Predictive and Prognostic Factors for the Outcome of the Patients Receiving Pegylated Liposomal Doxorubicin for Advanced Breast Cancer

Purpose: The treatment of advanced breast cancer (ABC) is still challenging aiming mainly to improve or maintain the quality of life. The efficacy of pegylated liposomal doxorubicin (PLD) was proven in patients with ABC. Because its expensive treatment there is a great need to find the predictive factors for the clinical outcome of PLD. Our purpose was to evaluate the factors which would affect the clinical outcomes in patients receiving PLD for advanced breast cancer. Methods: Retrospectively, we studied the medical records of 60 eligible patients during the period of seven years (Jan. 2011-Dec. 2017). All patients were treated in Medical Oncology Department, South Egypt Cancer Institute, Assiut University, Egypt. We included only patients with visceral metastasis who received at least 2 cycles of PLD and had radiological assessment after that. Clinical benefit rate of PLD and survival outcome were assessed and correlated with patients and disease characteristic. Results: The majority of patients had a performance status grade II (81.7%), recurrent disease (86.7%), more than one metastatic site (83.3%), and chemoresistance to previous anthracycline (75%). The clinical benefit rate (CBR) to PDL was 30%. We found statistical significant association between higher CBR and biological subtypes (p < 0.001), type of metastatic breast disease (p = 0.003), chemosensitivity to anthracycline (p < 0.001), and the number of previous lines of chemotherapy (p = 0.041). The median progression-free survival (PFS) was five months. There was a statistically-significant improvement of PFS among patients with anthracycline-sensitive tumors compared to those with anthracycline-resistant tumors (10 months vs. 5 months, respectively, p = 0.004). The most common toxicity was palmar-plantar erythrodysesthesia (28% for all grade and 9% for grade 3 or more). There was no severe cardiotoxicity or treatment-related death. How to cite this paper: Khallaf, S.M., Roshdy, J. and Ibrahim, A. (2020) Predictive and Prognostic Factors for the Outcome of the Patients Receiving Pegylated Liposomal Doxorubicin for Advanced Breast Cancer. Advances in Breast Cancer Research, 9, 21-33. https://doi.org/10.4236/abcr.2020.92003 Received: March 8, 2020 Accepted: April 7, 2020 Published: April 10, 2020 Copyright © 2020 by author(s) and Scientific Research Publishing Inc. This work is licensed under the Creative Commons Attribution International License (CC BY 4.0). http://creativecommons.org/licenses/by/4.0/ Open Access DOI: 10.4236/abcr.2020.92003 Apr. 10, 2020 21 Advances in Breast Cancer Research S. M. Khallaf et al. Conclusion: Pegylated liposomal doxorubicin appears to be more effective in patients with (luminal B with Her2neu positive, triple-negative and in her2neu amplified), also we noticed that de novo metastatic disease, patient who are not heavily pretreated tumors and patients with the anthracycline-sensitive tumor get more benefit from PLD than others.


Introduction
Globally, breast cancer is the most-common cancer in women after skin cancer [1]. Breast cancer is responsible for about 13.7% of cancer deaths in women worldwide [2]. This mortality is mainly related to metastatic or advanced disease [3].
The treatment of ABC is still challenging and mainly aiming to improve or maintain the quality of life, relieve the symptoms, and, to a lesser extent, improving the disease-related survivals [4].
There is no standard of care for ABC management; however, chemotherapy is a treatment option for many patients with ABC. Doxorubicin considered among the most active agents in [5].
Unfortunately, this known efficacy of doxorubicin in ABC is countered by its dose-limiting myelosuppression and cardiotoxicity [6] [7]. Myelosuppression may be life-threatening when sepsis occurs due to neutropenia that reaches its nadir 10 to 14 days after treatment [8]. The incidence of the cardiotoxicity is proportionally related to lifetime cumulative dose of doxorubicin which should not exceed 450 -500 mg/m 2 [9] [10] [11].
Pegylated liposomal doxorubicin (PLD) was manufactured through capsulation of doxorubicin with polyethylene glycol-coated liposome. This results in a new pharmacokinetic criterion; that PLD is restricted to the vascular space in the tissues having tight capillary junctions, such as the cardiac muscle and gastrointestinal tract. PLD can penetrate fenestrations of the vascular wall where its endothelial cells are either not tightly joined or disrupted by inflammation or tumor growth. Thus, PLD has less concentration at cardiac muscle and gastrointestinal tract which are the sites of its potential toxicity and more concentration at the tumor tissue resulting in lesser toxicity (cardiotoxicity, myelosuppression, and alopecia) and more or, at a lesser extent, equal efficacy when compared with conventional doxorubicin [12]- [17].
The dose-limiting toxicity of PLD is the palmar-plantar erythrodysesthesia (PPE), also known as a hand-foot syndrome [ [21]. Still, there is a great need to find the predictive factors for the clinical outcome of PLD in those patients. We conducted this retrospective study to find the possible predictive factors for the outcomes in those patients receiving PLD.

