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Keywords:

  • inflammatory breast cancer;
  • taxanes;
  • pathologic complete response;
  • progression-free survival;
  • estrogen receptor positivity;
  • metastatic disease

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES

BACKGROUND:

Treatments for inflammatory breast cancer (IBC) have changed over the last 15 to 20 years. The authors of this report undertook a retrospective review of patients who were treated at the Royal Marsden Hospital (RMH) to determine whether recurrence-free survival (RFS) and overall survival (OS) have improved as treatment regimens have altered.

METHODS:

Detailed clinical-pathologic data were collected on patients who were treated for primary IBC at RMH between 1990 and 2007. A Cox regression model was used to investigate the factors that influenced OS.

RESULTS:

The median OS was 3 years and 4 months, and the median RFS was 1 year and 10 months. RFS was better in patients who had received taxane-containing regimens; however, there was no OS benefit. A pathologic complete response (pCR) was observed in 13 of 89 patients (15%), and those who achieved a pCR had significantly better RFS but no improvement in OS. The type of chemotherapy did not affect the pCR rate. One hundred thirty of 155 patients received radiotherapy, and those who did not receive radiotherapy had significantly worse outcomes. A multivariate Cox regression analysis indicated that the date of diagnosis, estrogen receptor (ER) status, and the presence of metastatic disease at diagnosis were significant prognostic factors. Patients who were diagnosed during or after 2000 had a relative risk of mortality of 0.5 compared with patients who were diagnosed before 2000. ER-positive patients had a median OS of 4.5 years and a median of RFS of 2.6 years versus 2.9 years and 1.4 years, respectively, for ER-negative patients. Patients who had metastatic disease at presentation had an OS of 1.7 years versus 3.9 years for those without metastatic disease at presentation.

CONCLUSIONS:

Achieving a pCR improved RFS but had no impact on OS. Patients who had metastatic disease at the outset fared much worse, and positive ER status conferred a better outlook. Cancer 2010;116(11 suppl):2815–20. © 2010 American Cancer Society.

Inflammatory breast cancer (IBC) accounts for 2% to 5% of all breast cancers in the developed world but has a higher incidence in certain populations.1 Up to 30% of patients have metastatic disease at diagnosis.2 It is a clinical diagnosis characterized by erythema, warmth, edema, and peau d'orange appearance of the skin and often is associated with a painful breast. Dermal lymphatic emboli can be observed on histologic examination but only in approximately 75% of patients. A significant proportion of patients with IBC tend to have higher grade, hormone-insensitive, and human epidermal growth factor receptor 2 (Her2)-positive tumors compared with other types of breast cancer.1, 3, 4 Despite improvements in survival and outcomes for breast cancer generally over the last 20 years, patients with IBC continue to have a poorer prognosis with 5-year survival rates of 30% to 40%,1, 5 whereas the average comparable rates for patients with noninflammatory breast cancers are 70% to 80%. Treatments and standards of care for IBC have changed over time, so we decided to review the management of patients treated within the Breast Unit at the Royal Marsden Hospital (RMH) between 1990 and 2007 to determine whether recurrence-free survival (RFS) and overall survival (OS) have improved.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES

We carried out a retrospective review of 155 patients identified from the RMH Breast Unit database who were treated for primary IBC between 1990 and 2007. Data were collected from the RMH electronic patient record and patient case notes files. Patient characteristics, the modalities of primary treatment used (induction chemotherapy, surgery, radiotherapy, and endocrine therapy), histopathologic characteristics, the pathologic complete response (pCR) rate, the time to disease progression, treatment at recurrence, and the time to treatment failure were documented. OS data also were collected (from the date of primary diagnosis to the date of death from any cause or the date of last follow-up). RFS was measured from the date of diagnosis to the date of first recurrence or progression in any site.

A Cox regression (proportional hazards) model was used to identify independent prognostic factors among the following variables: patient age, estrogen receptor (ER) status, progesterone receptor (PR) status, Her2 status, histologic grade and subtype (ductal vs lobular), presence of metastatic disease, type of chemotherapy (anthracycline, taxane, other), endocrine therapy, use of anti-Her2 therapy, and date of diagnosis.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES

Patient and Tumor Characteristics

Patient and tumor characteristics were as expected for a cohort of patients with IBC, with relatively higher numbers of ER-negative, Her2-positive, and higher grade tumors.6, 7 The vast majority of patients had invasive ductal carcinoma (IDC), but a few tumors were lobular in origin. Testing for PR status and Her2 over expression was not done routinely in the United Kingdom at the beginning of the study period, which explains the higher number of patients for whom these parameters are unknown. Patient and tumor characteristics are listed in Table 1.

