REVIEW ARTICLE

Renata Duchnowska1, Ewa Chmielowska2, Joanna Streb3, Małgorzata Chudzik4, Bogumiła Czartoryska-Arłukowicz5, Małgorzata Litwiniuk6, Wojciech P. Olszewski7, Tadeusz Pieńkowski8, Ewa Kalinka-Warzocha9, Iwona Głogowska10

1Klinika Onkologii, Wojskowy Instytut Medyczny, Warszawa

2Oddział Kliniczny Onkologii, Centrum Onkologii, Bydgoszcz

3Oddział Kliniczny Onkologii, Szpital Uniwersytecki, Kraków

4Mazowiecki Szpital Onkologiczny, Wieliszew

5Oddział Onkologii, Białostockie Centrum Onkologii

6Klinika Onkologii, Uniwersytet Medyczny, Poznań

7Zakład Patomorfologii i Diagnostyki Laboratoryjnej, Centrum Onkologii — Instytut im. Marii Skłodowskiej-Curie, Warszawa

8Katedra i Klinika Hematologii, Onkologii i Chorób Wewnętrznych, Uniwersytet Medyczny, Warszawa

9Oddział Chemioterapii, Wojewódzki Szpital Specjalistyczny, Łódź

10Dział Medyczny Roche Polska Sp. z o.o.

The role of anthracyclines and dose dense therapy in an adjuvant setting, in HER2-positive early breast cancer, in clinical practice

ABSTRACT

Anthracyclines are antitumor antibiotics that are widely used in the treatment of breast cancer. A meta-analysis of previous randomised studies suggests a special role of anthracyclines in the adjuvant treatment of patients with HER2-positive breast cancer. In this group, anthracycline-based regimens have largely replaced CMF (cyclophosphamide, methotrexate, fluorouracil) schedule. More recently, regimens including anthracyclines with taxanes in combination with an anti-HER2 monoclonal antibody trastuzumab have found wide application in HER2-positive patients with higher risk of recurrence. A major contraindication to the use of anthracyclines is an increased risk of cardiac complications. In this article we present the current role of anthracyclines in adjuvant treatment of patients with HER2-positive breast cancer.

Key words: breast cancer, HER2, anthracyclines

Oncol Clin Pract 2016; 12, 1: 8–11

Introduction

Anthracyclines are cytostatic agents with proven so-called irreversible type I cardiotoxicity [1]. The course of myocardium damage after therapeutic doses of anthracyclines may be asymptomatic and lead to slowly progressing, sustained changes in cardiomyocytes. If no adequate prophylaxis is introduced the dilated cardiomyopathy or restrictive cardiomyopathy with decreased left ventricular ejection fraction (LVEF) and symptomatic circulatory insufficiency as well as arrhythmias develop as a consequence. It has been assessed that cumulative doses of anthracyclines related to increased risk of cardiomyopathy are as follows: for doxorubicin > 500 mg/m2 (> 450 mg/m2 in patients previously irradiated on a field containing myocardium), liposomal doxorubicin > 900 mg/m2, epirubicin > 720 mg/m2, mitoxantrone > 120 mg/m2, and idarubicin > 90 mg/m2 [2]. However, the acute myocardial damage that is not related to anthracyclines cumulative dose occurs within 24 hours after drug administration and typically presents with arrhythmia, usually nodal tachycardia, hypotension, and pulmonary oedema secondary to impaired systolic function of the left ventricle. There is also an increased risk for myelodysplastic syndrome (MDS) and acute myelogenous leukaemia (AML) in patients treated with anthracyclines [3].

In the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) meta-analysis deaths occurring before breast cancer recurrence or related to cardiologic complications, especially in patients aged over 55 years, were observed more frequently in cases with postoperative chemotherapy with anthracyclines in their medical history [4]. This meta-analysis did not include patients with HER2-positive phenotype receiving trastuzumab — monoclonal antibody with anti-HER2 activity — as their adjuvant treatment. On the other hand, there is another meta-analysis from 2008 in patients treated with anthracyclines, where the benefit of prolonged disease-free survival (DFS) and overall survival (OS) has been proven in an HER2-positive subpopulation [5]. To date, no predictive factor for treatment with anthracyclines has been identified. The most promising one was the expression level of topoisomerase 2 alpha (TOP2a), which is the DNA replication enzyme and the target for anthracyclines. However, the lack of standardised and validated methods for evaluation of TOP2a gene status does not allow its use as a biomarker in clinical practice [6].

