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.
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 . 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 . 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 .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.  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.
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).
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 .
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 . 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 .
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 . 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 .
In regard to BC subtype, Gagliato et al.  and Chavez-MacGregor et al.  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 . 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 . Despite the differences in OS, no differences in relapse free survival (RFS) or DFS were seen in TNBC patients . 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 . Many trials have demonstrated that the magnitude of benefit of adjuvant chemotherapy is less pronounced among hormone receptor-positive patients . 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 .
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.
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.
[1.] Peto R, Davies C, Godwin J, Gray R, Pan HC, Clarke M, et al. Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials. Lancet. 2012;379(9814):432-44.
[2.] Shannon C, Ashley S, Smith IE. Does timing of adjuvant chemotherapy for early breast cancer influence survival? J Clin Oncol. 2003;21(20):3792-7.
[3.] Cold S, During M, Ewertz M, Knoop A, Moller S. Does timing of adjuvant chemotherapy influence the prognosis after early breast cancer? Results of the Danish Breast Cancer Cooperative Group (DBCG). Br J Cancer. 2005;93(6):627-32.
[4.] Lohrisch C, Paltiel C, Gelmon K, Speers C, Taylor S, Barnett J, et al. Impact on survival of time from definitive surgery to initiation of adjuvant chemotherapy for early-breast cancer. J Clin Oncol. 2006;24(30):4888-94.
[5.] Chavez-MacGregor M, Clarke CA, Lichtensztajn DY, Giordano SH. Delayed initiation of adjuvant chemotherapy among patients with breast cancer. JAMA Oncol. 2016;2(3):322-9.
[6.] Fisher B, Gunduz N, Coyle J, Rudock C, Saffer E. Presence of a growth-stimulating factor in serum following primary tumor removal in mice. Cancer Res.1989;49(8):1996-2001.
[7.] Folkman J. Endothelial cells and angiogenic growth factors in cancer growth and metastasis. Introduction. Cancer Metastasis Rev. 1990;9(3):171-4.
[8.] Goldie JH, Coldman AJ. A mathematic model for relating the drug sensitivity of tumors to their spontaneous mutation rate. Cancer Treat Rep. 1979;63(11-12):1727-33.
[9.] Gunduz N, Fisher B, Saffer EA. Effect of surgical removal on the growth and kinetics of residual tumor. Cancer Res.1979;39(10):3861-5.
[10.] Simpson JF, Page DL. Status of breast cancer prognostication based on histopathologic data. Am J ClinPathol. 1994;102(4 Suppl 1):S3-8.
[11.] Gagliato Dde M, Gonzalez-Angulo AM, Lei X, Theriault RL, Giordano SH, Valero V, et al. Clinical impact of delaying initiation of adjuvant chemotherapy in patients with breast cancer. J Clin Oncol. 2014;32(8):735-44.
[12.] Yamamoto Y, Iwase H. Clinicopathological features and treatment strategy for triple-negative breast cancer. Int J Clin Oncol. 2010;15(4):341-51.
[13.] Foulkes WD, Smith IE, Reis-Filho JS. Triple-negative breast cancer. N Engl J Med. 2010;363(20):1938-48.
[14.] Pritchard KI, Shepherd LE, O'Malley FP, Andrulis IL, Tu D, Bramwell VH, et al. HER2 and responsiveness of breast cancer to adjuvant chemotherapy. N Engl J Med. 2006;354 (20):2103-11.
[15.] Alkis N, Durnali AG, Arslan UY, Kocer M, Onder FO, Tokluoglu S, et al. Optimal timing of adjuvant treatment in patients with early breast cancer. Med Oncol. 2011;28(4):1255-9.
[16.] Jara Sanchez C, Ruiz A, Martin M, Anton A, Munarriz B, Plazaola A, et al. Influence of timing of initiation of adjuvant chemotherapy over survival in breast cancer: a negative outcome study by the Spanish Breast Cancer Res Group (GEI-CAM). Breast Cancer Res Treat. 2007;101(2):215-23.
[17.] Nurgalieva ZZ, Franzini L, Morgan RO, Vernon SW, Liu CC, Du XL. Impact of timing of adjuvant chemotherapy initiation and completion after surgery on racial disparities in survival among women with breast cancer. Med Oncol. 2013;30(1):419.
[18.] Fedewa SA, Ward EM, Stewart AK, Edge SB. Delays in adjuvant chemotherapy treatment among patients with breast cancer are more likely in African American and Hispanic populations: a national cohort study 2004-2006. J Clin Oncol. 2010;28(27):4135-41.
[19.] Colleoni M, Gelber RD. Time to initiation of adjuvant chemotherapy for early breast cancer and outcome: the earlier, the better? J Clin Oncol. 2014;32(8):717-9.
