Breast Cancer

Multivariate analysis of survival in inflammatory breast cancer: impact of intensity of chemotherapy in multimodality treatment

Summary:

The prognosis of inflammatory breast cancer (IBC) is poor. We evaluated clinical and biopathological characteristics that could affect survival in 74 women with nonmetastatic IBC consecutively treated in our institution between 1976 and 2000. Patients received primary anthracycline-based chemotherapy at conventional doses (n=20) or high-dose chemotherapy (HDC) with haematopoietic stem cell support (HSCS) (n=54). After chemotherapy, 84% of patients underwent mastectomy, 95% were given radiotherapy and 55% tamoxifen. Immunohistochemistry data (ER, PR, ERBB2, P53) on pre-chemotherapy specimens suggested strong differences between IBC and non-IBC. The rate of pathological complete response to chemotherapy was 26% (27% with HDC and 17% with conventional doses, not significant). No single factor was found predictive of response. With a median follow-up of 48 months after diagnosis, the 5-year projected disease-free survival (DFS) was 24% and overall survival (OS) 41%. In multivariate analysis, the strongest independent prognostic factor was the delivery of HDC. The 5-year DFS and OS of patients were respectively 28 and 50% with HDC and 15 and 18% with conventional chemotherapy. These results and comparisons with other series of patients suggest a role for HDC with HSCS as part of the therapeutic approach in IBC. Further prospective studies are required to confirm it.

Main

Inflammatory breast cancer (IBC) is a rare (1–5% of cases), but often lethal form of breast cancer. Although survival has been improved by the introduction of primary chemotherapy the prognosis remains poor with a 5-year survival ranging from 20 to 50%.1,2

Pathologically, the tumour is rapidly progressive, highly angiogenic and invasive. IBC has been rarely investigated at the biological level and to date, very little is known about the molecular alterations involved in initiation and progression of the disease. Owing to the relative infrequency of the disease, no phase III study has been published or performed and current treatments are essentially based on data from retrospective noncontrolled studies or from registries. Reported prognostic features3 remain contested, although response to conventional chemotherapy — notably pathological response — seems to be a strong indicator of survival.4,5,6 The optimum neoadjuvant chemotherapy regimen, as well as accurate predictive factors, still have to be defined to improve response rate. Clearly, assessment of new systemic therapeutic approaches and better characterization of disease are required.

We retrospectively analysed a series of 74 consecutive cases of nonmetastatic IBC treated in our institution with induction anthracycline-based chemotherapy. Immunohistochemical analysis of tumours, response to chemotherapy and long-term survival are described. Several parameters including intensity of chemotherapy, pathological features and immunohistochemistry (IHC) are evaluated for a potential prognostic role.

Patients and methods

Patients and treatment

Patients were selected from the ‘Breast Cancer’ database of our institution. Eligibility criteria were histological diagnosis of invasive breast carcinoma with inflammatory clinical signs involving more than one-third of the breast (T4d classification, UICC TNM, 5th edition) and/or with tumour emboli in dermal lymphatic vessels, and absence of distant metastasis at time of diagnosis. Absence of metastases was defined according to baseline staging that included physical examination, biological blood tests, bilateral mammography and breast ultrasound, chest X-ray, liver ultrasound and radionuclide bone scan for all patients. After reviewing the medical records, 74 cases out of 101 women with IBC registered in our database were included in the present study. The other 27 patients were not included because of metastases at the time of diagnosis.

All patients were treated using a multimodal approach including surgery, chemotherapy and radiotherapy in most cases. For certain modalities, the type varied according to the era. Initial surgery ranged from tumour biopsy alone to tumour biopsy with skin biopsy and axillary dissection. After diagnosis, all patients received primary chemotherapy. For clinically nonprogressive patients, treatment was then completed by surgery and/or radiotherapy. Finally, tamoxifen 20 mg/day was given for 3–5 years to patients with positive oestrogen (ER) and/or progesterone receptors (PR), or when their status was unknown. After completion of locoregional treatment, patients were evaluated at 3-month intervals for the first 2 years and at 6-month intervals thereafter. Evaluations included clinical examination and blood tests completed in all patients and yearly mammography, chest X-ray, liver ultrasound and bone scan. Other examinations were performed only when indicated.