Table 1. Tumor Characteristics and Patient Demographics
CharacteristicNo. of Patients% of Total
  1. IDC indicates invasive ductal carcinoma; ILC, invasive lobular carcinoma; ER, estrogen receptor; PR, progesterone receptor; Her2, human epidermal growth factor receptor 2.

Pathology
 IDC13285
 ILC74.5
 Mixed21.3
 Unknown149
Grade
 121.3
 24126.5
 38152.3
 Unknown3120
ER status
 Positive5133
 Negative7447.7
 Unknown3019.3
PR status
 Positive159.7
 Negative4931.6
 Unknown9158.7
Her2 status
 Positive5938
 Negative5938
 Unknown3724
Metastases at presentation2818
Median age [range], y50 [24-83] 

Survival: OS and RFS

OS and RFS were comparable to previously published data1, 2 and were below the survival for patients with non-IBC. In our series of 155 patients, the median OS was 3 years and 4 months (95% confidence interval [CI], from 2 years and 5 months to 4 years and 3 months), and the median RFS was 1 year and 10 months (95% CI, from 1 year and 5 months to 2 years and 3 months) (Figs. 1 and 2).

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Figure 1. This Kaplan-Meier curve illustrates overall survival (OS). The median OS after diagnosis was 3 years and 4 months (95% confidence interval, from 2 years and 5 months to 4 years and 3 months.

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thumbnail image

Figure 2. This Kaplan-Meier curve illustrates recurrence-free survival (RFS) (note that patients who had metastatic disease at diagnosis were excluded from this analysis). The median RFS was 1 year and 10 months (95% confidence interval, from 1 year and 5 months to 2 years and 3 months).

Download figure to PowerPoint

Type of Cancer

The type of cancer (lobular vs ductal) was not identified as a significant factor in outcome (P = .7), although only 4.5% of patients in the current series had invasive lobular cancer (ILC), the vast majority (85%) had IDC, and rest had tumors of mixed or unknown origin. The numbers were too small in the ILC group to observe any difference in pCR or RFS.

Surgery

Eighty-one patients underwent some form of surgery, and 74 patients did not undergo any surgery. Of those who underwent surgery, the majority (66 of 81 patients) underwent mastectomy, and only 15 patients underwent breast-conserving surgery. Surgery had no significant impact on RFS or OS. RFS was 2.0 years for patients who underwent surgery compared with 1.4 years for those who did not undergo surgery, but the difference was not statistically significant (P = 1.0). OS was 2.9 years for those who underwent had surgery compared with 3.4 years for those who did not undergo surgery (P = .5).

Radiotherapy

One hundred thirty of the 155 patients received radiotherapy, and those who did not receive radiotherapy had significantly worse outcomes. OS was 3.6 years for those who received radiotherapy compared with 1.1 years for those who did not receive radiotherapy (P = .01). Similarly, RFS was 2 years for those who received radiotherapy compared with 0.8 years for those who did not Receive radiotherapy (P = .01). Of the 25 patients who did not receive radiotherapy, 8 patients had metastatic disease at diagnosis, and another 9 patients developed recurrent disease within 12 months of treatment.

Chemotherapy

Chemotherapy regimens varied during the study period (Table 2), but there was no statistically significant impact on either RFS (P = .9) or OS (P = .7) between the differing regimens (Table 3). The 5 patients who did not receive chemotherapy were excluded from the subsequent analyses of survival and RFS.

Table 2. Type of Chemotherapy and Number of Patients Treated According to Decade of Diagnosis
Year of DiagnosisType of Chemotherapy: No. of Patients (%)
CMF/MMAnthracyclinePlatinumTaxaneNoneTotal
  1. CMF indicates cyclophosphamide, methotrexate, and 4-fluorouracil; MM, methotrexate and mitozantrone.