Study Design
This retrospective study was based on the examination of the medical hospital records of patients with evidence of ABC during the period of seven years (Jan-

Statistical Analysis
The

Patients' Demographics and Tumor Characteristics
Sixty eligible patients were analyzed for results.

Response Rates
There was no case of complete response (CR

Survival Outcome
The median PFS was five months; 95% CI 4.05 -5.94 months ( Figure 1). Chemosensitivity to the previous anthracycline is the only factor that significantly affected the PFS; The median PFS was twice as long for patients with chemosensitive tumor compared to those with chemoresistant tumor (10 months; 95% CI 5.31 -14.68 versus 5 months; 95% CI 4.20 -5.79 respectively; p = 004) ( Figure 2).
Our results demonstrated that there was no significant effect of the studied factor on OS.

Adverse Effects
All cases received 296 cycles of PLD (range 3 -18). The dose reductions were required in eight cases (13.3%), while four cases (6.7%) could not tolerate PLD due to PPE (2 cases), stomatitis (one case), and hypersensitivity (one case). As shown in Table 3, the majority of adverse effects were of low grades. PPE was the most common non-hematological toxicity (28%) followed by stomatitis (25%) then diarrhea (17%), while neutropenia (5%) was the most common hematological toxicity, followed by anemia and leukopenia (4% for each adverse effect). No reported cases for severe cardiac toxicity. Also, there was no treatment-related death.

Discussion
In this retrospective study that included 60 patients with ABC received PLD. After data analysis, we found that CBR was 30%, with four among the investigated factors had a significant effect on CBR: biological subtypes, type of ABC, chemosensitivity, and order of PLD line.
We stated that the luminal B subtype had the best CBR, followed by TNBC, then HER2 amplified, and then the lowest CBR for luminal A (100%, 40.9%, 37.5%, and 4% respectively; p = 0.000). To best of our knowledge, no study addressed the effect of biological subtypes on CBR in patients received PLD as single agent for ABC; however, Fabi et al. [26] conducted a phase II clinical trial to determine the clinical efficacy and safety of PLD in combination with gemcitabine as a first-or second-line treatment option in patients with ABC. They reported that HER2 overexpression predicted response to PLD in ABC patients (CBR; 84.3% for patients with HER2-positive tumors vs. 74% for patients with HER2-positive tumors) [26]. CBR is higher than that of our study (37.5%); this may be due to Advances in Breast Cancer Research S. M. Khallaf et al.
CBR in patients with de novo ABC was about three times higherthan in patients with recurrent ABC (75% vs. 23.1% respectively; p = 0.003). To the best of our knowledge, there is no previous work on this topic regarding PLD.
As regards to the chemotherapy-related factors, patients with chemosensitive disease had about four times CBR higher than in patients with chemoresistant disease; (66.7% vs. 17.8%; p = 0.0001). Also, when PLD was given as the 3 rd line, CBR was higher than when given as the 4th line or more (50.0% vs. 22.7% respectively; p = 0.041). Aphase III German study conducted by Al-Batran et al. [13] and an Austrian observational trial conducted by Fiegl et al. [27] studied these factors. Al-Batran et al. showed slightly less CBR than that our study (24% vs. 30% respectively). In agreement with our data, this German study [13]  issue, but without details or direct conclusion. These two studies agree with our findings. The first one is conducted by Al-Batran et al. [13] who reported patients with a non-anthracycline-resistant disease has a higher PFS than those having an anthracycline-resistant disease; however, P-value was not reported. The second trial reported by Keller et al. [17] who indirectly confirmed the same finding.
They stated that PLD has a superior PFS compared to vinorelbine in the patients with non-anthracycline-resistant disease (3.7 vs. 2.6 months respectively), but in patients with anthracycline-resistant ABC, the median PFS is comparable (2.6 months for each group).
Median OS of our patients was 11 months (95% CI 9.48 -12.51 months), which is slightly less than that documented by Al-Batran et al. [ We do not report any case of severe cardiac toxicity. This is matching with previous studies published by Al-Batran et al. [13], Keller et al. [17], and Basso et al. [28] and likely similar results of studies conducted by Harbeck et al. [29] and Huober et al. [20]  The main limitations of our study are its retrospective nature and a relatively small number of sample size. Also, the PLD was given beyond previous two lines of palliative chemotherapy. We recommend a further prospective study including the larger sample size, with PLD given as a frontline therapy.

Conclusion
Pegylated liposomal doxorubicin appears to be more effective in patients' subgroups with specific tumor criteria including special biological subtypes (luminal B with human epidermal growth factor receptor 2 positive, triple-negative, and her2 amplified), de novo metastatic disease, not heavily pretreated tumors, and the anthracycline-sensitive tumor. Therefore, patients selection should be considered.

Conflicts of Interest
The authors declare no conflicts of interest regarding the publication of this paper.

Ethical Approval
This article does not contain any studies with animals performed by any of the authors. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.