Chemotherapy regimens with anthracyclines in early breast cancer treatment

In the adjuvant treatment of patients with HER2-positive breast cancer most frequently the regimens with anthracyclines then taxoids used sequentially are administered [4 × AC→12 × paclitaxel or 3 × FEC (fluorouracyl, epirubicin, cyclophosphamide) → 3 × docetaxel]. Nowadays there are no data to support use of 6 × FAC/FEC regimen in this group if the subsequent treatment with trastuzumab is scheduled [7]. Moreover, the results of the NSABP B-36 trial presented at the San Antonio Breast Cancer Symposium (SABCS) in 2014 did not show any difference in DFS and OS in the N0 population of breast cancer patients treated with 4 × AC regimen compared to 6 × FEC in an adjuvant setting [8]. If the reimbursement of treatment with trastuzumab is not available (in Poland it applies to the population with locally advanced inoperable breast cancer — clinical stage IIIB, IIIC) similar regimens to those used in the adjuvant treatment are used in the induction treatment, i.e.: 12 × paclitaxel → 4 × AC or 4 × AC → 12 × paclitaxel, 3 × FEC100 → 3 × docetaxel100, 4 × AC → 4 × docetaxel75–100, 6 × TAC (docetaxel, doxorubicin, cyclophosphamide), 6 × TC (docetaxel, cyclophosphamide), 4–6 × AT (doxorubicin, docetaxel), 6 × FAC/FEC75–100 [9].

There have been several clinical trials that have proven the increased risk of circulatory insufficiency in HER2-positive patients who had undergone the adjuvant treatment with trastuzumab in combination with regimens containing anthracyclines [2, 10]. It especially regards the patients with overweight (body mass index, BMI > 25 kg/m2) and patients with higher total dose of anthracyclines administered before trastuzumab treatment. The increased risk for cardiac toxicity was observed in patients of age higher than 50 years, with hypertension, documented ischaemic heart disease, cardiac insufficiency, decreased left ventricular ejection fraction (< 55%) at baseline, or the reduction of LVEF by 10–15 percentage points during treatment with paclitaxel or trastuzumab [11-14]. For this reason, as well as based on the results of the pivotal trial published by Slamon et al. [15], one should avoid use of the combination of trastuzumab and anthracyclines in advanced breast cancer. There is an exception of the neoadjuvant setting, and the combined treatment with trastuzumab and anthracyclines is allowed if cumulative dose of doxorubicin and epirubicin does not exceed 180 mg/m2 and 360 mg/m2, respectively [16–19]. The results of clinical trials with the neoadjuvant treatment: NOAH, GeparQuattro, as well as HannaH with subcutaneous trastuzumab, did not reveal increased risk of cardiotoxicity; however, there is no data regarding so-called late complications [16–20]. The safety and efficacy of combination with trastuzumab and liposomal doxorubicin were proven mainly in the treatment of metastatic or locally advanced breast cancer [21–24]. It is recommended that every patient treated with trastuzumab should be carefully followed in terms of cardio-vascular monitoring, i.e. to take medical history and perform physical examination to detect potential signs and symptoms of circulatory insufficiency as well as to perform electrocardiography and echocardiography.

The chemotherapy regimens without anthracyclines in early breast cancer

In 2006 the results of a relatively small 9735 US Oncology trial on 1016 patients with breast cancer were published, which proved the superiority of chemotherapy with docetaxel and cyclophosphamide (TC) versus the regimen with doxorubicin and cyclophosphamide (AC) in terms of disease-free survival (DFS) [25]. After longer (lasting seven years) follow-up the prolongation of overall survival (OS) was proven as well [26]. The additional advantage of TC regimen was decreased risk of cardiac complications [25, 26]. It should be emphasised that HER2 status was assessed retrospectively in only 170 women. In the Breast Cancer International Research Group (BCIRG 006) trial the risk of cardiac complications was decreased in patients with HER2-positive breast cancer treated with docetaxel, carboplatin AUC6 (area under-the-curve), and trastuzumab (TCH regimen) versus the regimen 4 × AC → 4 × docetaxel with trastuzumab (AC→TH) [11]. The results of BCIRG 006 trial after 10-year follow up were presented on SABCS symposium in December 2015 and confirmed previous data. In patients treated with AC → TH regimen vs. TCH regimen the symptomatic circulatory insufficiency (21 vs. 4 patients, p = 0.0005), decreased LVEF (200 vs. 97 patients, p < 0.0001), and cases of acute myeloid leukaemia (AML) (7 vs. 0 patients) were observed more frequently. The addition of trastuzumab to chemotherapy irrespectively of its regimen (AC → T or TC) positively influenced DFS (HR = 0.72; 95% CI 0.61–0.85, p < 0.0001; HR = 0.77; 95% CI 0.65–0.90, p = 0.0011 respectively) and OS (HR = 0.63; 95% CI 0.51–0.79, p < 0.0001; HR = 0.76; 95% CI 0.62–0.93, p = 0.0075, respectively). Moreover, there was no difference regarding DFS between AC → TH and TCH regimens detected in pN-positive patients, including those with involvement of ≥ 4 of the axillary lymph nodes. Additionally to similar benefits regarding the DFS and OS, the TCH regimen allows the reduction of total time required for adjuvant treatment by 12 weeks due to early introduction of trastuzumab. It should be emphasised that the results of the North Central Cancer Treatment Group (N9831) trail indicate improved efficacy of concurrent use of trastuzumab with paclitaxel after four cycles of AC chemotherapy regarding the DFS and OS when compared to the sequential administration of the drugs [27]. There are no medical contraindications for concurrent use of the postoperative irradiation and trastuzumab. Currently used shortened radiotherapy with mild hypofractionation (40 Gy or 42.5 within approximately 3 weeks) [28, 29] enables the concurrent administration of trastuzumab at three-week schedule, with a slight (up to 3 days) delay of the next cycle. However, this applies only to patients in whom dose hypofrationation is widely accepted (pT1-2, age > 50 years, with no prior chemotherapy and no need of boost to the tumor bed). However, the majority of patients administered trastuzumab does not comply with these conditions. The results of the phase II clinical trial without a control group published lately proved the efficacy of paclitaxel with trastuzumab in the adjuvant treatment of patients with HER2-possitive breast cancer in the clinical stage I (pT1b, T1c; N0) [30]. However, one should remember that in Poland in the case that axillary lymph nodes involvement is not present the trastuzumab may be introduced only if the diameter of the invasive component of the cancer is equal to or higher than 1 cm [9]. In another clinical trial in a population of patients with lower clinical stage of breast cancer with metastatic involvement of 0–3 axillary lymph nodes, four courses of AC chemotherapy are alternative to 12 courses of paclitaxel administered weekly (AC vs. paclitaxel: five-year relapse-free survival (RFS): 91 vs. 88%; OS 95 vs. 94%) [31]. In only 48% of patients the HER2 status was verified in this trial, and in the majority of these cases the receptor over-expression and/or the gene amplification were not confirmed.

Intensification of peri-operative treatment (dose dense; dd)

The ddAC → paclitaxel regimen administered every two weeks with granulocyte-colony stimulating factor (G-CSF) support is the option for adjuvant treatment of HER2-negative breast cancer with high proliferation index [32, 33]. The data published so far suggest that the benefit from dose intensification can be achieved in patients aged < 50 years with phenotype of the triple-negative breast cancer [32, 33]. Importantly, the risk of adverse events during the dose dense chemotherapy was comparable with the risk of side effects of conventional chemotherapy. However, there is no data regarding the risk of myelodysplastic syndrome (MDS) and acute leukaemias as well as late complications. The role of dose dense chemotherapy in the neoadjuvant setting has not been established yet. The recommendations of the European Society for Medical Oncology and the National Comprehensive Cancer Network for neoadjuvant treatment are based on extrapolation from the adjuvant setting. At the same time, the results of a trial led by Baldini et al. [34] with recruitment of 150 patients has not revealed the benefits of dose intensification of CEF inductive chemotherapy regimen. The role of dose dense chemotherapy in patients with HER2-positive breast cancer is a subject of a couple of ongoing clinical trials, including the BERENICE trial referring to the optimal chemotherapy regimen in neoadjuvant treatment — by comparing the dose dense AC chemotherapy (administered every two weeks with support of G-CSF) with subsequent twelve cycles of weekly paclitaxel and trastuzumab and pertuzumab given every three weeks to four cycles of FEC chemotherapy with subsequent four cycles of docetaxel combined with trastuzumab and pertuzumab administered every three weeks [NCT02132949]. It should be emphasised that in the trial published by Dang et al. [35] there was no increased risk of cardiac complications in patients receiving the adjuvant treatment consisting of 4 × ddAC → 4 × paclitaxel with trastuzumab. However, the potential risk of late complications including the occurrence of MDS and AML related to dd-chemotherapy has not been established.

Conclusions

There is no need for obligatory use of anthracyclines in the adjuvant treatment of early HER2-positive breast cancer. These agents are contraindicated in patients with cardiologic comorbidities. However, in young patients who undergo the radical treatment and have long life-expectancy the risk of early and late post-anthracycline cardiomyopathy should prompt use of chemotherapy without anthracyclines. It especially regards small N0 breast tumours because the efficacy of taxanes combined with trastuzumab suggest that it is possible to avoid anthracycline use. The proven high efficacy of taxanes in the treatment of patients with breast cancer caused divergence from anthracyclines, which has been observed since 2005 in the USA (data from Medicare and Marketscan database) [29]. If there are no cardiologic contraindications the adjuvant chemotherapy based on anthracyclines should be administered in patients with unfavourable prognostic factors: higher clinical stage of the disease and/or with metastatic lesions in regional lymph nodes. According to data published so far, anthracyclines should not be combined with trastuzumab. The only exception may be the neoadjuvant treatment when such a combination is allowed if the cumulative dose of doxorubicin is not higher than 180 mg/m2 and for epirubicin not higher than 360 mg/m2. The ongoing trials will define the role of perioperative dose dense systemic treatment in patients with HER2-positive breast cancer.

Address for correspondence:

Dr hab. n. med. Renata Duchnowska

Klinika Onkologii,

Wojskowy Instytut Medyczny, Warszawa

e-mail: rdtt@wp.pl

Oncology in Clinical Practice

2016, Vol. 12, No. 1, 8–11

Translation: dr n. med. Jakub Żołnierek

Copyright © 2016 Via Medica

ISSN 2450–1654

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