We undertook this population-based study to see if there have been improvements in survival among women with stage III inflammatory breast cancer (IBC), over time. Our results show a significant improvement in survival of patients diagnosed with IBC over a two-decade time span in this large population-based study. This suggests that therapeutic strategies researched and evolved in the context of non-inflammatory breast cancer have also had a positive impact in women with IBC.
Keywords: inflammatory breast cancer, stage III, survival, time trends
Abstract
Background
Our group has previously reported that women with inflammatory breast cancer (IBC) continue to have worse outcome compared with those with non-IBC. We undertook this population-based study to see if there have been improvements in survival among women with stage III IBC, over time.
Patient and methods
We searched the Surveillance, Epidemiology and End Results Registry to identify female patients diagnosed with stage III IBC between 1990 and 2010. Patients were divided into four groups according to year of diagnosis: 1990–1995, 1996–2000, 2001–2005, and 2006–2010. Breast cancer-specific survival (BCSS) was estimated using the Kaplan–Meier method and compared across groups using the log-rank test. Cox models were then fit to determine the association of year of diagnosis and BCSS after adjusting for patient and tumor characteristics.
Results
A total of 7679 patients with IBC were identified of whom 1084 patients (14.1%) were diagnosed between 1990 and 1995, 1614 patients (21.0%) between 1996 and 2000, 2683 patients (34.9%) between 2001 and 2005, and 2298 patients (29.9%) between 2006 and 2010. The 2-year BCSS for the whole cohort was 71%. Two-year BCSS were 62%, 67%, 72%, and 76% for patients diagnosed between 1990–1995, 1996–2000, 2001–2005, and 2006–2010, respectively (P < 0.0001). In the multivariable analysis, increasing year of diagnosis (modeled as a continuous variable) was associated with decreasing risks of death from breast cancer (HR = 0.98, 95% confidence interval 0.97–0.99, P < 0.0001).
Conclusion
There has been a significant improvement in survival of patients diagnosed with IBC over a two-decade time span in this large population-based study. This suggests that therapeutic strategies researched and evolved in the context of non-IBC have also had a positive impact in women with IBC.
introduction
Significant therapeutic advances have been made in the realm of early-stage breast cancer management that has led to an improvement in survival outcome over the decades. Aggregate data from large randomized clinical trials presented by the Early Breast Cancer Trialists' Collaborative group has shown that 6 months of an adjuvant anthracycline-based polychemotherapy regimen reduces the annual breast cancer death rate by 38% for women younger than 50 years and by 20% for those women aged 50–69 years [1]. The addition of a taxane has also been demonstrated to improve both disease-free and overall survival (OS) [2, 3]. Furthermore, the introduction of the monoclonal antibody trastuzumab into the adjuvant treatment of women with HER2-positive breast tumors has been shown to reduce the risk of death and recurrence by almost 40% [4, 5].
In parallel to the development of more efficacious therapeutic regimens has been a deeper understanding of the heterogeneity of breast cancer exemplified by the fact that we now recognize at least five different subtypes each with its own associated natural history [6]. We also recognize that inflammatory breast cancer (IBC) is a rare subtype of locally advanced breast cancer (LABC) characterized by a number of distinct features. First, IBC has a unique set of diagnostic criteria with the American Joint Committee on Cancer (AJCC) specifically classifying IBC as T4d and clinically defines it as ‘a clinicopathologic entity characterized by diffuse erythema and edema of the breast, often without an underlying palpable mass’ [7]. Secondly, IBC is known to have a worse prognostic outcome, a lower frequency of luminal A subtype, and a higher frequency of HER2-enriched subtype compared with non-IBC breast tumors [8, 9].