Pathological evaluation

To standardize diagnoses, all available tumour sections pre- and post-chemotherapy were reviewed blindly de novo by two pathologists (ECJ, JJ) prior to analysis. Material before chemotherapy came from the primary tumor in most of cases, and from skin or axillary nodes in eight cases. Tumours were typed using the WHO histological criteria. Superficial dermal lymphatic invasion was diagnosed on serial sections if necessary and was distinguished from direct dermal tumour invasion. Histoprognostic grade was measured according to European recommendations.7

The expression of four proteins was measured using IHC as previously mentioned.8 Antibodies were directed against ER (6F11.2; Novocastra, Newcastle, UK), PR (PgR636; Dako, Trappes, France), P53 (D01; Immunotech, Marseille, France) and ERBB2 (CB11; Novocastra, Newcastle, UK). Slides were evaluated under a light microscope by two pathologists (ECJ, JJ). Values were dichotomized with a positivity cut off equal to 1% (ER, PR, P53) or 2 or 3+ (ERBB2, HercepTest kit scoring guidelines).

Post-chemotherapy mastectomy specimens were examined to determine pathological response. Analysis concerned several tissue sections (a minimum of 20 per specimen) taken from each quadrant, from the nipple areolar complex and from areas suspected of tumour involvement. Response was scored in four grades as described:9 grade 1, disappearance of all tumour both on macroscopic and microscopic examination; grade 2, presence of in situ carcinoma of the breast with no invasive tumour; grade 3, presence of invasive carcinoma with stromal alterations such as sclerosis or fibrosis reflecting partial response; grade 4, no or few alterations in tumour appearance reflecting chemoresistance. Grades 1 and 2 were considered as pathologically complete responses (PCR), while grades 3 and 4 were considered failures. Axillary lymph nodes, when available post-chemotherapy, were examined to determine presence or absence of tumour residue: in cases of grade 1 or 2 response, but with positive lymph nodes, response was classified as failure.

Statistical analysis

Differences in patient characteristics between the chemotherapy groups (with vs without HDC) were tested by the χ2 test (categorical variables) or the Mann-Whitney test (continuous variables). Correlations between pathological response (PCR vs no PCR) and the following factors were investigated using the Fisher exact test: SBR grade, dermal lymphatic invasion, IHC data and chemotherapy regimen (with vs without HDC). All P-values were two-sided.

Disease-free survival (DFS) and overall survival (OS) were calculated from the date of diagnosis until, respectively, date of first disease progression wherever this was, and date of death whatever its cause, or date of last status report if the patient was alive. Metastasis-free survival (MFS) was calculated from the date of diagnosis until date of first distant metastasis, but patients with locoregional relapse before metastastic relapse were censored. Follow-up was measured from the date of diagnosis to the date of last follow-up for live patients. Data concerning patients without disease progression, death or metastatic relapse at last follow-up were censored. Survival curves were estimated using the Kaplan–Meier method. The prognostic impact of the above-cited factors, age and pathological response were assessed in univariate analysis by the log-rank test and in multivariate analysis by the Cox's proportional hazards modelling. All statistical tests were two-sided at the 5% level of significance. Statistical analysis was performed using SAS software (SAS Institute. Inc., version 8.2).

