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OPTIMAL TIME FOR ADJUVANT THERAPY INITIATION IN BREAST CANCER PATIENTS: A SINGLE CENTER EXPERIENCE/OPTIMALNO VREME ZA POCETAK ADJUVANTNE TERAPIJE KOD PACIJENATA SA KARCINOMOM DOJKE: ISKUSTVO JEDNOG CENTRA.

Introduction

Meta-analysis of adjuvant chemotherapy randomized controlled trials has shown that adjuvant chemotherapy may decrease the risk of breast cancer (BC) mortality by 30 - 40% in regard to patients without chemotherapy [1]. Today, adjuvant chemotherapy is routinely recommended in 60 - 70% of BC patients after surgery. Postponing the start of adjuvant chemotherapy for more than 90 days following surgery may significantly increase the risk of death in BC patients. The optimal time for initiation of adjuvant chemotherapy after surgery is still controversial. Currently, there are no guidelines recommending the optimal time for initiation of adjuvant chemotherapy in BC patients.

Retrospective studies evaluating the role of early initiation of chemotherapy reported conflicting results [2-4]. Most patients with BC start adjuvant chemotherapy within 30 to 40 days after surgery. It is thought that chemotherapy administration delayed beyond this time can decrease the benefit provided by cytotoxic systemic therapies [5]. Possible explanations for these effects include accelerated growth of micro-metastases after primary tumor resection, increased tumor angiogenesis, or development of primary resistance [6-10].

Studies differ with respect to patient and disease characteristics including the arbitrarily selected cut-off to the definition of early versus delayed beginning of therapy [11].On the other hand, it is known that BC is a heterogeneous disease and certain subtypes of BC, such as triple negative BC (TNBC) and human epidermal growth factor receptor 2 (HER2) positive BC are associated with worse prognosis because of increased risk of recurrence, which probably has impact on the benefit from adjuvant chemotherapy [12-14]. A most recent report from Gagliato et al. [11] indicates that the delayed adjuvant chemotherapy is particularly meaningful for patients with advanced disease, TNBC, and trastuzumab-treated HER2+ tumors.

According to the results of a retrospective study, the authors suggest that early initiation of chemotherapy is very important for the outcome of these patients [4, 15, 16].

The researchers found that factors such as socioeconomic status, health insurance coverage and ethnicity were associated with delayed treatment [17, 18].

To determine the relationship between time to chemotherapy (TTC) and survival in women with BC, we conducted a retrospective study at the Oncology Institute of Vojvodina, Serbia. It remains unclear whether TTC has a differential impact among the distinct BC subtypes. Therefore, we conducted this retrospective analysis using our single-institution data to evaluate the association between TTC and outcomes according to tumor characteristics and BC subtypes. Our country is one of the developing countries with limited financial resources for health insurance.

Material and Methods

During 2010-2012, there were 1075 consecutive patients who were diagnosed with stage I-III BC and underwent surgery at the Oncology Institute of Vojvodina. Patients with stage IV BC are generally treated with palliative chemotherapy and were excluded from this study. Among them, 458 were excluded for the following reasons: 256 received no adjuvant chemotherapy, 72 were having neoadjuvant chemotherapy, and 130 had inflammatory BC, unknown tumor size or surgery type, or incomplete or unknown chemotherapy or surgery data. The final study cohort included 617 patients.

Our analysis included women aged 18 to 99 years who underwent a surgical resection and adjuvant chemotherapy as initial treatment. Patients were excluded if they had not had a surgery or chemotherapy, who initiated treatment > 365 days following surgery, and those who were treated with neoadjuvant chemotherapy or radiation therapy before surgery. We examined three levels of adjuvant chemotherapy delay ([less than or equal to] 30, 31 to 60, and [greater than or equal to] 61 days delay). These were divided into 3 groups: less than or equal 30 days (n = 173), 31 - 60 days (n = 353) and equal or over 61 days (n = 91). The time to adjuvant chemotherapy was defined by the days from the most definitive resection of the primary site to the first administration of chemotherapy. The definitive surgical procedure at the primary site included excision biopsy, lumpectomy, and mastectomy.

We obtained information on the age at diagnosis, type of surgery, tumor pathologic stage (according to the American Joint Committee on Cancer (AJCC)/International Union Against Cancer (IUAC) Tumor Node and Metastasis (TNM) classification, lymphovascular invasion (LVI), tumor grade, histology, and comorbidities. We also obtained data on estrogen receptor (ER), progesterone receptor (PgR), and HER2 status. BC subtype was defined as hormone receptor-positive (ER-positive and/or PgR-positive and HER2-negative), HER2-positive (HER2-positive regardless of hormone receptor status), and TNBC (HER2-negative and hormone receptor-negative). We identified the chemotherapy received and classified it as anthracycline-based, anthracycline and taxane-based, or other type. In addition, for the HER2-positive tumors, we further categorized them as trastuzumab-treated and non-trastuzumab treated, since the use of adjuvant trastuzumab was approved in our country in 2005.

Patients were categorized according to TTC categories, and this variable was calculated from the date of definitive surgery to the date of the first dose of adjuvant chemotherapy administration. Patients' TTC categories were 30 days or less, 31 to 60 days, 61 or more days. Descriptive statistics were used to evaluate the characteristics of patients according to TTC, and the distribution was compared using [chi square] test. The outcome of interest was disease free survival (DFS). DFS was calculated from the time of surgery to the first relapse (local, regional, and/or distant), last follow-up or death in the absence of relapse. All the patients were followed-up for at least 6 months. The Kaplan-Meier product limit method was used to estimate the 5-year DFS with 95% confidence intervals (CIs) in all patients according to TTC and other patients' and clinical characteristics. Groups were compared by using the log-rank statistic.

Cox proportional hazards regression models were developed to determine association between TTC and survival outcomes after adjustment for potential confounders. Variables in the model included age (as a continuous variable), pathologic tumor size according to TNM classification (T1, T2, T3), pathological nodal status according to TNM classification (N1, N2, N3), histologic grade, histologic type of BC (ductal, lobular and other), presence of lymphovascular and perineural invasion, hormone receptor (ER- and PgR positive and negative), HER2 status (positive and negative), TNBC, type of surgery and presence of comorbidities. We classified the received chemotherapy as antracycline-based, antracycline/taxane-based, cyclophosphamide, methotrexate, fluorouracil (CMF) type and hormone therapy.