There is no doubt that we have come a long way in the management of IBC. This is highlighted by the fact that before 1974 IBC was considered to be a uniformly fatal disease with a 5-year actuarial OS of <5% and a median survival of only 15 months [10]. With the introduction of a multidisciplinary management approach incorporating an anthracycline-based chemotherapy regimen and radiation therapy, this disease is now associated with 15-year survival rates of ∼20%–30% [11, 12]. We have previously shown that despite these advances, patients with IBC continue to have a poorer prognostic outcome compared with patients who have non-IBC [13]. The aim of this retrospective population-based study was to determine whether there has been a stepwise improvement in survival among women with stage III IBC over the last two decades reflecting the introduction of a number of efficacious therapeutic regimens that have been approved by the Food and Drug Administration (FDA).
patient and methods
patient population
We used data obtained from population registries participating in the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) registry that covers ∼26% of the population in the United States [14]. We searched the18-SEER registries database released in April 2013. Search was restricted to female patients with stage III IBC, with a single primary, diagnosed between 1990 and 2010. SEER registry began collecting hormone receptor information in 1990, and we thus excluded patients who were diagnosed before 1990. In the most recent version, SEER provides an adjusted AJCC 6th edition stage criteria for patients diagnosed between 1988 and 2003 that is derived from the earlier extent of disease criteria and a derived AJCC 6th edition stage for cases diagnosed from 2004. For this study, IBC was defined according to the adjusted and derived AJCC 6th edition criteria.
statistical analysis
Patients were divided into four groups according to year of diagnosis: (a) 1990–1995, (b) 1996–2000, (c) 2001–2005, and (d) 2006–2010. Patient characteristics were compared according to year of diagnosis group using the χ2 test.
Follow-up cutoff was 31 December 2010. OS was calculated from the date of diagnosis to the date of death from any cause or the follow-up cutoff. Breast cancer-specific survival (BCSS) was calculated from the date of diagnosis to the date of death from breast cancer or the follow-up cutoff censoring patients who died from causes other than breast cancer. Survival outcomes were estimated using the Kaplan–Meier product limit method and compared across groups using the log-rank statistic. Specifically, the 2-year overall and BCSS rates for each individual year was estimated and plotted with 95% confidence intervals (CIs). A locally weighted least squares (LOWESS) [15] curve was fit to the individual year estimates without specifying a parametric model. In addition, we conducted a prespecified subset analyses stratified by year of diagnosis according to race, hormonal receptor status, and age group. A Bonferroni correction was used for multiple comparisons.
Cox proportional hazards models were fit to determine the association between year of diagnosis and survival outcomes after adjustment for patient characteristics. Variables included in the final model were based on clinical and statistical significance. Results were expressed in hazard ratios (HRs) and 95% CIs. P values <0.05 were considered statistically significant. All tests were two-sided. Statistical analyses were carried out using SAS 9.2(SAS Institute, Cary, NC) and S-Plus 7.0 (Insightful Corporation, Seattle, WA).
results
patient characteristics
Table 1 summarizes patient and tumor characteristics. The final analysis included 7679 patients of whom 1084 (14.1%), 1614 (21.0%), 2683 (34.9%), and 2298 (29.9%) patients were diagnosed between 1990–1995, 1996–2000, 2001–2005 and 2006–2010, respectively. Median age of diagnosis was 56 years. In total, 1097 patients (14.3%) were of black race, 6141 patients (80%) were of white race, 412 patients (5.4%) were classified as other race, and the race of 29 patients (0.4%) was unknown. Among patients for whom information was known 50.9% had estrogen receptor-positive disease.
Table 1.