Results

Patients and treatment

In total, 74 patients with nonmetastatic IBC, consecutively treated in our institution between January 1976 and October 2000, were included in this study. The median age at diagnosis was 51 years (range, 24–81) and 47% of women were premenopausal. Tumour characteristics are listed in Table 1. Initial surgery included both tumour and skin biopsies in 64% of cases. Other cases corresponded to tumour biopsy alone (25%), skin biopsy alone (7%) or axillary dissection alone (4%). Globally, an axillary lymph node dissection was performed in 59% of patients and a skin biopsy in 71%. After diagnosis, all women received intravenous primary polychemotherapy. Different regimens were used during this period, but all were anthracycline-based except for four patients, and cycles were globally delivered within the scheduled time whatever the period of treatment. Until 1985, patients (n=9) received conventional doses of 4–6 cycles of AVCF or FAC regimens combining, respectively, doxorubicin (30 mg/m2, day 1), vincristine (1 mg/m2, day 2), cyclophosphamide (300 mg/m2, days 3–6), fluorouracil (400 mg/m2, days 3–6) or fluorouracil (500 mg/m2, day 1), doxorubicin (50 mg/m2, day 1), cyclophosphamide (500 mg/m2, day 1). From 1985 onwards and for all patients less than 65 years of age who accepted such a strategy, high-dose chemotherapy (HDC) with haematopoietic stem cell support (HSCS) was administered (n=54). Other women received conventional regimens (n=11). Thus, two groups of patients were distinguished with respect to chemotherapy doses: 20 patients (27%) received conventional doses and 54 patients (73%) received HDC with HSCS. Intensification was late for 14 of them, administered as a consolidation regimen as soon as possible after 4–5 cycles of conventional regimens even in nonresponding patients; in this case HDC combined cyclophosphamide (60 mg/kg/day from day −3 to day −2, total dose 120 mg/kg) and melphalan (140 mg/m2 day−1) with or without mitoxantrone (12 mg/m2/day from day −7 to day −5, total dose 36 mg/m2). Haematological rescue consisted of autologous haematopoietic stem cells initially collected from bone marrow, then from peripheral blood for the last patients. From 1993, and for 40 patients, intensification was sequential, delivered as first-line therapy immediately after diagnosis. It consisted of four cycles of a dose-intensified regimen combining the same drugs as those used at conventional doses, with collection of peripheral blood stem cells after cycles 1 and 2, and reinfusion after cycles 3 and 4 (cyclophosphamide 6 g/m2 and doxorubicin 75 mg/m2 cycle 1; cyclophosphamide 3 g/m2 and doxorubicin 75 mg/m2 cycle 2; cyclophosphamide 3 g/m2, doxorubicin 75 mg/m2 and fluorouracil 2.500 mg/m2 cycles 3 and 4).10 No purging of graft was performed. After completion of chemotherapy 62 patients underwent mastectomy, with axillary dissection (25 cases) if not performed at diagnosis. Mastectomy was not performed in 12 patients: three patients experienced disease progression during induction chemotherapy and nine patients (five in the HDC group and four in the other chemotherapy group) refused mastectomy. After surgery or when surgery was not performed, external beam radiotherapy targeting the chest wall and regional lymph node areas was delivered (95% of patients). Finally, 55% of women received additional tamoxifen.

Table 1 Tumour characteristics

Pathological response

Out of 62 mastectomy specimens, 52 were available for assessment of pathological response. Complete pathological response (PCR) was described in 26% of cases with 20% of grade 1 and 6% of grade 2 responses (Table 2). In all, 61% of specimens contained a component of invasive tumour tissue (grade 3) and 13% displayed no sign of response (grade 4). Although the PCR rate of the 45 mastectomy specimens from patients treated with HDC (27% of available specimens) was greater than that of the six specimens from patients treated with conventional doses (17% of available specimens), the difference was not statistically significant. No significant correlation was found between response and any parameter tested.

Table 2 Pathological response to primary chemotherapy and clinical outcome (n=74)

Clinical outcome

In all, 19 patients experienced a local relapse, one experienced a regional node relapse, and 47 a metastatic relapse (Table 2) that was the first event in 36 cases. The most frequent site of first metastasis was bone. Others included skin, liver, lungs, pleura and brain. Globally, 48 out of 74 patients relapsed (65%) at median times of 15 (range, 3–81) months after diagnosis. Two patients (from the HDC group) developed a second cancer, endometrial cancer (after 46 months of tamoxifen) and acute myeloid leukaemia respectively 54 and 67 months after diagnosis. In total, 41 patients died at a median of 26 (range, 2–125) months after diagnosis; 39 from breast cancer and two from other causes unrelated to chemotherapy. At the present time, with a median follow-up of 48 (range, 9–173) months after diagnosis, 33 patients are alive, 24 without evidence of disease. The 3- and 5-year projected survivals are, respectively, 40% (95% CI 27.7–52.1; median 24 months) and 24% (95% CI 12.5–36.1) for DFS and 54% (95% CI 41.5–66.5; median 38 months) and 41% (95% CI 28.5–53.9) for OS. The 3- and 5-year projected MFS are, respectively, 49% (95% CI 35.3–62.7; median 34 months) and 34% (95% CI 20.3–47.7).