Results are expressed in hazard ratios and 95% CIs. P values [less than or equal to] 0.05 were considered statistically significant. Statistical analyses were carried out using Statistical Package for the Social Sciences (SPSS) 18.0.

The National Code on Clinical Trials has declared that ethics approval is not necessary for retrospective studies. Before this retrospective study our institutional board was informed that this study was conducted in accordance with the principles of the Declaration of Helsinki.

Results

The present retrospective study investigated the association between the initiation time of adjuvant chemotherapy and DFS in 617 operable BC patients. The median age at diagnosis was 55 years, and 62.4% (385) of patients were older than 50. A total of 173 (28%) patients started chemotherapy within less than 31 days; 353 (57.2%) between 31 and 60 days; and 91 (14.7%) started chemotherapy 61 or more days after surgery. Median time to initiation of adjuvant treatment was 43 days (range, 14 to 92). At the median follow-up of 54.4 months, 113 patients (18.3%) experienced distant recurrence i.e. metastases, most commonly in the bones and hepatic metastases, and 7 patients (6.2%) had experienced recurrence of BC.

Table 1 lists the patients' characteristics according to timing of adjuvant chemotherapy. Significant differences among groups were found regarding the age (p = 0.001) and comorbidity (p = 0.003). However, women with delayed chemotherapy were likely to to be older and have associated diseases. Globally, 69.2% of patients presented with hormone receptor positive tumors, versus 30.8% of patients that presented with hormone receptor negative tumors. However, 15.2% of patients had HER-2 positive and 23.2% TNBC. A total number of 239 (38.7%) patients received adjuvant anthracycline-based chemotherapy; 304 (49.3%) received anthracycline and taxane based chemotherapy; 40 (6.5%) received CMF-type chemotherapy; 94 (15.2%) received trastuzumab, and 343 (69%) patients received adjuvant hormone therapy.

Table 2 summarizes the 5-year DFS for all the investigated patients according to TTC, patients' and tumor characteristics. Median follow-up was 54.4 months. Survival analysis, using the Kaplan-Meier method for DFS according to TTC, demonstrated that there were no differences in DFS among the groups that received adjuvant treatment at different timings (Graph 1). The 5-year DFS estimate was 81.5%, 81.0%, 84.6% (log-rank p = 0.728) among patients who initiated chemotherapy < 30 days, 31-60, and > 61 days, respectively, after surgery.

The Cox proportional hazards model was used to adjust the analysis for known prognostic factors such as age, comorbidity, pathologic tumor size, number of positive lymph nodes, vascular and perineural invasion, hormonal receptors status, tumor grade, HER-2 status, histological type of BC, surgery modality and chemotherapy regimen. In the univariate analysis, DFS was significantly higher in patients with T1 tumor, without vascular and perineural invasion, histological grade 2, up to three lymph nodes involved, estrogen and progesterone positive tumor, and breast conservative surgery (Table 3).

Multivariate analysis of independent prognostic factors for DFS identified nodal status and tumor size (Table 4).

Subsequently, we investigated 5-year DFS for all the patients according to the BC subtype. The 5-year DFS estimate was 85.8% (p = 0.001) in patients with luminal-A subtype (ER positive, HER2 negative, Ki-67 < 20%, Progesterone high) at a median follow-up of 62.7 months; in patients with luminal-B subtype (Luminal B (HER2 negative) ER positive, HER negative and either Ki-67 > 20% or Progesterone low, Luminal B (HER2 positive) ER positive, HER2 positive, any Ki-67, any Progesterone) 78.3% (p = 0.534) at a median follow-up of 55.9 months; in patients with TNBC 73.4% at a median follow-up of 58,1 months, and in patients with HER2+ 77.1% (p = 0.448) at a median follow-up of 55.5 months (Table 5).

Discussion

Adjuvant chemotherapy is one of the most important therapies for BC patients. The optimal time to initiate chemotherapy after surgery is still unknown. Due to the potential ethical problems it is unlikely that a prospective clinical trial will be undertaken to explore the association between delayed chemotherapy initiation and survival in BC patients. The lack of change in the attitude towards timing of adjuvant chemotherapy might be related not only to the reported controversial results, but also to the increased requests for additional testing or procedures used to decide whether or not to offer adjuvant chemotherapy [19].

All the published findings related to the treatment outcome associated with the timing of adjuvant chemotherapy initiation are retrospective. The categorization of the time of initiation as proper, early or delayed has no clinical basis, and it is based on the prejudices related to habits in the clinical practice. In clinical trials, a routine criterion for the adjuvant chemotherapy of BC is the initiation of adjuvant therapy within 6 to 8 weeks after surgical treatment, and the initiation out of this timeframe seems to be unusual and potentially harmful. The published randomized controlled clinical trials do not directly suggest the time to initiate chemotherapy after surgery. The time to therapy initiation ranges from 2 to 12 weeks in different trials [20-23]. In clinical practice, many factors may affect the time interval between surgery and adjuvant chemotherapy. Some of the frequently involved factors are related to patients' clinical condition and comorbidities. Delays in treatment initiation are more likely to occur in Medicare patients and in low-income populations [24]. In a large, multi-institutional cohort of women with BC, time from diagnosis to initiation of adjuvant chemotherapy was approximately 12 weeks. This interval increased steadily from 10.8 to 13.3 weeks between 2003 and 2009. The greatest effects were associated with diagnostic and therapeutic interventions, including immediate post-mastectomy reconstruction, reexcision, and use of the 21-gene reverse transcriptase polymerase chain reaction (RT-PCR) assay [25].

Our study showed that 85% of BC patients started adjuvant chemotherapy within 3 months of definitive surgery. Within these 3 months, we found no association between the initiation of chemotherapy and DFS, meaning that the prognosis was similar for patients starting chemotherapy within 3 weeks after surgery and those starting chemotherapy up to 13 weeks after surgery. This is in agreement with results of other studies [26, 27]. A large population-based study did not demonstrate any benefit in overall survival (OS) from an early start of adjuvant chemotherapy among Danish BC patients treated within 3 months of definitive surgery, or for any subgroups with potentially fast growing tumors according to increasing number of involved axillary lymph nodes, increasing malignancy grade or negative hormone receptor status [3]. If chemotherapy is delayed for more than 5 months, then the concept of being adjuvant no longer holds.

Adjuvant chemotherapy decreases the risk of BC mortality through eradication of micro-metastatic tumor deposits. Some clinical studies suggest that an adjuvant chemotherapy delay for up to 12 weeks will significantly reduce the effectiveness of systemic therapy. Results of meta-analyses show that OS decreases by 13% and DFS by 14% every four weeks that adjuvant chemotherapy is delayed [28].

In regard to BC subtype, Gagliato et al. [11] and Chavez-MacGregor et al. [5] categorized patients in to hormone receptor-positive, receptor tyrosineprotein kinase erbB-2 (ERBB2) positive, and TNBC subgroups. Results showed that a WT (whole time) of 31-60 days had no significant impact on patients with ERBB2+ tumors or hormone receptor-positive tumors, while with TNBC, a WT 31-60 days resulted in a 26% increased risk of death. We did not find a statistically significant adverse effect on DFS among patients with ERBB2+ tumors or hormone receptor-positive tumors who had a WT longer than 60 days. In our study, all patients who were ERBB+ received trastuzumab. The HER-2 overexpression or amplification in BC is associated with worse prognosis in untreated patients and may also be associated with poor prognosis [29-31]. Also, our patients who were TNBC had statistically significantly shorter DFS. TNBC is known to have a more aggressive behavior when compared with other BC subtypes [32]. Gagliato et al. have shown that the TNBC subgroup experienced a detrimental effect in delaying initiation of adjuvant chemotherapy in terms of OS, with a 75% and 54% increased risk of death for those women who received chemotherapy 31 to 60 days and [greater than or equal to] 61 days after definitive surgery [11]. Despite the differences in OS, no differences in relapse free survival (RFS) or DFS were seen in TNBC patients [11]. It is important to mention that there is a lack of targeted therapies for this population and that chemotherapy is the only effective known treatment.

As expected, in a multivariate analysis, independent predictive factors for shorter DFS were more than 3 lymph nodes involvement and tumor size T3. In our study, there was no difference in DFS between hormone receptor positive and negative BC patients. Early initiation of chemotherapy had an impact on hormone receptor-negative patients in comparison to hormone receptor-positive patients [27]. Many trials have demonstrated that the magnitude of benefit of adjuvant chemotherapy is less pronounced among hormone receptor-positive patients [33]. Tamoxifen and aromatase inhibitors are important and effective agents in the treatment of BC and their use in adjuvant treatment reduces the risk of death and recurrence [34-36].

There is also a possibility that the detrimental effect associated with delayed TTC among hormone receptor-positive patients is related to a delay in the initiation of endocrine therapy [3].

The main limitation of this study is that it is not randomized. Despite our median follow-up of 54.4 months, it is possible that longer follow-up is needed, particularly to evaluate the effect of delay in adjuvant chemotherapy initiation among patients with hormone receptor-positive BC. Two thirds of the patients had hormone receptor--positive disease, and there was no indication that TTC for these patients made any difference at all. Endocrine manipulation may act a more positive role than earlier initiation of chemotherapy in ER positive patients.

A larger number of studies, especially those with subgroup analyses are needed. Smaller subpopulations of patients were identified in whom delays (beyond 60 days) to chemotherapy initiation might have been avoided. The magnitude of the benefit of adjuvant chemotherapy might indeed be greater in locally advanced BC, with higher probability of micro-metastatic disease, and initiation within 60 days might be an appropriate guideline for these patients. The impact also varies in regard to subtypes and an early initiation of adjuvant chemotherapy is particularly important for patients with luminal-B, TNBC and HER2+ tumors.

The recognition of the heterogeneity of BC has recently led to the concept that investigations of tailored adjuvant treatment in specific subpopulations, through international collaboration, are the key to improve the outcome in patients with early BC.

Conclusion

In conclusion, our retrospective study did not show that the timing of adjuvant chemotherapy initiation affected the outcome in patients with early breast cancer. The current report suggests that unnecessary delay in initiation of chemotherapy may be unwise in patients in whom the effect of adjuvant chemotherapy is expected to be significant. Early initiation of adjuvant chemotherapy is particularly relevant in patients with advanced-stage breast cancer at diagnosis, those with triple-negative breast cancer, and patients with trastuzumab-treated human epidermal growth factor receptor 2-positive tumors. Since the realization of a prospective trial that should definitely provide reliable data seems to be unlikely, only retrospective trials with sufficient statistical power and valuable data, to detect differences among groups, can help to explain this interesting issue.

References

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Rad je primljen 5. IX 2018.

Recenziran 1. X 2018.

Prihvacen za stampu 15. X 2018.

BIBLID.0025-8105:(2018):LXXI:11-12:394-403.

Oncology Institute of Vojvodina, Sremska Kamenica (1)

University of Novi Sad, Faculty of Medicine (2)

Bojana VRANJKOVIC (1), Dragana PETROVIC (1), Jelena RADIC (1, 2), Maja POPOVIC (1, 2), Ivana KOLAROV BJELOBRK (1, 2) and Nemanja PETROVIC (1, 2)

Corresponding Author: Dr Bojana Vranjkovic, Institut za onkologiju Vojvodine, 21204 Sremska Kamenica, Put Doktora Goldmana 4, E-mail: bojanavranjkovic1985@gmail.com

https://doi.org/10.2298/MPNS1812394V
Table 1. Patient and clinical characteristics by interval from surgery
to adjuvant chemotherapy among patients with stage I to III breast
cancer
Tabela 1. Karakteristike pacijenata i intervali zapocinjanja
hemioterapije nakon zavrsenog hirurskog lecenja za pacijente stadijuma
I do III sa karcinomom dojke

Characteristics                       Interval from surgery to
                                      chemotherapy initiation (days)
Karakteristike                        Interval od hirurgije do pocetka
                                      hemioterapije (u danima)
                                      [less than or equal to] 30 days
                                      [less than or equal to] 30 dana
                                      (n = 173)

