 21 35.59 Response to initial GP therapy Response 25 51.79 30 50.85 0.920 Stable disease 12 21.43 11 18.64 0.709 EGFR and CK5/6 status 0.752 CK5/6 and/or EGFR positive 45 80.36 46 77.97 CK5/6 and/or EGFR negative 11 19.64 13 22.03 ECOG PS, Eastern Cooperative Oncology Group performance status; mTNBC, metastatic triple-negative breast cancer; EGFR, epidermal growth factor receptor.