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Trends in survival for patients with metastatic breast cancer: is survival improving?

Abstract

Introduction

The treatment of patients with metastatic breast cancer (mBC) is one of the most difficult problems in clinical oncology. Clinical trial results suggest that novel therapies may be having a favorable impact on the survival of mBC patients, but the real impact of new therapies on OS rates has yet to be established. The aim of this outcome study was to evaluate the most reliable parameters to define the long-term result in terms of OS of different treatment strategies for mBC patients in a real-world clinical practice.

Materials and methods

A retrospective analysis of consecutive patients diagnosed with mBC between February 2001 and December 2008 and treated at our medical oncology unit was performed.

Results

We evaluated 70 female patients. At the last follow-up all patients had died. Median OS was 31.55 months (range, 2.33-100.13). There was no statistically significant difference in OS (p = 0.284) between the period 2001-2004 and the period 2005-2008. We did not find any statistically significant difference in OS even in the transition from one year to the next (p = 0.154).

Conclusions

The results of the current analysis suggest that the OS of women with mBC has not improved in the last years. However, these results should be interpreted with caution, considering the difficulty of determining changes in survival over time. Larger studies are needed to corroborate our findings.

Tumori 2015; 101(4): 347 - 352

Article Type: ORIGINAL RESEARCH ARTICLE

DOI:10.5301/tj.5000301

Authors

Jacopo Giuliani, Andrea Bonetti

Article History

Disclosures

Financial support: None.
Conflict of interest: None declared.

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Introduction

About 6% of newly diagnosed cases of breast cancer occur as metastatic disease at the onset and about 30% of women initially diagnosed with earlier stages develop advanced or metastatic disease (1). The treatment of patients with metastatic breast cancer (mBC) is one of the most difficult problems in clinical oncology. Long experience and clinical advances in recent decades including the synthesis of anticancer drugs with new mechanisms of action have led to progress in the treatment of mBC, with a substantial impact on overall survival (OS) (2). Despite advances in treatment options, mBC is considered an incurable disease, and the aims of treatment in this setting are symptom control, improvement of quality of life, and prolongation of survival. Anthracycline and taxane combination regimens have shown the highest activity and efficacy in mBC patients compared with other regimens (3, 4), but most patients need second or subsequent lines of therapy. The advent of targeted therapies, such as the addition of trastuzumab to chemotherapy in patients with HER2-overexpressing tumors, has led to improved survival compared with chemotherapy alone (5). Also the use of adjuvant chemotherapy has resulted in improved disease-free survival (DFS) and thus, indirectly, improved OS (6-7-8). Concerning the metastatic setting, clinical trial results suggest that novel therapies may be having a favorable impact on survival, but the real impact of new therapies on OS rates has yet to be established. Moreover, we do not know if the detection of early-stage disease or improvements in treatment are responsible for the decreased death rate (9).

Given that few data concerning OS in mBC patients have been reported in the literature in recent years (9), this outcome study aimed to evaluate the most reliable parameters that may define the long-term results in terms of OS of different treatment strategies for mBC patients in a real-world clinical practice.

Materials and methods

A retrospective analysis of consecutives patients with a diagnosis of mBC between February 2001 and December 2008 and followed at the Medical Oncology Unit of Mater Salutis Hospital, Legnago (Italy) was performed. All information was obtained from case records and review of the patients’ medical history. We excluded patients in whom the follow-up time (FUT) was less than 1 month. FUT was defined as the time patients were followed at our institution, i.e., the difference between the date of last follow-up and the date of taking charge. Tumor size (pT) was defined as the maximum tumor diameter measured by the pathologist. The absence or presence of lymph node involvement (pN) was histologically confirmed according to the American Joint Committee on Cancer (AJCC), as described by other authors (10). The Scarff-Bloom-Richardson classification was used to define histological grade. Estrogen receptors (ER) and progesterone receptors (PR) were expressed as the percentage of positivity in the overall cell population using a quantitative standard immunoenzymatic method. The monoclonal antibody MIB1, whose index was expressed as a percentage, was used for immunostaining of the Ki67 antigen (10). Liver ultrasound, standard chest x-ray, CT scan and bone scan were used to exclude the presence of distant metastases. Univariate analysis for OS, considering all the different prognostic factors, was performed according to the Kaplan-Meier method. The statistical significance (p<0.05) of differences was evaluated with the log-rank test, censoring surviving patients at the last follow-up time; the initial date for survival was calculated from the date mBC was first recognized. The Cox regression model was used for multivariate analysis. Finally, we investigated whether during these years there had been an increase in survival and whether the increase was statistically significant, including the covariate “year” in the Cox Model. The chi-square test, Student’s t-test, or Fisher’s exact test, was used in order to exclude any possible relationship between the results and the different prognostic risk categories.

Results

We evaluated 70 patients. All patients were female. Median FUT was 55.14 months (range, 2.43-206.41 months). At the last follow-up all patients had died. Median OS was 31.55 months (range, 2.33-100.13, Fig. 1); median DFS was 27.37 months (range, 0-180.23). Median age was 57 years (range, 20-86); 51 patients (72.9%) were classified as young (<65 years) and 19 (27.1%) as older patients (≥65 years). The prevalent histology (76.8%) was invasive ductal carcinoma (IDC), especially luminal B (53.1%), ER (81.8%) and PR (68.8%) positive, with HER2/neu overexpression in 54.0% of patients and with an intermediate proliferative index (54.5%). There was a predominance of pT2 (40.0%) and pN1 (30.9%) cases. Most patients had not received neoadjuvant chemotherapy (87.1%) but did receive adjuvant therapy (54.3%). The most common adjuvant chemotherapy agents were anthracyclines, used alone (54.1%) or sequentially with taxanes (18.9%); 54.3% of patients received adjuvant hormone therapy consisting mostly of tamoxifen (76.3%). Most patients (85.7%) did not have metastatic disease at first diagnosis. The metastatic sites were equally distributed between bone, soft tissues and visceral sites. Forty percent of patients received more than 3 lines of chemotherapy and only 1 line of hormone therapy (48.2%) in the metastatic setting. In univariate analysis, a positive PR had a statistically significant positive impact on OS (p<0.001, Fig. 2). Comparison between the 4 molecular subtypes (luminal A, luminal B, HER2 driven, triple negative) confirmed a survival difference (Fig. 3), with long OS for both luminal A (32.63 months) and luminal B (34.53 months) types in comparison to HER2-driven (18.68 months) and triple-negative (16.61 months) tumors. The general case study is summarized in Table I. In multivariate analysis, only a positive PR status (p = 0.005) was confirmed as a prognostic factor. No statistically significant difference in OS was found between the period 2001-2004 and the period 2005-2008 (p = 0.284; Tab. II, Fig. 4). We chose these periods in order to have 2 well-matched groups of patients. We did not observe any statistically significant difference in OS even in the transition from 1 year to the next (p = 0.154). The chi-square test excluded any possible relationship between results and the belonging to different molecular subtyping (p = 0.811).

The general case study

Variable Value No. (%) Median OS (months) P value
No. = number of patients; OS = overall survival; IDC = invasive ductal carcinoma; ILC = invasive lobular carcinoma; MIB1/Ki67 low cutpoint <10%; MIB1/Ki67 intermediate = 10%-30%; MIB1/Ki67 high cutpoint ≥30%; ER = estrogen receptor; PR = progesterone receptor; ER-positive = ≥1% positively staining cells by immunohistochemistry; PR-positive = ≥1% positively staining cells by immunohistochemistry; luminal A = ER+ and/or PR+, HER2- and Ki67 low; luminal B = ER+ and/or PR+, HER2+ or Ki67 high; HER2 driven = ER-, PR-, HER2+; triple negative = ER-, PR-, HER2-; anthra = anthracyclines; CMF = cyclophosphamide, methotrexate and 5-fluorouracil; AI = aromatase inhibitor (anastrozole, letrozole, exemestane); switch = tamoxifen followed by AI; SNC = central nervous system.
Histology IDC 43 (76.8) 27.37
ILC 12 (21.4) 31.09
Others 1 (1.8) 34.54 0.855
Missing 14 (20.0)
pT pT1 15 (27.3) 31.09
pT2 22 (40.0) 39.08
pT3 4 (7.3) 17.47 0.461
pT4 14 (25.5) 27.37
Missing 15 (21.4)
pN pN0 12 (21.8) 26.97
pN1 17 (30.9) 27.37
pN2 14 (25.5) 31.71 0.968
pN3 12 (21.8) 25.99
Missing 15 (21.4)
MIB1/Ki67 Low 12 (21.8) 31.71
Intermediate 30 (54.5) 34.54
High 13 (23.6) 14.97 0.081
Missing 22 (28.6)
ER Positive 54 (81.8) 32.86
Negative 12 (18.2) 18.68 0.109
Missing 4 (5.7)
PR Positive 44 (68.8) 36.02
Negative 20 (31.3) 16.61 <0.001
Missing 6 (8.6)
HER2/neu overexpression Yes 27 (54.0) 31.71
No 23 (46.0) 31.38 0.905
Missing 20 (28.6)
Molecular subtyping Luminal A 13 (26.5) 32.63
Luminal B 26 (53.1) 34.53
HER2 driven 6 (12.2) 18.68 0.041
Triple negative 4 (8.2) 16.61
Missing 21 (30.0)
Neoadjuvant chemotherapy Yes 9 (12.9) 30.10
No 61 (87.1) 31.38 0.233
Adjuvant chemotherapy Yes 38 (54.3) 26.97
No 32 (45.7) 32.63 0.059
Type of adjuvant chemotherapy Anthra 20 (54.1) 25.99
Anthra→ taxane 7 (18.9) 20.53
Taxane 1 (2.7) 17.47 -
CMF 9 (24.3) 31.09
Adjuvant hormone therapy Yes 38 (54.3) 34.54
No 32 (45.7) 30.10 -
Type of adjuvant hormone therapy Tamoxifen 29 (76.3) 41.94
AI-upfront 5 (13.2) 16.61 -
Switch 4 (10.5) 24.70
Metastatic disease ab initio Yes 10 (14.3) 31.38
No 60 (85.7) 31.09 0.701
Type of metastases Bone 13 (18.6) 24.70
Bone + visceral 2 (2.9) 30.10 0.791
SNC 3 (4.3) 36.97
Soft tissues 31 (44.3) 31.71
Visceral 16 (22.9) 36.02
Visceral + soft tissues 5 (7.1) 20.53
Trastuzumab for metastatic disease Yes 17 (24.3) 31.71 -
No 53 (75.7) 31.38
Number of lines of chemotherapy 1 16 (29.1) 14.37
2 17 (30.9) 42.63 0.001
≥3 22 (40.0) 41.71
Number of lines of hormone therapy 1 26 (48.2) 24.54
2 16 (29.6) 34.54 0.049
≥3 12 (22.2) 49.51

Differences in overall survival between 2001-2004 and 2005-2008

Years Median (months)
Estimation Standard error 95% Confidence interval
Lower limit Upper limit
2001-2004 35.395 4.990 25.614 45.176
2005-2008 30.099 3.716 22.815 37.382
Global 31.382 3.750 24.032 38.731

Overall survival (OS) in the general case study.

Univariate analysis for overall survival considering progesterone receptor status.

Comparison between the 4 molecular subtypes (luminal A, luminal B, HER2 driven, triple negative) in terms of overall survival.

Kaplan-Meier curves for overall survival considering the 2 subgroups (2001-2004 vs. 2005-2008).