Age, years/Starost, godine
Median/Medijana                        52
Range/Raspon                           26-76
Age
[greater than or equal to]50          105 (60.7%)
years/
[greater than or equal to]50
godina
starosti
Comorbidity/Komorbiditet
Absent/Odsutni                        130 (75.1%)
Present/Prisutni                       43 (24.9%)
Pathologic tumor size
according to TNM
classifikation/Velicina
tumora prema TNM
klasifikaciji
T1                                     69 (39.9%)
T2                                     68 (39.3%)
T3                                     36 (20.8%)
Vascular/lymphatic
invasion/Vaskularna/limf
na invazija
Absent/Odsutna                         67 (38.7%)
Present/Prisutna                      106 (61,3%)
Perineural
invasion/Perineuralna
invazija
Absent/Odsutna                         92 (53.2%)
Present/Prisutna                       81 (46.8%)
Histological
grade/Histoloski gradus
GI                                      9 (5.2%)
GII                                    67 (38.7%)
GIII                                   97 (56.1%)
No. of involved lymph
nodes/Broj zahvacenih
limfnih cvorova
0                                      73 (42.2%)
1- 3                                   53 (30.6%)
3- 9                                   27 (15.6%)
[greater than or equal to] 10          20 (11.6%)
Histological type of
breast cancer/Histoloski
tip karcinoma dojke
Ductal/Duktalni                       159 (91.9%)
Lobular/Lobularni                       5 (2.9%)
Other/Ostali tipovi                     9 (5.2%)
Estrogen
receptor/Estrogenski
receptor
Positive/Pozitivan                    115 (66.5%)
Negative/Negativan                     58 (33.5%)
Progesterone
receptor/Progesteronski
receptor
Positive/Pozitivan                    107 (61.8%)
Negative/Negativan                     66 (38.2%)
Breast cancer
subtype/Podtip karcinoma dojke
HER2-positive/HER2 pozitivan           29 (16.8%)
Triple-negative/Trostruko negativan    27 (15.6%)
Hormone
receptor-positive/Hormonski
receptor pozitivan                     99 (57.2%)
Surgery/Vrsta operacije
BSC/Postedna operacija                127 (73.4%)
Mastectomy/Mastektomija                46 (26.6%)
Chemotherapy/Hemioterapija
CMF-type/CMF protokol                   9 (5.2%)
Anthracycline-based/Antraciklinski     58 (33.5%)
protokol
Anthracycline+Taxane/                  99 (57.2%)
Antraciklini+Taksani
Hormone therapy/Hormonska               7 (4.0%)
terapija
Trastuzumab among
HER2-positive patients
(n= 231)
Trastuzumab kod
HER2-pozitivnih
pacijentkinja
No/Ne                                  28 (49.1%)
Yes/Da                                 29 (50.9%)

Characteristics                       Interval from surgery to
                                      chemotherapy initiation (days)
Karakteristike                        Interval od hirurgije do pocetka
                                      hemioterapije (u danima)
                                       31-60 days    [greater than
                                                     or equal to] 61
                                                     days
                                       31-60 dana    [greater than or
                                                     equal to]61 dan
                                       (n = 353)     (n = 91)

Age, years/Starost, godine
Median/Medijana                        54            57
Range/Raspon                           25-77         36-80
Age [greater than or                  237 (67.1%)   67 (73.6%)
equal to] 50
years/[greater than or
equal to] 50 godina
starosti
Comorbidity/Komorbiditet
Absent/Odsutni                         247 (70.0%)   50 (54.9%)
Present/Prisutni                       106 (30.0%)   41 (45.1%)
Pathologic tumor size
according to TNM
classifikation/Velicina
tumora prema TNM
klasifikaciji
T1                                     130 (36.8%)   26 (28.6%)
T2                                     157 (44.5%)   48 (52.7%)
T3                                     66 (18.7%)    17 (18.7%)
Vascular/lymphatic
invasion/Vaskularna/limf
na invazija                                  0.80
Absent/Odsutna                         145 (41.1%)   39 (42.9%)
Present/Prisutna                       208 (58.9%    52 (57.1%)
Perineural invasion/
Perineuralna invazija
Absent/Odsutna                         192 (54.4%)   52 (57.1%)
Present/Prisutna                       161 (45.6%)   39 (42.9%)
Histological grade/Histoloski gradus
GI                                      30 (8.5%)    10 (11.0%)
GII                                    138 (39.1)    32 (35.2%)
GIII                                   185 (52.4%)   49 (53.8%)
No. of involved lymph
nodes/Broj zahvacenih
limfnih cvorova                              0.31
0                                      167 (47.3%)   38 (41.8%)
1- 3                                    93 (26.3%)   34 (37.4%)
3- 9                                    51 (14.4%)   14 (15.4%)
[greater than or equal to] 10           42 (11.9%)    5 (5.5%)
Histological type of
breast cancer/Histoloski
tip karcinoma dojke                        0.48
Ductal/Duktalni                        315 (89.2%)   77 (84.6%)
Lobular/Lobularni                       15 (4.2%)     6 (6.6%)
Other/Ostali tipovi                     23 (6.5%)     8 (8.8%)
Estrogen receptor/
Estrogenski receptor
Positive/Pozitivan                     227 (64.3%)   58 (63.7%)
Negative/Negativan                     126 (35.7%)   33 (36.3%)
Progesterone receptor/
Progesteronski receptor
Positive/Pozitivan                     208 (58.9%)   55 (60.4%)
Negative/Negativan                     145 (41.1%)   36 (39.6%)
Breast cancer subtype/
Podtip karcinoma dojke
HER2-positive/HER2 pozitivan            49 (13.9%)   16 (17.6%)
Triple-negative/Trostruko negativan     72 (20.4%)   12 (13.2%)
Hormone receptor-positive/
Hormonski receptor pozitivan           195 (55.2%)   49 (53.8%)
Surgery/Vrsta operacije
BSC/Postedna operacija                 269 (76.2%)   68 (74.7%)
Mastectomy/Mastektomija                 84 (23.8%)   23 (25.3%)
Chemotherapy/Hemioterapija
CMF-type/CMF protokol                   22 (6.2%)     9 (9.9%)
Anthracycline-based/                   147 (41.6%)   34 (37.4%)
Antraciklinski protokol
Anthracycline+Taxane/                  166 (47.0%)   39 (42.9%)
Antraciklini+Taksani
Hormone therapy/Hormonska               18 (5.1%)     9 (9.9%)
terapija
Trastuzumab among
HER2-positive patients
(n= 231)
Trastuzumab kod
HER2-pozitivnih
pacijentkinja
No/Ne                                   67 (57.7%)   26 (61.9%)
Yes/Da                                 49 (42.3%)    16 (38.1%)