1990-199920 (26)33 (42.9)24 (31.2)0 (0)0 (0)77 (100)
2000-10070 (0)27 (34.6)1 (1.3)45 (57.5)5 (6.4)78 (100)
Total20 (12.9)60 (38.7)25 (16.1)45 (29)5 (3.2)155 (100)
Table 3. Overall Survival and Recurrence-Free Survival According to Type of Chemotherapy
Type of ChemotherapyMedian OS, yPMedian RFS, yP
  1. OS indicates overall survival; RFS, recurrence-free survival; CMF, cyclophosphamide, methotrexate, and 5-fluorouracil; MM, mitoxantrone and methotrexate.

CMF/MMM3.6 2.0 
Anthracycline based3.3.71.7.9
Platinum based3.4 1.6 
Taxane based3.0 2.0 

pCR

In total, 13 patients achieved a pCR. This included 4 patients who had a pCR on postchemotherapy biopsy but who did not proceed to surgery. Patients who achieved a pCR had a significantly better RFS than patients who did not; and, although it was not statistically significant, there was a trend toward improved OS in those who achieved a pCR. In the patients who achieved a pCR, the median OS has not yet been reached (9 of 13 patients remain alive) compared with a median OS of 3.7 years in the non-pCR group (95%CI, 2.2-5.3 years; P = .2). Likewise, in the pCR group, the median RFS has not yet been reached (9 of 13 patients remain disease free) compared with a median RFS of 2.0 years in the non-pCR group (95%CI, 1.5-2.4 years; P = .025).

Chemotherapy and pCR

There was a trend toward increased pCR rates with the addition of taxanes, but the difference was not statistically significant. Of 106 patients who received a nontaxane regimen, 2 patients had a documented pCR after surgery, and another 4 patients had a probable pCR with no evidence of residual disease on multiple biopsies after chemotherapy (6 of 106 patients; 5.7%), whereas 7 of 44 patients (15.9%) who received a taxane-containing regimen achieved a pCR.

In total, 81 of 150 patients who received neoadjuvant chemotherapy went on to undergo definitive surgery; of these, 2 of 51 patients (4%) in the nontaxane group had a pCR compared with 7 of 30 patients (23%) in the taxane group. Although these numbers are very small and are not statistically significant, they are consistent with the benefits that have been described5, 7-9 from the addition of taxanes to treatment regimens for IBC.

Anti-Her2 Therapy and pCR

Thirty-eight percent of our IBC cohort had Her2-over expressing breast cancer (3+ on immunohistochemistry or positive florescence in situ hybridization results), and 24% had unknown Her2 status, largely dating from before 2000 when Her2 testing was not routinely performed. Trastuzumab was not available for early breast cancer before 2005 in the United Kingdom; and, because of the time frame of our study, very few patients received anti-Her2 therapy. However, of the 21 patients who received trastuzumab, 13 were treated for early breast cancer and went on to undergo definitive surgery, and 4 of those patients (30.8%) achieved a pCR.

The Influence of Chemotherapy Regimen on the pCR Rate

The influence of chemotherapy regimen on the pCR rate for the 81 patients who underwent surgery is shown in Table 4.

Table 4. Chemotherapy Regimen and Pathologic Complete Response Rate in Patients Who Underwent Definitive Surgery
Treatment RegimenTotal No. of PatientsNo. of Patients Who Achieved a pCR (%)
  1. pCR indicates pathologic complete response.

Nontaxane-based chemotherapy512 (4)
Taxane-based chemotherapy307 (23)
Taxane-based treatment with trastuzumab134 (30)

Prognostic Factors

Results from the univariate and multivariate Cox regression analyses of prognostic variables are shown in Tables 5 and 6. On multivariate analysis, both ER status and the presence of metastases at diagnosis were independently significant. Patients who had positive ER status had a median OS of 4.5 years versus 2.9 years for ER-negative patients (P = .002) and had an RFS of 2.6 versus 1.4 years for ER-negative patients (P = .001). Patients who had metastatic disease at presentation had an OS of 1.7 years versus 3.9 years for those who did not (P = .002). The date of diagnosis (before or after 2000) also was significant, and it is noteworthy that this cutoff date corresponds with the increasing use of taxanes in treatment regimens; although, in our study, the type of chemotherapy regimen had no statistically significant impact on either RFS or OS.