Univariate analysis (Table 3) identified three factors associated with an unfavourable clinical outcome: negativity of PR staining, negativity of both PR and ER (vs positivity of one or two receptors) (Figures 1a and b) and absence of HDC (Figures 1c and d). The 3- and 5-year projected survivals, respectively, are 45% (95% CI 37.8–52.5; median 27 months) and 28% (95% CI 13.0–41.5) for DFS and 65% (95% CI 50.5–78.9; median 49 months) and 50% (95% CI 34.0–64.5) for OS for patients with HDC and HSCS, and are 22% (95% CI 1.7–43.3; median 13 months) and 15% (95% CI 00.0–37.1) for DFS and 25% (95% CI 3.8–45.3; median 19 months) and 18% (95% CI 00.0–33.4) for OS for patients without HDC. No difference was noted between late or initial intensification. Difference remained significant for MFS between patients treated with conventional chemotherapy (5-year MFS 18%, median 15 months) and patients treated with HDC (5-year MFS 38%, median 44 months; P=0.003, log-rank test). On multivariate analysis, three parameters remained significantly associated with survival (Table 3). Patients who received HDC with HSCS had a better DFS (RR=2.12, 95% CI 1.2–4.0, P=0.018) and OS (RR=2.28, 95% CI 1.1–4.4, P=0.004) than patients who received conventional chemotherapy. Similarly, patients whose tumour expressed ER and/or PR displayed a better OS (RR=2.12, 95% CI 1.1–4.1, P=0.022) than patients with ER- and PR-negative tumour. Finally, patients with PR-positive tumour displayed better OS (RR=2.53, 95% CI 1.1–5.5, P=0.016) than patients with PR-negative tumours.

Table 3 Univariate and multivariate analyses
Figure 1
figure1

Survival for all 74 nonmetastatic inflammatory breast cancer patients according to prognostic factors. (a,b) according to the hormone receptor status of tumours (ER−/PR− vs others), (c,d) according to the doses of primary chemotherapy (HDC with HSCS vs no HDC).

Discussion

We report the long-term results achieved with primary chemotherapy in 74 consecutive nonmetastatic IBC patients, including patients treated with HDC and HSCS.

Our population displayed characteristics similar to a series described in the literature. Most of patients had clinically palpable axillary lymph nodes and most tumours were ductal carcinoma, with high SBR grade and negative hormone receptor status.1 Published molecular studies of IBC are very rare and include small numbers of patients.11,12,13,14,15,16 We identified a significant correlation between nuclear detection of P53 and negative ER status (P=0.04, χ2 test), as described in NIBC.17 However, our immunohistochemical results also suggested important molecular differences between IBC and NIBC. Mutations of the TP53 gene, associated with strong nuclear detection, have been reported in 30% of NIBC.18 Such an alteration was more frequent in our series of IBC (53% of cases), in agreement with the literature.14,16,19 We found ERBB2 to be overexpressed in 43% of IBC. This high prevalence as compared with NIBC20 has been previously reported.11,13,14,15,16 This particular status of most tested proteins probably reflects a different role for these molecules in the pathogenesis and evolution of IBC and NIBC. Notably frequent alterations of P53 and ERBB2 might account in part for the aggressiveness of IBC.

Today, chemotherapy protocols including anthracyclines are the most frequently used in IBC with a 5-year survival ranging from 20 to 50%.1,2 In this analysis of consecutive patients, different anthracycline-based regimens were administered over the study period. Differences in doses and dose-intensity allowed two groups of patients to be distinguished. Initially, patients received conventional doses, but from 1985 they were systematically included in clinical trials of HDC with HSCS. Rational included: disappointing results with conventional chemotherapy, chemosensitivity of disease, dose–response and dose–intensity relationships demonstrated with alkylating agents,21 and increase of pathological response rates by using semi-intensive chemotherapy without HSCS.9,22 Over the study period, two types of intensification were performed: late intensification following conventional chemotherapy, then front-line sequential HDC. Some of these patients have been previously reported.10,23 Mastectomy following chemotherapy was performed in most cases and allowed evaluation of the pathological response to chemotherapy. Pathological complete response was observed in 26% of all patients, in 17% of those treated with conventional doses and in 27% of those treated with HDC (not significant). These rates are comparable with those published for conventional or semi-intensive chemotherapy (from 0 to 25%)4,8,24,25,26,27 and for HDC with HSCS (from 14 to 39%).10,23,28,29 As pathological response has been reported as a prognostic factor,4,5,24,25,26,30,31 the identification of predictive factors is warranted. To date, no single clinicopathological parameter has been proved reliably predictive in IBC and very few data are available about molecular features.15,19,23 In our series, no factor correlated with response.

With a median follow-up of 48 months, the multimodal therapeutic approach in our 74 patients led to 5-year DFS and OS rates of 24 and 41% respectively. Among all factors tested, only two positively affected survival: the presence of hormone receptors and the delivery of HDC with HSCS. Achievement of a clinical or pathological response to conventional chemotherapy has often been correlated with a longer survival.4,5,6,24,25,26,30,31 In our series, absence of prognostic significance of PCR might be because of the small number of patients in the conventionally treated group and the predominance of cases treated with HDC among the assessed specimens. Indeed, in this situation, such a correlation appears less evident.23,28,29 If confirmed, such a difference between conventional and intensive chemotherapy might reflect a selection effect rather than a therapeutic effect: achievement of PCR after conventional doses might occur with a very good prognosis tumour, more prone to display favourable clinical outcome. Whether the protein expression of ERBB2 and P53 have prognostic value in IBC remains to be investigated. In our series, PR-negative status and ER- and PR-negative status were significantly associated with poor OS as previously reported.32,33

On multivariate analysis, the strongest prognostic factor was the delivery of HDC with HSCS. Patients who received HDC experienced longer DFS and OS than did patients receiving conventional doses. Such comparison was made possible by systematic introduction of HDC from 1985 in the treatment of IBC patients, even those who did not respond to conventional chemotherapy. The long observation period of this study (24 years) and the size of our series (74 patients) might introduce some heterogeneity in patients and treatments and complicate statistics, justifying caution when assessing the value of HDC. However, inclusion criteria and staging evaluation were similar for all women and our two so-defined groups of patients were balanced with respect to clinical, pathological and molecular parameters of tumours (Table 1). As expected, the median age of patients from the HDC group was slightly less than that of conventionally treated patients and might introduce a bias in favour of the HDC group, but the difference was not significant. All patients had received anthracycline-based chemotherapy and treatment was similar concerning delivery of tamoxifen or radiotherapy (P>0.05, Fisher exact test). Mastectomy was more frequent (P=0.01, Fisher exact test) in the HDC group (most patients were included in clinical trials aimed to evaluate pathological response), but its benefit remains debatable when compared with radiotherapy alone.34 Furthermore, although methods of locoregional treatment may have changed over the study period and might impact upon local relapse rate, this rate was not statistically different between the two groups (P>0.05, Fisher exact test) and the long-term MFS was better in the HDC group. Publications about HDC with HSCS in IBC are few and quote data from the International Bone Marrow Transplant Registry35 and since 1997, from some pilot or phase II studies where HDC was delivered either as consolidation23,28,29,36,37,38,39 or as first-line therapy.10 Globally, even if it is difficult to compare these studies, which are often multicentre and/or with small heterogeneous cohorts in terms of treatment and follow-up, the 3- or 4-year DFS rates (from 45 to 65%) and OS rates (from 52 to 89%) are similar to each other and comparable to our series. To date, no randomised clinical trial has compared HDC with HSCS and conventional chemotherapy in IBC, probably because of the rarity of disease and the absence of real consensus chemotherapy. However, even if comparisons remain difficult, these results of HDC, including those of our present series, are encouraging when compared to conventional chemotherapy.3,4,22,40,41 The long period of observation may introduce bias in favour of HDC that we have delivered to our more recent patients. Recent data for IBC show improvement in survival with more modern regimens. Notably, conventional doses of anthracyclines have been increased from AVCF with an impact on survival. This improvement in outcome was confirmed in our series (data not shown), and, because the more recent patients received HDC, coincided with increased doses of cytotoxic drugs, suggesting a role for intensity of chemotherapy. Further advances in conventional chemotherapy are expected with modern regimens being investigated that include both anthracycline and taxane.6,42,43 However, the 5-year survival of our HDC group seems similar or slightly higher than one would expect to see with these more modern regimens, and taxanes might be introduced in HDC regimens also. Even if longer follow-up is required, prospective randomised studies comparing the best conventional regimen vs HDC are warranted in IBC. Nonetheless, the difficulty of these studies and the relatively high rate of relapse after conventional or HDC necessitate testing in parallel with other systemic therapeutic strategies such as maintenance therapy with current or innovative drugs.

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Acknowledgements

This work was supported in part by the Association pour la Recherche sur le Cancer (ARC Printemps 2002, Grant No. 4719).

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Correspondence to P Viens.

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Bertucci, F., Tarpin, C., Charafe-Jauffret, E. et al. Multivariate analysis of survival in inflammatory breast cancer: impact of intensity of chemotherapy in multimodality treatment. Bone Marrow Transplant 33, 913–920 (2004). https://doi.org/10.1038/sj.bmt.1704458

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Keywords

  • high-dose chemotherapy
  • immunohistochemistry
  • inflammatory breast cancer
  • prognosis

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