Characteristics
Karakteristike

                                                      p

Age, years/Starost, godine
Median/Medijana                                      0.001
Range/Raspon
Age [greater than or                                 0.20
equal to] 50 years/
[greater than or
equal to] 50 godina
starosti
Comorbidity/Komorbiditet
Absent/Odsutni                                       0.003
Present/Prisutni
Pathologic tumor size
according to TNM
classifikation/Velicina
tumora prema TNM
klasifikaciji
T1                                                   0.30
T2
T3
Vascular/lymphatic
invasion/Vaskularna/limf na invazija
Absent/Odsutna
Present/Prisutna
Perineural invasion/Perineuralna invazija            0.83
Absent/Odsutna
Present/Prisutna
Histological grade/
Histoloski gradus                                    0.50
GI
GII
GIII
No. of involved lymph
nodes/Broj zahvacenih
limfnih cvorova
0
1- 3
3- 9
[greater than or equal to] 10
Histological type of
breast cancer/Histoloski
tip karcinoma dojke
Ductal/Duktalni
Lobular/Lobularni
Other/Ostali tipovi
Estrogen receptor/Estrogenski
receptor                                             0.86
Positive/Pozitivan
Negative/Negativan
Progesterone receptor/Progesteronski
receptor                                             0.81
Positive/Pozitivan
Negative/Negativan
Breast cancer subtype/Podtip
karcinoma dojke
HER2-positive/HER2 pozitivan                         0.55
Triple-negative/Trostruko negativan                  0.18
Hormone receptor-positive/Hormonski
receptor pozitivan                                   0.85
Surgery/Vrsta operacije                              0.92
BSC/Postedna operacija
Mastectomy/Mastektomija
Chemotherapy/Hemioterapija                           0.08
CMF-type/CMF protokol
Anthracycline-based/
Antraciklinski protokol
Anthracycline+Taxane/Antraciklini+Taksani
Hormone therapy/Hormonska
terapija
Trastuzumab among
HER2-positive patients
(n= 231)
Trastuzumab kod
HER2-pozitivnih
pacijentkinja
No/Ne                                                0.09
Yes/Da

Legend: BSC--breast conservative surgery; CMF--cyclophosphamide,
methotrexate, 5-fuorouracile; [P.sup.a] value for diferent distribution
in 3 groups tested by heterogeneous [chi square]
Legenda: BSC--postedna operacija dojke, CMF--ciklofosfamid,
metotreksat, 5-fuorouracil; [P.sup.a] vrednost za razlicitu
distribuciju u okviru 3 grupe je testirana [chi square] testom;
HER2--receptor 2 humanog epidermalnog faktora rasta; TNM--Tumor Nodus
Metastaze

Table 2. Survival estimate for DFS according to patient characteristics
among patients with stage I to III BC treated with adjuvant chemotherapy
Tabela 2. Prezivljavanje pacijenata i period bez bolesti u odnosu na
karakteristike pacijenata obolelih od karcinoma dojke stadijuma I do III

                                      Interval from surgery to
                                      chemotherapy initiation (days)
                                      Interval od operacije do pocetka
                                      hemioterapije (u danima)
                                      [less than or equal to] 30
                                      days/[less than or equal to]
                                      30 dana
                                      (n = 173)
                                      No. of       5-year
                                      patients     DFS (%)
                                      Broj         5-godisnji
                                      pacijenata    DFS

Age [greater than                         94        76.6%
or equal to] 50
years/ [greater than
or equal to] 50 godina
starosti
Age < 50 years/< 50                       79        87.3%
godina starosti
Comorbidity absent/                      130        85.4%
Odsutni komorbiditeti
Comorbidity present/                      43        69.8%
Prisutni komorbiditeti
Pathologic tumor size
according to TNM
classification/Velicina
tumora prema TNM
klasifikaciji
T1                                        69        85.5%
T2                                        68        83.8%
T3                                        36        69.4%
Vascular/lymphatic invasion absent        67        82.1%
Odsutna vaskularna/limfna invazija
Vascular/lymphatic invasion present      106        81.1%
Prisutna vaskularna/limfna invazija
Perineural invasion absent                92        85.9%
Odsutna perineuralna invazija
Perineural invasion present               81        76.5%
Prisutna perineuralna invazija
Histological grade/Histoloski gradus
GI                                         9       100%
GII                                       67        79.1%
GIII                                      97        81.4%
No. of involved
lymph nodes/Broj zahvacenih
limfnih cvorova
0                                         73        89.0%
1-3                                       53        92.5%
4-9                                       27        59.3%
[greater than or equal to]10              20        55.0%
Histological type of breast
cancer/Histoloski tip
karcinoma dojke
Ductal/Duktalni                          159        80.5%
Lobular/Lobularni                          5        100%
Other/Ostali tipovi                        9        88.9%
ER negative/ER negativan                  58        70.7%
ER positive/ER pozitivan                 115        87.0%
PgR negative/PgR negativan                66        72.7%
PgR positive/PgR pozitivan               107        86.9%
HER2-positive/HER2 pozitivan              28        75.0%
HER2-negative/HER2 negativan             145        82.8%
Triple-negative/Trostruko                 27        74.1%
negativan
Hormone receptor-positive                 99        87.9%
Hormon receptor pozitivan
Hormone receptor-negative                 50        70.0%
Hormon receptor negativan
Surgery/Operacija
BSC/Postedna                             127        85.6%
Mastectomy/Mastektomija                   46        71.7%
Chemotherapy/Hemioterapija
CMF-type/CMF protokol                      9        44.4%
Anthracycline-based/                      58        84.5%
Antraciklinski protokol
Anthracycline+Taxane                      99        81.9%
Antraciklini+Taksani
Hormone therapy/                           7        100%
Hormonska terapija
Trastuzumab among
HER2-positive patients/                   28        75.0%
Trastuzumab kod HER2
pozitivnih
pacijentkinja

                                      Interval from surgery to
                                      chemotherapy initiation (days)
                                      Interval od operacije do pocetka
                                      hemioterapije (u danima)
                                      31-60 days/31-60 dana
                                      (n = 353
                                       No. of pa-   5-year
                                       tients       DFS (%)
                                       Broj         5-godisnji
                                       pacijenata   DFS
Age [greater than                        226        83.2%
or equal to] 50
years/ [greater than
or equal to] 50 godina
starosti
Age < 50 years/< 50                      127        77.2%
godina starosti
Comorbidity absent/                      247        81.0%
Odsutni komorbiditeti
Comorbidity present/                     106        81.1%
Prisutni komorbiditeti
Pathologic tumor size
according to TNM
classification/Velicina
tumora prema TNM
klasifikaciji
T1                                       130        90.8%
T2                                       157        75.8%
T3                                        66        74.2%
Vascular/lymphatic invasion absent       145        86.2%
Odsutna vaskularna/limfna invazija
Vascular/lymphatic invasion present      208        77.4%
Prisutna vaskularna/limfna invazija
Perineural invasion absent               192        87.5%
Odsutna perineuralna invazija
Perineural invasion present              161        73.3%
Prisutna perineuralna invazija
Histological grade/Histoloski gradus
GI                                        30        93.3%
GII                                      138        83.3%
GIII                                     185        77.3%
No. of involved
lymph nodes/Broj zahvacenih
limfnih cvorova
0                                        167        89.2%
1-3                                       93        83.9%
4-9                                       51        72.2%
[greater than or equal to]10              42        52.4%
Histological type of breast
cancer/Histoloski tip
karcinoma dojke
Ductal/Duktalni                          315        81.3%
Lobular/Lobularni                         15        86.7%
Other/Ostali tipovi                       23        73.9%
ER negative/ER negativan                 126        77.0%
ER positive/ER pozitivan                 227        83.3%
PgR negative/PgR negativan               145        76.6%
PgR positive/PgR pozitivan               208        84.1%
HER2-positive/HER2 pozitivan              42        85.7%
HER2-negative/HER2 negativan             311        80.4%
Triple-negative/Trostruko                 72        73.8%
negativan
Hormone receptor-positive                195        83.6%
Hormon receptor pozitivan
Hormone receptor-negative                113        75.2%
Hormon receptor negativan
Surgery/Operacija
BSC/Postedna                             269        83.6%
Mastectomy/Mastektomija                   84        73.8%
Chemotherapy/Hemioterapija
CMF-type/CMF protokol                     22        90.9%
Anthracycline-based/                     147        79.6%
Antraciklinski protokol
Anthracycline+Taxane                     166        80.1%
Antraciklini+Taksani
Hormone therapy/                          18        88.9%
Hormonska terapija
Trastuzumab among
HER2-positive patients/                   42        85.7%
Trastuzumab kod HER2
pozitivnih
pacijentkinja

                                      Interval from surgery to
                                      chemotherapy initiation (days)
                                      Interval od operacije do pocetka
                                      hemioterapije (u danima)
                                      [greater than or equal to] 61
                                      days/[greater than or equal
                                      to] 61 dan
                                      (n = 353
                                        (n = 91
                                        No. of       5-year
                                        patients     DFS (%)
                                        Broj         5-godisnji
                                        pacijenata   DFS

Age [greater than                         65          80.0%
or equal to] 50
years/ [greater than
or equal to] 50 godina
starosti
Age < 50 years/< 50                       26          96.2%
godina starosti
Comorbidity absent/                       50          90.0%
Odsutni komorbiditeti
Comorbidity present/                      41          78.0%
Prisutni komorbiditeti
Pathologic tumor size
according to TNM
classification/Velicina
tumora prema TNM
klasifikaciji
T1                                        26          88.6%
T2                                        48          81.3%
T3                                        17          88.2%
Vascular/lymphatic invasion absent        39          92.3%
Odsutna vaskularna/limfna invazija
Vascular/lymphatic invasion present       52          78.8%
Prisutna vaskularna/limfna invazija
Perineural invasion absent                52          86.5%
Odsutna perineuralna invazija
Perineural invasion present               39          82.1%
Prisutna perineuralna invazija
Histological grade/Histoloski gradus
GI                                        10           100%
GII                                       32          90.6%
GIII                                      49          77.6%
No. of involved
lymph nodes/Broj zahvacenih
limfnih cvorova
0                                         38          86.8%
1-3                                       34          85.3%
4-9                                       14          78.6%
[greater than or equal to]10               5          80.6%
Histological type of breast
cancer/Histoloski tip
karcinoma dojke
Ductal/Duktalni                           77          85.7%
Lobular/Lobularni                          6          66.7%
Other/Ostali tipovi                        8          87.5%
ER negative/ER negativan                  33          81.8%
ER positive/ER pozitivan                  58          86.2%
PgR negative/PgR negativan                36          83.3%
PgR positive/PgR pozitivan                55          85.5%
HER2-positive/HER2 pozitivan              14          57.7%
HER2-negative/HER2 negativan               8          89.6%
Triple-negative/Trostruko                 12          100%
negativan
Hormone receptor-positive                 49          83.7%
Hormon receptor pozitivan
Hormone receptor-negative                 27          77.8%
Hormon receptor negativan
Surgery/Operacija
BSC/Postedna                              68          88.6%
Mastectomy/Mastektomija                   23          87.0%
Chemotherapy/Hemioterapija
CMF-type/CMF protokol                      9          77.8%
Anthracycline-based/                      34          91.2%
Antraciklinski protokol
Anthracycline+Taxane                      39          79.5%
Antraciklini+Taksani
Hormone therapy/                           9          88.9%
Hormonska terapija
Trastuzumab among
HER2-positive patients/                   14          57.1%
Trastuzumab kod HER2
pozitivnih
pacijentkinja

                                      Interval from surgery to
                                      chemotherapy initiation (days)
                                      Interval od operacije do pocetka
                                      hemioterapije (u danima)
                                          p
                                         log-rank

                                         0.375
Age [greater than                        0.035
or equal to] 50
years/ [greater than
or equal to] 50 godina
starosti
Age < 50 years/< 50                      0.252
godina starosti
Comorbidity absent/                      0.266
Odsutni komorbiditeti
Comorbidity present/
Prisutni komorbiditeti
Pathologic tumor size
according to TNM
classification/Velicina
tumora prema TNM
klasifikaciji
T1                                       0.472
T2                                       0.359
T3                                       0.361
Vascular/lymphatic invasion absent       0.315
Odsutna vaskularna/limfna invazija
Vascular/lymphatic invasion present      0.778
Prisutna vaskularna/limfna invazija
Perineural invasion absent               0.907
Odsutna perineuralna invazija
Perineural invasion present              0.497
Prisutna perineuralna invazija
Histological grade/Histoloski gradus
GI                                       0.545
GII                                      0.374
GIII                                     0.753
No. of involved
lymph nodes/Broj zahvacenih
limfnih cvorova
0                                        0.879
1-3                                      0.339
4-9                                      0.395
[greater than or equal to]10             0.580
Histological type of breast
cancer/Histoloski tip
karcinoma dojke
Ductal/Duktalni                          0.601
Lobular/Lobularni                        0.359
Other/Ostali tipovi                      0.554
ER negative/ER negativan                 0.437
ER positive/ER pozitivan                 0.687
PgR negative/PgR negativan               0.476
PgR positive/PgR pozitivan               0.860
HER2-positive/HER2 pozitivan             0.070
HER2-negative/HER2 negativan             0.179
Triple-negative/Trostruko                0.157
negativan
Hormone receptor-positive                0.658
Hormon receptor pozitivan
Hormone receptor-negative                0.702
Hormon receptor negativan
Surgery/Operacija
BSC/Postedna                             0.908
Mastectomy/Mastektomija                  0.384
Chemotherapy/Hemioterapija
CMF-type/CMF protokol                    0.020
Anthracycline-based/                     0.253
Antraciklinski protokol
Anthracycline+Taxane                     0.963
Antraciklini+Taksani
Hormone therapy/                         0.767
Hormonska terapija
Trastuzumab among
HER2-positive patients/                  0.070
Trastuzumab kod HER2
pozitivnih
pacijentkinja

Legenda: DFS - period bez bolesti; ER - receptori za estrogen,
PgR - receptori za progesteron, HER2--receptor 2 humanog epidermalnog
faktora rasta; CMF - ciklofosfamaid, metotreksat, 5-fuorouracil,
TNM--Tumor Nodus Metastaze

Table 3. Univariate analysis hazard ratio: DFS according to timing of
adjuvant chemotherapy
Tabela 3. Hazard racio univarijantna analiza: periodi bez bolesti u
odnosnu na zapocinjanje adjuvantne terapije

Variable
Varijable

Age/Starost                             Continuous/Kontinuirana
Comorbidity/Komorbiditeti               absent vs. present/Prisutan vs
Pathologic tumor size according         odsutan
to TNM calssification/Tumorska
velicina prema TNM klasifikaciji
T1                                      Reference/Referentna vrednost
T2
T3
Vascular/lymphatic invasion             Absent vs. present/Prisutan vs
                                        odsutan
Vaskularna/limfna invazija
Perineural invasion                     Absent vs. present/Prisutan vs
                                        odsutan
Perineuralna invazija
Histological grade/Histoloski gradus
GI                                      Reference/Referentna vrednost
GII
GIII
No. of involved lymph
nodes/Broj zahvacenih
limfnih cvorova
0                                       Reference/Referentna vrednost
1-3
4-9
[greater than or equal to]10
Histological type of breast
cancer/Histoloski tip
karcinoma dojke
Ductal/Duktalni
Lobular/Lobularni
Other/Ostali tipovi                     Reference/Referentna vrednost
Estrogen receptor/Estrogenski receptor  Positive vs. negative/Pozitivan
                                        vs negativan
Progesteron receptor                    Positive vs. negative/Pozitivan
Progesteronski receptor                 vs negativan
HER2 receptor/HER2 receptor             Negative vs. positive/Pozitivan
                                        vs negativan
Triple-negative/Trostruko-negativni     Positive vs. negative/Pozitivan
                                        vs negativan
Surgery modality/Tip operacije          BCS vs. Mastectomy/Postedna
                                        vs mastektomija
Scheme of chemotherapy used/
Hemioterapijski protokol
CMF-type/CMF protokol
Anthracycline-based
Antraciklinski protokol
Anthracycline+Taxane
Antraciklini+ Taksani
Hormone therapy/Hormonska terapija      Reference/Referentna vrednost
Hormone receptor/Hormonski receptor     Positive vs. negative/Pozitivan
                                        vs negativan
TTC, days/Vreme do zapocinjanja
 hemioterapije
[less than or equal to] 30              Reference/Referentna vrednost
31-60
[greater than or equal to] 61

Variable                          B     HR     CI            p
Varijable

Age/Starost                     -0.002  0.998  0.980-1.015   0.784
Comorbidity/Komorbiditeti        0.363  1.438  0.978-2.114   0.065
Pathologic tumor size
according to TNM
calssification/Tumorska
velicina prema TNM
klasifikaciji
T1
T2                               0.737  2.091  1.306-3.347   0.002
T3                               0.930  2.535  1.490-4.313   0.001
Vascular/lymphatic invasion      0.472  1.603  1.075-2.389   0.021
Vaskularna/limfna invazija
Perineural invasion              0.684  1.981  1.357-2.892   0.001
Perineuralna invazija
Histological grade/
Histoloski gradus
GI
GII                              1.473  4.364  1.054-18.072  0.042
GIII                              1744  5.722  1.402-23.350  0.015
No. of involved lymph
nodes/Broj zahvacenih
limfnih cvorova
0
1-3                              0.214  1.239  0.726-2.114   0.432
4-9                              1.140  3.127  1.874-5.219   0.001
[greater than or                 1.597  4.940  2.985-8.175   0.001
equal to]10
Histological type of
breast cancer/Histoloski
tip karcinoma dojke
Ductal/Duktalni                 -0.083  0.921  0.448-1.893   0.822
Lobular/Lobularni               -0.261  0.770  0.232-2.559   0.670
Other/Ostali tipovi
Estrogen receptor/               0.492  1.635  1.129-2.368   0.009
Estrogenski receptor
Progesteron receptor             0.504  1.656  1.145-2.396   0.007
Progesteronski receptor
HER2 receptor/HER2 receptor      0.244  1.276  0.794-2-051   0.314
Triple-negative/                 0.595  1.813  1.226-2.681   0.003
Trostruko-negativni
Surgery modality/Tip operacije  -0.510  0.600  0.406-0.887   0.010
Scheme of chemotherapy
used/Hemioterapijski protokol
CMF-type/CMF protokol            0.950  2.586  0.699-9.560   0.154
Anthracycline-based              0.696  2.006  0.621-6.480   0.245
Antraciklinski protokol
Anthracycline+Taxane             0.797  2.220  0.694-7.098   0.179
Antraciklini+ Taksani
Hormone therapy/
Hormonska terapija
Hormone receptor/                0.599  1.820  1.254-2.642   0.002
Hormonski receptor
TTC, days/Vreme do
zapocinjanja hemioterapije
[less than or equal to] 30
31-60                            0.008  1.008  0.662-1.537   0.969
[greater than or equal to] 61   -0.221  0.802  0.428-1502    0.490

Legenda: HR--odnos rizika, CI - indeks poverenja, BCS--breast
conservative surgery; TNM - Tumor Nodus Metastaze; HER2--receptor
2 humanog epidermalnog faktora rasta; CMF - ciklofosfamaid,
metotreksat, 5-fuorouracil, B- beta

Table 4. Multivariate analysis of prognostic factors for disease-free
survival (DFS)
Tabela 4. Prognosticki faktori koji uticu na period bez bolesti u
multivarijantnoj analizi

Variable/Varijabla

Pathologic tumor size
according to TNM
classification/Tumorska
velicina prema TNM klasifikaciji
T1                                     Reference/Referentna vrednost
T2
T3
Vascular/lymphatic invasion            Absent vs. present/odsutan vs
                                       prisutan
Vaskularna/limfna invazija
Perineural invasion                    Absent vs. present/odsutan vs
                                       prisutan
Perineuralna invazija
Histological grade/Histoloski gradus
GI                                     Reference/Referentna vrednost
GII
GIII
No. of involved lymph nodes/
Broj zahvacenih limfnih cvorova
0                                      Reference/Referentna vrednost
1-3
4-9
[greater than or equal to]10
Estrogen receptor                      Positive vs. negative/pozitivan
                                       vs negativan
Estrogenski receptor
Progesteron receptor                   Positive vs. negative/pozitivan
                                       vs negativan
Progesteronski receptor
Triple-negative/Trostruko-negativan    Positive vs. negative/pozitivan
                                       vs negativan
Surgery modality/Tip operacije         BSC vs. Mastectomy/Postedna
                                       vs mastektomija
Hormone receptor                       Positive vs. negative/pozitivan
Hormonski receptori                    vs negativan

Variable/Varijabla                     B     HR     CI 95%        p

Pathologic tumor size
according to TNM
classification/Tumorska
velicina prema TNM
klasifikaciji
T1
T2                                    0.412  1.509  0.925-2.462   0.099
T3                                    0.618  1.856  1.070-3.549   0.050
Vascular/lymphatic invasion           0.151  1.163  0.730-1.853   0.525
Vaskularna/limfna invazija
Perineural invasion                   0.285  1.330  0.854-2.072   0.207
Perineuralna invazija
Histological grade/
Histoloski gradus
GI
GII                                   1.138  3.120  0.742-13.128  0.121
GIII                                  1.185  3.272  0.782-13.690  0.105
No. of involved lymph
nodes/Broj zahvacenih
limfnih cvorova
0
1-3                                   0.126  1.135  0.648-1.985   0.658
4-9                                   0.926  2.525  1.460-4.365   0.001
[greater than or equal to]10          1.381  3.981  2.320-6.830   0.0001
Estrogen receptor                    -0.077  0.926  0.280-3.008   0.898
Estrogenski receptor
Progesteron receptor                  0.181  1.198  0.587-2.443   0.620
Progesteronski receptor
Triple-negative/Trostruko-negativan   0.408  1.503  0.756-2.988   0.245
Surgery modality/Tip operacije       -0.142  0.868  0.537-1.402   0.562
Hormone receptor                      0.228  1.256  0.286-5.505   0.763
Hormonski receptori

Legenda: TNM - Tumor Nodus Metastaze, CI - interval poverenja, HR -
odnos rizika, B - beta

Table 5. Survival estimate for DFS according to breast cancer subtype
among patients with stage I to III BC treated with adjuvant chemotherapy
Tabela 5. Procena prezivljavanja i period bez bolesti u odnosu na
podtip karcinoma dojke za pacijente stadijuma

Breast cancer subtype                No. of patients  No. of events
Podtip karcinoma dojke               Broj pacijenata  Broj dogadaja

Luminal-A/Luminal-A                  380              54
Luminal-B/Luminal-B                   46              10
HER2-positive/HER2 pozitivan          48              11
Triple-negative/Trostruko negativan  143              38

Breast cancer subtype                5-Year DFS      p
Podtip karcinoma dojke               5-godisnji DFS

Luminal-A/Luminal-A                  85.8%           0.001
Luminal-B/Luminal-B                  78.3%           0.534
HER2-positive/HER2 pozitivan         77.1%           0.448
Triple-negative/Trostruko negativan  73.4%           0.003

Legenda: BSC--breast conservative surgery, HER2--receptor 2 humanog
epidermalnog faktora rasta; DFS - period bez bolesti
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Title Annotation:PROFESSIONAL ARTICLE/STRUCNI CLANAK
Author:Vranjkovic, Bojana; Petrovic, Dragana; Radic, Jelena; Popovic, Maja; Bjelobrk, Ivana Kolarov; Petrov
Publication:Medicinski Pregled
Date:Nov 1, 2018
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