[20.] Bonadonna G, Valagussa P, Moliterni A, Zambetti M, Brambilla C. Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer: the results of 20 years of follow-up. N Engl J Med. 1995;332(14):901-6.
[21.] Henderson IC, Berry DA, Demetri GD, Cirrincione CT, Goldstein LJ, Martino S, et al. Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol. 2003;21(6):976-83.
[22.] Levine MN, Bramwell VH, Pritchard KI, Norris BD, Shepherd LE, Abu-Zahra H, et al. Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer. national cancer institute of canada clinical trials group. J Clin Oncol. 1998;16(8):2651-8.
[23.] French Adjuvant Study Group. Benefit of a high-dose epirubicin regimen in adjuvant chemotherapy for node-positive breast cancer patients with poor prognostic factors: 5-year follow-up results of French Adjuvant Study group 05 randomized trial. J Clin Oncol. 2001;19(3):602-11.
[24.] Bleicher RJ, Ruth K, Sigurdson ER, Ross E, Wong YN, Patel SA, et al. Preoperative delays in the US Medicare population with breast cancer. J Clin Oncol. 2012;30(36):4485-92.
[25.] Vandergrift JL, Niland JC, Theriault RL, Edge SB, Wong YN, Loftus LS, et al. Time to adjuvant chemotherapy for breast cancer in National Comprehensive Cancer Network institutions. J Natl Cancer Inst. 2013;105(2):104-12.
[26.] Buzdar AU, Smith TL, Powell KC, Blumenschein GR, Gehan EA. Effect of timing of initiation of adjuvant chemotherapy on disease-free survival in breast cancer. Breast Cancer Res Treat. 1982;2(2):163-9.
[27.] Colleoni M, Bonetti M, Coates AS, Castiglione-Gertsch M, Gelber RD, Price K, et al. Early start of adjuvant chemotherapy may improve treatment outcome for premenopausal breast cancer patients with tumors not expressing estrogen receptors. The International Breast Cancer Study Group. J Clin Oncol. 2000;18(3):584-90.
[28.] Zhan QH, Fu JQ, Fu FM, Zhang J, Wang C. Survival and time to initiation of adjuvant chemotherapy among breast cancer patients: a systematic review and meta-analysis. Oncotarget. 2018;9(2):2739-51.
[29.] Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235(4785):177-82.
[30.] Paik S, Hazan R, Fisher ER, Sass RE, Fisher B, Redmond C, et al. Pathologic findings from the National Surgical Adjuvant Breast and Bowel Project: prognostic significance of erbB-2 protein overexpression in primary breast cancer. J Clin Oncol. 1990;8(1):103-12.
[31.] Gilcrease MZ, Woodward WA, Nicolas MM, Corley LJ, Fuller GN, Esteva FJ, et al. Even low-level HER2 expression may be associated with worse outcome in node-positive breast cancer. Am J Surg Pathol. 2009;33(5):759-67.
[32.] Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Press M, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011;365(14):1273-83.
[33.] Joensuu H, Kellokumpu-Lehtinen PL, Bono P, Alanko T, Kataja V, Asola R, et al. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med. 2006;354(8):809-20.
[34.] Baum M, Budzar AU, Cuzick J, Forbes J, Houghton JH, Klijn JG, et al. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet. 2002;359(9324):2131-9.
[35.] Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for earlystage breast cancer. N Engl J Med. 2003;349(19):1793-802.
[36.] Coombes RC, Hall E, Gibson LJ, Paridaens R, Jassem J, Delozier T, et al. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med. 2004;350(11):1081-92.
Rad je primljen 5. IX 2018.
Recenziran 1. X 2018.
Prihvacen za stampu 15. X 2018.
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: email@example.com
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
|Printer friendly Cite/link Email Feedback|
|Title Annotation:||PROFESSIONAL ARTICLE/STRUCNI CLANAK|
|Author:||Vranjkovic, Bojana; Petrovic, Dragana; Radic, Jelena; Popovic, Maja; Bjelobrk, Ivana Kolarov; Petrov|
|Date:||Nov 1, 2018|
|Previous Article:||EARLY STROKE AFTER CAROTID ENDARTERECTOMY--A CASE SERIES DURING A 5-YEAR PERIOD/RANI MOZDANI UDAR NAKON KAROTIDNE ENDARTEREKTOMIJE--PRIKAZ SERIJE...|
|Next Article:||ADENOCARCINOMA OF THE APPENDIX MIMICKING COMPLICATED APPENDICITIS IN THE ELDERLY--A REPORT OF TWO CASES/ADENOKARCINOM APENDIKSA KOJI IMITIRA...|