Table 5. Prognostic Factors: Univariate Analysis
VariableNo. of PatientsMedian RFS, yPMedian OS, yP
  1. RFS indicates recurrence-free survival; OS, overall survival; ER, estrogen receptor; PR, progesterone receptor; Her2, human epidermal growth factor receptor 2; N/A, not applicable.

ER status
 Positive512.6.0014.5.002
 Negative741.4 2.9 
 Unknown30    
PR status
 Positive151.9.83.4.6
 Negative492.0 5.7 
 Unknown91    
Her2 status
 Positive591.7.53.20.5
 Negative592.0 3.9 
 Unknown37    
Metastatic diagnosis
 Yes28N/AN/A1.7.002
 No127  3.9 
Chemotherapy
 Anthracycline801.7.73.3.7
 Taxane422.0 3.0 
 Other281.4 3.3 
Endocrine treatment
 Yes 2.1.013.9.05
 No 1.5 2.7 
Her2 treatment
 Herceptin/lapatinib212.0.61.91.0
 None21.7 3.3 
Table 6. Prognostic Factors: Multivariate Analysis
VariableRFS, yOS, yRR (95% CI)
  1. RFS indicates recurrence-free survival; OS, overall survival; RR, relative risk; CI, confidence interval; ER, estrogen receptor.

ER status
 Positive2.64.51.0
 Negative1.42.62.3 (1.4-4.1)
 P.001.002.002
Metastatic diagnosis
 No 3.91.0 (1.5-5.4)
 Yes 1.72.9
 P..002.002
Date of diagnosis
 1990-1999  1.0
 2000-2007  0.5 (0.3-0.9)
 P  .03

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES

According to our retrospective review, IBC continues to be associated with a poor prognosis despite advances in treatment, but there is a trend toward improved pCR rates with the addition of taxanes and perhaps a further incremental benefit in adding trastuzumab to treatment regimens for patients with Her2-positive disease. There is a small group of patients with IBC (15%-20%) that does well with long-term survival >10 years, and it is possible that these are the patients who achieve a pCR, hence reducing their subsequent risk of recurrence and metastatic disease.

In our series, achieving a pCR did improve RFS but had no significant impact on OS; however, there are data to suggest that the addition of a taxane to chemotherapy regimens has a benefit in terms of both RFS and OS.5, 7-9 The date of diagnosis also was associated with a lower relative risk of mortality, which coincided with the introduction of taxane treatments as standard chemotherapy, but this was significant only after adjusting for ER status. In terms of Her2-targeted therapies, although the numbers of patients in our series were too small to be of any statistical significance, there seemed to be a further increase in the pCR rate with the addition of trastuzumab, and it is well recognized that treatment with trastuzumab confers a further survival benefit to patients who over express Her2.10

It is noteworthy that surgery did not seem to have an impact on RFS or OS in this group of patients. This may be because, for many patients, surgery was a treatment decision taken at a later date rather than at the time of diagnosis. It is probable that whether or not a patient underwent surgery depended on the response to treatment. There also was an historic period in the study during which patients with IBC received radiotherapy alone after induction chemotherapy, particularly those who had achieved a good or complete clinical response. Treatment with radiotherapy seemed to confer an advantage, confirming the importance of optimizing local control in IBC. Positive ER status conferred a better outlook, both in terms of RFS and OS; and it was not surprising that the presence of metastatic disease at diagnosis was an adverse prognostic feature.

New targeted treatments, such as lapatinib (a small-molecule tyrosine kinase inhibitor that targets both Her1 and Her2) and vascular endothelial growth factor inhibitors, are available now, and it will be interesting to determine whether these treatments contribute a further survival benefit. Current attempts to improve treatment responses in patients with IBC should focus on the addition of these novel targeted treatments (ie, Her2 and other IBC-related molecular targets) to existing taxane-based regimens with the aim of increasing pCR rates, which may act as a surrogate for survival.

CONFLICT OF INTEREST DISCLOSURES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES

This supplement was sponsored by the Houston Affiliate of Susan G. Komen for the Cure, the National Cancer Institute, and the State of Texas Rare and Aggressive Breast Cancer Research Program. The First International Inflammatory Breast Cancer Conference was supported in part by GlaxoSmithKline, Pfizer, Eli Lilly and Company, and Cardinal Health. We acknowledge National Health Service funding to the National Institutes for Health Research Biomedical Research Center.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES