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.
A retrospective analysis of consecutive patients diagnosed with mBC between February 2001 and December 2008 and treated at our medical oncology unit was performed.
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).
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
AuthorsJacopo Giuliani, Andrea Bonetti
- • Accepted on 14/01/2015
- • Available online on 30/04/2015
- • Published in print on 24/07/2015
This article is available as full text PDF.
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
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,
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.|
|HER2/neu overexpression||Yes||27 (54.0)||31.71|
|Molecular subtyping||Luminal A||13 (26.5)||32.63|
|Luminal B||26 (53.1)||34.53|
|HER2 driven||6 (12.2)||18.68||
|Triple negative||4 (8.2)||16.61|
|Neoadjuvant chemotherapy||Yes||9 (12.9)||30.10|
|Adjuvant chemotherapy||Yes||38 (54.3)||26.97|
|Type of adjuvant chemotherapy||Anthra||20 (54.1)||25.99|
|Anthra→ taxane||7 (18.9)||20.53|
|Adjuvant hormone therapy||Yes||38 (54.3)||34.54|
|Type of adjuvant hormone therapy||Tamoxifen||29 (76.3)||41.94|
|Metastatic disease ab initio||Yes||10 (14.3)||31.38|
|Type of metastases||Bone||13 (18.6)||24.70|
|Bone + visceral||2 (2.9)||30.10||0.791|
|Soft tissues||31 (44.3)||31.71|
|Visceral + soft tissues||5 (7.1)||20.53|
|Trastuzumab for metastatic disease||Yes||17 (24.3)||31.71||-|
|Number of lines of chemotherapy||1||16 (29.1)||14.37|
|Number of lines of hormone therapy||1||26 (48.2)||24.54|
Differences in overall survival between 2001-2004 and 2005-2008
|Estimation||Standard error||95% Confidence interval|
|Lower limit||Upper limit|
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).
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.