Discussion

The reported study considered a consecutive case series of 8 years, with a median FUT of more than 4 years; the median age (57 years) is close to that reported by national cancer registries (11). In the current data set the median OS was 31.55 months, which was longer than the median survival of 18-24 months for mBC reported by other studies (1). We chose to consider only OS and not progression-free survival (PFS) because, in the absence of a prospective design to determine whether disease progression has occurred at specific, defined intervals, this measurement is fraught with potential bias because patients may be followed with differing frequencies depending on whether or not they are in a clinical trial, or what therapy they receive. Despite this, OS seems constant throughout the study duration without significant increases over the years. A previous study (9) analyzed the survival of 834 women with advanced breast cancer in a real-world clinical practice: variables that predicted longer survival after breast cancer recurrence were smaller primary tumor size, lower disease stage, fewer involved lymph nodes, longer DFS, ER-positive tumors, and a nonvisceral dominant site of disease recurrence. This experience is similar to our study; to our knowledge no other similar study has been carried out in recent years. In particular, the above study (9) suggested that the survival of women with recurrent breast cancer improved between 1974 and 2000 (p<0.001); this was confirmed by the multivariate analysis, in which the number of years to recurrence was associated with a trend toward improved survival, with a 1% reduction in risk for each increasing year. Unlike that study (which referred to the years prior to 2000) we did not find significant increases in survival over the years. However, the lack of statistical significance in the present study may be partly due to the small sample size.

In addition, the present study did not confirm the importance of lymph node status, the size of the invasive component of the tumor, ER status, and the role of HER2 as independent predictors of survival in patients with metastatic breast cancer (12-13-14-15-16). Moreover, our data showed the favorable prognostic role of PR positivity, which is in agreement with data in the literature (17), concerning biomolecular classification (luminal A, luminal B, HER2 driven, triple negative) our data are in agreement with literature too, confirmed a long OS for both luminal A (32.63 months) and luminal B (34.53 months) subtypes (18). Instead, with regard to the metastatic setting, the number of lines of chemotherapy (p<0.001) and hormone therapy (p = 0.019) was found to have a significant impact on OS.

We are aware of the limits of a retrospectve study, the small size of the cohort, and the possibility that data from a single institution merely reflect the habits of a particular set of physicians. Also, the increasing use of screening mammography in recent years and the resulting earlier diagnoses may have contributed to the changed distribution of patient features (9). We selected a group of patients who had been treated at a single institution with similar initial screening procedures and follow-up in order to minimize the ascertainment bias. Moreover, the patients described here represent the complete consecutive series of patients who underwent systemic treatment with chemotherapy at our unit in the period under consideration. The patients were treated in a homogeneous way and carefully staged before the start of treatment and at regular intervals thereafter.

Combination therapy for mBC versus monotherapy or sequential single agents remains a controversial issue and its success depends on individual patient characteristics and specific treatment goals (19). However, higher overall response rates may not necessarily translate into superior survival outcomes (1). The combination of traditional chemotherapeutics with targeted biological agents, such as trastuzumab (5) and more recently lapatinib and bevacizumab, can produce a clinical synergism with a potential improvement in survival (1). While multiple treatments are available, the median survival for mBC is still approximately 2 years. Few randomized trials have provided direct evidence that improvements in overall response rates would translate into long-term survival benefits in the treatment of mBC (20-21-22-23). To date, only the taxanes, aromatase inhibitors, and trastuzumab have been associated with significant improvements in OS across the population (24-25-26). We probably have reached a plateau of good results in mBC and it is hard to move away from the currently attained OS values, as demonstrated by our results. However, some authors have pointed out that continual improvement in PFS is being obtained with the new targeted therapies and that OS is not necessarily a primary endpoint in mBC (27). In fact, in the last few years new drugs and/or changes in the standard of care have been approved based on improvement in PFS (taken as the primary endpoint in a large number of randomized controlled trials), without a corresponding increase in OS (28). Cortazar et al (29) in a review of 12 RCTs in mBC showed that less than 10% of the variation in OS is explained by variation in PFS, suggesting that the relationship between PFS and OS is weak in mBC, especially for second-/third-line therapy.

In summary, the results of the current analysis suggest that the OS of women with mBC has not been improving during the last years, and that a plateau of good results in terms of survival has already been reached. Even so, our results should be interpreted with caution, given the difficulty in determining changes in survival over time. Other, larger experiences than the one reported here will be needed to corroborate our findings.

Disclosures

Financial support: None.
Conflict of interest: None declared.
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Authors

Affiliations

  • Department of Oncology, Mater Salutis Hospital, ASL 21 della Regione Veneto, Legnago (Verona) - Italy

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