Patient and tumor characteristics stratified by year of diagnosis
| All patients (N = 7679) | Year of diagnosis |
|||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| 1990–1995 (N = 1084) |
1996–2000 (N = 1614) |
2001–2005 (N = 2683) |
2006–2010 (N = 2298) |
|||||||
| n (%) | n | % | n | % | n | % | n | % | P | |
| Age at diagnosis | ||||||||||
| Median (years) | 56 | 55 | 56 | 56 | 56 | <0.0001 | ||||
| 20–35 | 420 (5.5) | 51 | 4.7 | 97 | 6.0 | 133 | 5.0 | 139 | 6.0 | |
| 36–50 | 2239 (29.2) | 354 | 32.7 | 482 | 29.9 | 763 | 28.4 | 640 | 27.9 | |
| 51–65 | 2856 (37.2) | 359 | 33.1 | 541 | 33.5 | 1034 | 38.5 | 922 | 40.1 | |
| >65 | 2164 (28.2) | 320 | 29.5 | 494 | 30.6 | 753 | 28.1 | 597 | 26.0 | |
| Race | ||||||||||
| White/other | 6553 (85.7) | 948 | 87.5 | 1397 | 86.6 | 2276 | 85.2 | 1932 | 84.7 | 0.10 |
| Black | 1097 (14.3) | 136 | 12.5 | 216 | 13.4 | 395 | 14.8 | 350 | 15.3 | |
| Marital status | ||||||||||
| Married | 3888 (52.5) | 574 | 54.4 | 781 | 50.4 | 1375 | 52.8 | 1158 | 52.6 | 0.24 |
| Single | 3523 (47.5) | 482 | 45.6 | 768 | 49.6 | 1229 | 47.2 | 1044 | 47.4 | |
| Grade | <0.0001 | |||||||||
| I | 154 (2) | 18 | 1.7 | 16 | 1.0 | 57 | 2.1 | 63 | 2.7 | |
| II | 1566 (20.4) | 147 | 13.6 | 312 | 19.3 | 554 | 20.6 | 553 | 24.1 | |
| III | 4593 (59.8) | 599 | 55.3 | 1016 | 62.9 | 1633 | 60.9 | 1345 | 58.5 | |
| Unknown | 1366 (17.8) | 320 | 29.5 | 270 | 16.7 | 439 | 16.4 | 337 | 14.7 | |
| AJCC stage | ||||||||||
| IIIB | 4971 (64.7) | 481 | 44.4 | 962 | 59.6 | 1817 | 67.7 | 1711 | 74.5 | |
| IIIC | 1713 (22.3) | 202 | 18.6 | 353 | 21.9 | 637 | 23.7 | 521 | 22.7 | |
| III not otherwise specified | 995 (13) | 401 | 37.0 | 299 | 18.5 | 229 | 8.5 | 66 | 2.9 | |
| Radiation | ||||||||||
| Yes | 3816 (49.7) | 439 | 40.5 | 778 | 48.2 | 1410 | 52.6 | 1189 | 51.7 | <0.0001 |
| No | 3863 (50.3) | 645 | 59.5 | 836 | 51.8 | 1273 | 47.4 | 1109 | 48.3 | |
| Surgery of primary site | ||||||||||
| Mastectomy | 6177 (80.7) | 770 | 71.0 | 1304 | 80.9 | 2226 | 83.1 | 1877 | 82.1 | <0.0001 |
| Partial | 1164 (15.2) | 105 | 9.7 | 205 | 12.7 | 451 | 16.8 | 403 | 17.6 | |
| Surgery not otherwise specified | 24 (0.3) | 6 | 0.6 | 12 | 0.7 | 1 | 0.0 | 5 | 0.2 | |
| No surgery | 294 (3.8) | 203 | 18.7 | 91 | 5.6 | 0 | 0.0 | 0 | 0.0 | |
| Node positivity | ||||||||||
| Positive | 4138 (53.9) | 370 | 34.1 | 873 | 54.1 | 1622 | 60.5 | 1273 | 55.4 | <0.0001 |
| Negative | 892 (11.6) | 31 | 2.9 | 109 | 6.8 | 326 | 12.2 | 426 | 18.5 | |
| Unknown | 2649 (34.5) | 683 | 63.0 | 632 | 39.2 | 735 | 27.4 | 599 | 26.1 | |
| Nodes examined | ||||||||||
| 0 | 2291 (29.8) | 650 | 60.0 | 563 | 34.9 | 606 | 22.6 | 472 | 20.5 | <0.0001 |
| 1–3 | 484 (6.3) | 35 | 3.2 | 67 | 4.2 | 178 | 6.6 | 204 | 8.9 | |
| 4–9 | 1178 (15.3) | 63 | 5.8 | 222 | 13.8 | 511 | 19.0 | 382 | 16.6 | |
| 10+ | 3334 (43.4) | 299 | 27.6 | 683 | 42.3 | 1244 | 46.4 | 1108 | 48.2 | |
| Unknown | 392 (5.1) | 37 | 3.4 | 79 | 4.9 | 144 | 5.4 | 132 | 5.7 | |
| Estrogen receptor status | ||||||||||
| Positive | 3241 (42.2) | 396 | 36.5 | 619 | 38.4 | 1121 | 41.8 | 1105 | 48.1 | <0.0001 |
| Negative | 3127 (40.7) | 335 | 30.9 | 603 | 37.4 | 1128 | 42.0 | 1061 | 46.2 | |
| Unknown | 1311 (17.1) | 353 | 32.6 | 392 | 24.3 | 434 | 16.2 | 132 | 5.7 | |
| Progesterone receptor status | ||||||||||
| Positive | 2552 (33.2) | 329 | 30.4 | 515 | 31.9 | 861 | 32.1 | 847 | 36.9 | <0.0001 |
| Negative | 3741 (48.7) | 382 | 35.2 | 690 | 42.8 | 1363 | 50.8 | 1306 | 56.8 | |
| Unknown | 1386 (18) | 373 | 34.4 | 409 | 25.3 | 459 | 17.1 | 145 | 6.3 | |
univariate analysis
Median follow-up among all patients was 30 months (range, 0–250 months). At the time of this analysis, 4616 patients (60%) had died from all causes and 3914 (51%) had died from breast cancer. Median BCSS and OS for the whole cohort was 50 and 42 months, respectively (supplementary Table S1, available at Annals of Oncology online). OS and BCSS increased across the four time periods. The individual year 2-year OS and BCSS estimates, together with a LOWESS fit of the estimates, and the group year survival estimates, are presented in Figure 1. Two-year BCSS were 62%, 67%, 72%, and 76% for patients diagnosed between 1990–1995, 1996–2000, 2001–2005, and 2006–2010, respectively (P < 0.0001).
Figure 1.
Two-year (A) breast cancer-specific survival and (B) overall survival over time. Inserts show FDA approvals of various chemotherapeutic and biological agents for adjuvant treatment of breast cancer.
Table 2 summarizes unadjusted survival estimates stratified by year of diagnosis among predefined subgroups. OS and BCSS significantly increased across the four time periods regardless of race, hormone receptor status, and age (Figure 2A–D).
Table 2.
Survival estimates stratified by year of diagnosis
| 2-year overall survival estimate (95% CI) | P | 2-year breast cancer-specific survival estimate (95% CI) | P | |
|---|---|---|---|---|
| Black patients | ||||
| Year of diagnosis | ||||
| 1990–1995 | 0.5 (0.41–0.58) | 0.01 | 0.52 (0.43–0.6) | 0.002 |
| 1996–2000 | 0.48 (0.41–0.54) | 0.51 (0.44–0.58) | ||
| 2001–2005 | 0.57 (0.52–0.62) | 0.61 (0.56–0.66) | ||
| 2006–2010 | 0.61 (0.55–0.67) | 0.67 (0.61–0.72) | ||
| White patients | ||||
| Year of diagnosis | ||||
| 1990–1995 | 0.58 (0.55–0.62) | <0.0001 | 0.63 (0.6–0.66) | <0.0001 |
| 1996–2000 | 0.65 (0.63–0.68) | 0.69 (0.67–0.72) | ||
| 2001–2005 | 0.7 (0.68–0.72) | 0.74 (0.72–0.75) | ||
| 2006–2010 | 0.75 (0.73–0.77) | 0.78 (0.75–0.8) | ||
| Hormonal receptor positive | ||||
| Year of diagnosis | ||||
| 1990–1995 | 0.69 (0.64–0.73) | 0.0004 | 0.75 (0.7–0.79) | 0.0007 |
| 1996–2000 | 0.8 (0.77–0.83) | 0.85 (0.82–0.87) | ||
| 2001–2005 | 0.82 (0.79–0.84) | 0.85 (0.83–0.87) | ||
| 2006–2010 | 0.84 (0.82–0.87) | 0.87 (0.85–0.89) | ||
| Hormonal receptor negative | ||||
| Year of diagnosis | ||||
| 1990–1995 | 0.5 (0.45–0.55) | <0.0001 | 0.52 (0.46–0.57) | <0.0001 |
| 1996–2000 | 0.52 (0.48–0.56) | 0.55 (0.51–0.59) | ||
| 2001–2005 | 0.59 (0.56–0.62) | 0.62 (0.59–0.65) | ||
| 2006–2010 | 0.64 (0.61–0.67) | 0.67 (0.64–0.7) | ||
| Age 20–35 | ||||
| Year of diagnosis | ||||
| 1990–1995 | 0.59 (0.44–0.71) | 0.004 | 0.59 (0.44–0.71) | 0.003 |
| 1996–2000 | 0.64 (0.54–0.73) | 0.65 (0.54–0.73) | ||
| 2001–2005 | 0.72 (0.63–0.79) | 0.73 (0.65–0.8) | ||
| 2006–2010 | 0.84 (0.76–0.9) | 0.86 (0.78–0.92) | ||
| Age 36–50 | ||||
| Year of diagnosis | ||||
| 1990–1995 | 0.67 (0.61–0.71) | <0.0001 | 0.68 (0.63–0.73) | <0.0001 |
| 1996–2000 | 0.7 (0.65–0.73) | 0.72 (0.68–0.76) | ||
| 2001–2005 | 0.74 (0.71–0.77) | 0.75 (0.72–0.78) | ||
| 2006–2010 | 0.78 (0.74–0.82) | 0.8 (0.76–0.84) | ||
| Age 51–65 | ||||
| Year of diagnosis | ||||
| 1990–1995 | 0.58 (0.53–0.63) | <0.0001 | 0.59 (0.54–0.64) | <0.0001 |
| 1996–2000 | 0.67 (0.63–0.7) | 0.69 (0.65–0.73) | ||
| 2001–2005 | 0.72 (0.69–0.74) | 0.73 (0.71–0.76) | ||
| 2006–2010 | 0.76 (0.73–0.79) | 0.78 (0.74–0.81) | ||
| Age 66+ | ||||
| Year of diagnosis | ||||
| 1990–1995 | 0.47 (0.42–0.53) | 0.005 | 0.59 (0.53–0.64) | 0.007 |
| 1996–2000 | 0.54 (0.5–0.59) | 0.62 (0.57–0.66) | ||
| 2001–2005 | 0.57 (0.53–0.6) | 0.67 (0.63–0.7) | ||
| 2006–2010 | 0.61 (0.56–0.65) | 0.68 (0.63–0.72) | ||
Figure 2.
Breast cancer-specific survival stratified by year of diagnosis among (A) patients of white race, (B) patients of black race, (C) patients with hormone receptor-positive disease, and (D) patients with hormone receptor-negative disease.
multivariate analysis
In the multivariable model, increasing year of diagnosis was associated with a decreasing risk of death from breast cancer (HR = 0.98, 95% CI 0.97–0.99, P < 0.0001) (Table 3). Other factors significantly associated with an improved BCSS included negative nodes, being of white race, having hormone receptor-positive disease, and having lower grade of disease. Similar results were obtained for OS.
Table 3.
Multivariable cox proportional hazards model (models adjusted for SEER registries)
| Overall survival |
Breast cancer-specific survival |
|||||
|---|---|---|---|---|---|---|
| Hazard ratio | 95% CI | P | Hazard ratio | 95% CI | P | |
| Year of diagnosis (continuous) | 0.98 | 0.97–0.99 | <0.0001 | 0.98 | 0.97–0.99 | <0.0001 |
| Age in years (continuous) | 1.017 | 1.015–1.019 | <0.0001 | 1.007 | 1.005–1.010 | <0.0001 |
| Race: Black versus White/other | 1.37 | 1.26–1.5 | <0.0001 | 1.37 | 1.25–1.51 | <0.0001 |
| Marital status: single versus married | 1.21 | 1.13–1.29 | <0.0001 | 1.18 | 1.1–1.26 | <0.0001 |
| Grade: III versus I/II | 1.44 | 1.32–1.56 | <0.0001 | 1.57 | 1.44–1.73 | <0.0001 |
| Stage: IIIC versus IIIB | 1.76 | 1.62–1.9 | <0.0001 | 1.83 | 1.68–1.99 | <0.0001 |
| Stage: IIINOS versus IIIB | 1.07 | 0.97–1.18 | 0.18 | 1.07 | 0.96–1.19 | 0.23 |
| Radiation: no versus yes | 1.36 | 1.27–1.46 | <0.0001 | 1.31 | 1.22–1.41 | <0.0001 |
| Surgery: partial versus mastectomy | 1.43 | 1.29–1.58 | <0.0001 | 1.45 | 1.3–1.62 | <0.0001 |
| Surgery: surgery NOS versus mastectomy | 0.99 | 0.6–1.66 | 0.98 | 1.02 | 0.59–1.77 | 0.94 |
| Surgery: no surgery versus mastectomy | 1.39 | 1.2–1.61 | <0.0001 | 1.54 | 1.31–1.81 | <0.0001 |
| Node positivity: negative versus positive | 0.48 | 0.42–0.55 | <0.0001 | 0.43 | 0.37–0.5 | <0.0001 |
| Nodes examined (continuous) | 0.979 | 0.973–0.984 | <0.0001 | 0.978 | 0.972–0.984 | <0.0001 |
| Hormonal receptor status: negative versus positive | 1.68 | 1.57–1.8 | <0.0001 | 1.82 | 1.69–1.96 | <0.0001 |
discussion
The goal of this population-based study was to look at trends in survival among women with stage III IBC. A number of important observations were made. First, between 1990 and 2010, a more than 22-month improvement in median BCSS and a 14% improvement in 2-year BCSS was observed. In the multivariable model, each increasing year of diagnosis from 1990 was associated with a decreasing risk of death from breast cancer. Secondly, improvement in survival over time was observed regardless of race, hormone receptor status, and age.
The results observed in our study are in contrast to prior retrospective studies that have attempted to answer a similar question. Gonzalez et al. [8] reported on a cohort of 398 women with IBC treated at the MD Anderson Cancer Center(MDACC) between 1974 and 2005 and reported that increasing year of diagnosis was not significantly associated with a decrease in risk of recurrence (HR = 1.0, 95% CI 0.97–1.04) or death (HR = 0.97, 95% CI 0.94–1.01). Panades et al. [16] reported on a cohort of 308 women with IBC diagnosed in British Columbia between 1980 and 2000. The authors reported a significant improvement in 10-year locoregional recurrence-free survival (42.1% versus 64.6%, P = 0.01) with no significant difference in 10-year BCSS (27.4% versus 28.6%, P = 0.37) among patients diagnosed between 1980 and 1990 compared with those diagnosed between 1991 and 2000. The reason for the difference in results observed between our study and the ones reported previously may be attributed to a number of factors. First, the number of patients with IBC enrolled in the previous studies was so small that could make small differences in survival over time difficult to detect. Secondly, our analysis concentrated on patients diagnosed over the last two decades while in the prior studies the majority of patients were diagnosed in the 1980s and 1990s. Indeed, during the last decade, the FDA has approved a number of important agents for the treatment of breast cancer including aromatase inhibitors and trastuzumab. Thirdly, the majority of patients in the prior studies received anthracycline-based regimens with less than half of them receiving a taxane. Similar to patients with non-IBC, the addition of taxanes to an anthracycline-based chemotherapy regimen has also been shown to significantly improve survival among patients with IBC [17]. As illustrated in Figure 1, the use of adjuvant paclitaxel was approved by the FDA in 1999 and although SEER does not document type of chemotherapy administered it is likely that most patients did receive it over the last decade and thus may account for one factor contributing to the significant improvement in survival observed in our study.
Over the last decade, there have been significant advances in the understanding of IBC at the molecular level through efforts of organizations such as the World IBC consortium. This consortium recently reported on the molecular profile of IBC using the largest series of IBC samples [9]. The investigators reported on the affymetrix profiles from 137 patients with IBC and 252 patients with non-IBC, which were analyzed using unsupervised and supervised techniques, observing that the frequency of molecular subtypes were different with patients with IBC tumors exhibiting higher frequencies of HER2-enriched subtypes (22% versus 9%, P < 0.001) and lower frequency of luminal A subtype (19% versus 42%, P < 0.001) compared with patients with non-IBC. Several retrospective studies have reported that, in the absence of trastuzumab, HER2 status is not an independent adverse prognostic factor among patients with IBC, unlike that observed among patients with non-IBC [18, 19]. However, when trastuzumab is added to the treatment regimen of patients with HER2-positive IBC a significant improvement in prognostic outcome is observed similar to that seen for patients with HER2-positive non-IBC [18]. Gianni et al. [20] reported on a prospective phase III trial of 235 women with HER2-positive LABC of whom 63 had IBC who were randomized to receive either neoadjuvant chemotherapy alone or in combination with trastuzumab. The authors reported a significantly higher pCR rate (38% versus 19%) and 3-year event-free survival (71% versus 56%) among patients who received trastuzumab. In an updated analysis presented at the recent American Society of Clinical Oncology symposium, the authors reported a significant improvement in the 5-year event-free survival (57.5% versus 43.3%, P = 0.016) and 5-year BCSS (77.4% versus 63.9%, P = 0.023) favoring the group who received trastuzumab [21]. The question that arises is whether the use of trastuzumab among patients with HER2-positive IBC has contributed in improving survival over time among patients with IBC as a whole. The use of adjuvant trastuzumab was FDA approved in 2006 and results from our study show a 4% improvement in 2-year BCSS when comparing patients with IBC diagnosed between 2001 and 2005, and those diagnosed between 2006 and 2010. In a recent study, Tsai et al. [22] reported on differences in survival among patients with IBC treated before and after October 2006, respectively, at the MDACC. All patients with HER2-positive IBC treated after October 2006 received trastuzumab. The authors reported a significant improvement in 3-year OS among patients treated after October 2006 compared with those treated before this time period (82% versus 63%, P = 0.02).
In summary, the results of our study show a significant stepwise improvement in survival over the last two decades among women with stage III IBC. The data presented suggest that therapeutic strategies researched and evolved in the context of non-IBC have also had a positive impact among women with IBC. We acknowledge that our study has a number of important limitations including the retrospective nature of the study design and the fact that SEER does not have information on HER2 status, type of chemotherapy administered or its sequence with locoregional treatment strategies. With IBC being a rare disease comprising of ∼1%–5% of all breast cancers, the large number of patients afforded by this population-based study is its main strength in allowing us to detect small differences in survival [23]. The improvement in survival observed may be attributed to the use of neoadjuvant regimens, aggressive locoregional treatment, improved diagnostic imaging for staging, as well as introduction of a number of important efficacious chemotherapeutic and biological agents over the last two decades [12, 21]. Data derived from SEER clearly demonstrates that, although IBC is rare, its incidence is rising [23]. Moreover, despite the demonstrated improvement in survival over time, the prognostic outcome of women with IBC continues to be poorer compared with those with non-IBC [13]. It is thus imperative that newer agents be developed and investigated specifically for IBC. Agents targeting VEGF (bevacizumab, semaxanib), HER2 (lapatinib, pertuzumab, afatinib), chemokine receptors (CXCR4 and CCR7), FAK1, ALK, and E-cadherin are currently being actively explored [24]. The way forward will be dictated by current collaborative efforts of organizations such as the world IBC consortium that are dedicated to a deeper understanding of the molecular biology of IBC and to the conduct of larger scale prospective multicenter clinical trials.
disclosure
The authors have declared no conflicts of interest.
Supplementary Material
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