J.Y. Pierga

Prognostic value of persistent node involvement after neoadjuvant chemotherapy in patients with operable breast cancer

Neoadjuvant chemotherapy is able to reduce the size of the majority of breast tumours and down-stage axillary-node status. The aim of this study was to assess the prognostic value of persistent node involvement after neoadjuvant chemotherapy. A total of 488 patients with T2–T3, N0–N1 breast cancer treated by neoadjuvant chemotherapy followed by tumour excision and axillary lymph-node dissection between 1981 and 1992 were selected from the Institut Curie database. Median follow-up was 7 years. Overall objective response rate before local treatment was 52% and breast tumour size was reduced in 83% of patients. No pathologic nodal involvement was observed in 46.5% of patients. Patients with ≥ eight positive nodes had a very poor median disease-free survival of only 20 months. Their 10-year disease-free survival rate was 7%, while the 10-year disease-free survival rate for patients with no node involvement was 64%. Median survival for patients with ≥ eight nodes positive was 48 months and the 10-year survival rate was 26% (P < 0.0001). On multivariate analysis, outcome was strongly correlated with pathological nodal status, tumour grade, hormonal receptor status and clinical response of the tumour. In conclusion, patients with extensive nodal involvement after neoadjuvant chemotherapy have a very poor outcome. Second-line treatment should be considered in this population.

Prognostic factors for survival after neoadjuvant chemotherapy in operable breast cancer: the role of clinical response

The aim of this retrospective study was to assess predictive factors for clinical response to preoperative chemotherapy and prognostic factors for survival. From 1981 to 1992, 936 patients with T2-T3, N0-N1 breast cancer who received 2-6 months (median 4) of preoperative chemotherapy were selected from the Institute Curie database. Preoperative treatment was followed by surgery and/or radiotherapy. Median follow-up was 8.5 years (range 7-211 months). The objective response rate before surgery and/or radiotherapy was 58.3%. In stepwise multivariate analysis (Cox model), favourable prognostic factors for survival were the absence of pathological axillary lymph node involvement (Relative Risk (RR) 1.54; P=0.0004), low histological tumour grade (RR=1.54; P=0.0017), clinical response to preoperative chemotherapy (RR=1.45, P=0.0013), positive progesterone receptor (PR) status (RR=1.56; P=0.0001), smaller tumour size (RR=1.37; P=0.005) and lack of clinical lymph node involvement (RR=1.42; P=0.007). The association of clinical tumour response with survival is independent of the baseline characteristics of the tumour. Clinical response could be used as a surrogate marker for evaluation of the efficacy of neoadjuvant chemotherapy before assessment of the pathological response.

Second malignancies after breast cancer: the impact of different treatment modalities.

Treatment for non-metastatic breast cancer (BC) may be the cause of second malignancies in long-term survivors. Our aim was to investigate whether survivors present a higher risk of malignancy than the general population according to treatment received. We analysed data for 16 705 BC survivors treated at the Curie Institute (1981–1997) by either chemotherapy (various regimens), radiotherapy (high-energy photons from a 60Co unit or linear accelerator) and/or hormone therapy (2–5 years of tamoxifen). We calculated age-standardized incidence ratios (SIRs) for each malignancy, using data for the general French population from five regional registries. At a median follow-up 10.5 years, 709 patients had developed a second malignancy. The greatest increases in risk were for leukaemia (SIR: 2.07 (1.52–2.75)), ovarian cancer (SIR: 1.6 (1.27–2.04)) and gynaecological (cervical/endometrial) cancer (SIR: 1.6 (1.34–1.89); P<0.0001). The SIR for gastrointestinal cancer, the most common malignancy, was 0.82 (0.70–0.95; P<0.007). The increase in leukaemia was most strongly related to chemotherapy and that in gynaecological cancers to hormone therapy. Radiotherapy alone also had a significant, although lesser, effect on leukaemia and gynaecological cancer incidence. The increased risk of sarcomas and lung cancer was attributed to radiotherapy. No increased risk was observed for malignant melanoma, lymphoma, genitourinary, thyroid or head and neck cancer. There is a significantly increased risk of several kinds of second malignancy in women treated for BC, compared with the general population. This increase may be related to adjuvant treatment in some cases. However, the absolute risk is small.

HER2 status of bone marrow micrometastasis and their corresponding primary tumours in a pilot study of 27 cases: a possible tool for anti-HER2 therapy management?

Discrepancies have been reported between HER2 status in primary breast cancer and micrometastatic cells in bone marrow. The aim of this study was to assess HER2 gene status in micrometastatic cells in bone marrow and corresponding primary tumour. Micrometastatic cells were detected in bone marrow aspirations in a prospective series of 27 breast cancer patients by immunocytochemistry (pancytokeratin antibody). HER2 status of micrometastatic cells was assessed by fluorescence in situ hybridisation (FISH), respectively in 24 out of 27. Primary tumour HER2 status was assessed by immunohistochemistry (CB11 antibody) and by FISH in 20 out of 27 of the cases. HER2 was amplified or overexpressed in five out of 27 (18.5%) primary tumours and in four out of 27 (15%) micrometastatic cells. In two cases, HER2 was overexpressed and amplified in primary tumour, but not in micrometastatic cells, whereas, in one case, HER2 presented a low amplification rate (six copies) in micrometastatic cells not found in the primary tumour. We demonstrated that negative and positive HER2 status remained, in the majority of the cases, stable between the bone marrow micrometastasis and the primary tumour. Therefore, the efficiency of anti-HER2 adjuvant therapy could be evaluated, in a clinical trial, by sequential detection of HER2-positive micrometastatic cells within the bone marrow, before and after treatment.

Efficacy and safety of bevacizumab-based combination regimens in patients with previously untreated metastatic colorectal cancer: Final results from a randomised phase ii study of bevacizumab plus 5-fluorouracil, leucovorin plus irinotecan versus bevacizumab plus capecitabine plus irinotecan (FNCLCC ACCORD 13/0503 study)

BACKGROUND The combination of bevacizumab and bolus 5-fluorouracil, leucovorin and irinotecan is highly effective in patients with metastatic colorectal cancer (mCRC). This randomised, multicenter, non-comparative phase II trial assessed the efficacy and safety of bevacizumab plus oral capecitabine plus irinotecan (XELIRI) or infusional 5-fluorouracil, leucovorin plus irinotecan (FOLFIRI) as first-line therapy for patients with mCRC. PATIENTS AND METHODS Patients received bevacizumab 7.5mg/kg on day 1 plus XELIRI (irinotecan 200mg/m(2) on day 1 and oral capecitabine 1,000 mg/m(2) bid on days 1-14) every 3 weeks or bevacizumab 5mg/kg on day 1 plus FOLFIRI (5-fluorouracil 400mg/m(2) on day 1 plus 2,400 mg/m(2) as a 46-h infusion, leucovorin 400mg/m(2) on day 1, and irinotecan 180 mg/m(2) on day 1) every 2 weeks. Patients aged ≥ 65 years received a lower dose of capecitabine (800 mg/m(2) twice daily). The primary endpoint was 6-month progression-free survival (PFS) rate. RESULTS A total of 145 patients were enrolled (bevacizumab-XELIRI, n=72; bevacizumab-FOLFIRI, n=73). The 6-month PFS rate was 82% (95% confidence intervals (CI) 71-90%) in the bevacizumab-XELIRI arm and 85% (95% CI 75-92%) in the bevacizumab-FOLFIRI arm. In both the bevacizumab-XELIRI and bevacizumab-FOLFIRI arms, median PFS and overall survival (OS) were 9 and 23 months, respectively. The most frequent toxicities were grade 3/4 neutropenia (bevacizumab-XELIRI 18%; bevacizumab-FOLFIRI 26%) and grade 3 diarrhoea (12% and 5%, respectively). CONCLUSIONS This randomised non-comparative study demonstrates that bevacizumab-XELIRI and bevacizumab-FOLFIRI are effective regimens for the first-line treatment of patients with mCRC with manageable toxicity profiles.

Clinical significance of proliferative potential of occult metastatic cells in bone marrow of patients with breast cancer

There is increasing statistical evidence that the presence of tumour cells in bone marrow detected by immunocytochemistry represents an important prognostic indicator in breast cancer, but their individual capacity to become clinical metastases is unknown. The aim of this study was to assess the proliferative capacity of these occult metastatic cells in the bone marrow of patients with various stages of breast cancer. We obtained bone marrow aspirates from 60 patients with breast cancer before treatment with chemotherapy: 17 stage II, 12 stage III and 31 stage IV. After bone marrow culture for 6–34 days (median: 17 days) under specific cell culture conditions, viable epithelial cells were detected by cytokeratin staining in 40 patients (66%). Expansion of tumour cells was poorly correlated with tumour cell detection on primary screening (P=0.06). There was a nonsignificant correlation between the number and the presence of expanded tumour cells and the UICC stage of the patients. On primary screening, tumour cell detection was positive in 56% of patients and was correlated with clinical UICC stage (P=0.01). However, with a median follow-up of 23 months, expansion of tumour cells from bone marrow was associated with decreased patient survival (P=0.04), whereas the survival difference according to detection of CK-positive cells on primary screening was not statistically significant. In conclusion, viable tumour cells can be detected in the bone marrow of breast cancer patients. Their proliferative potential could be predictive of outcome and deserves further investigation.

Predictive factors of response to first-line chemotherapy in 1426 women with metastatic breast cancer.

Since response to chemotherapy is a major determinant of survival in metastatic breast cancer, the purpose of our study was to analyse the predictive factors of response. 1426 patients enrolled into eight consecutive randomised trials of anthracycline-based first-line chemotherapy in metastatic breast cancer, between 1977 and 1992, were analysed. A forward stepwise logistic regression analysis was used. The objective response rate (ORR) to chemotherapy in the total population was 63.6% (95% confidence interval (CI): 61.5-67.7). The complete response rate was 17.5%. Multivariate analysis defined adjuvant chemotherapy, lactate dehydrogenase (LDH), Karnofsky index (KI), and pleural and lung metastases to be the five main variables correlated with ORR. A predictive score was calculated using the coefficient of these five variables, The score was established as follows: -1.32+0.54 (if prior adjuvant chemotherapy) +0.80 (low KI) +0.75 (raised LDH) +0.49 (lung metastases) +0.51 (pleural metastases). A low score (less than -0.78) was associated with an ORR greater than 70.0%, representing 41.2% of our population. An intermediate score (between -0.78 and 0) was associated with an ORR of 50 to 70%, representing 37.5% of our population and a positive score was associated with an ORR of less than 50%, representing 21.3% of our population. This score can be used to predict objective response rates to first-line anthracycline-based chemotherapy. This method now needs to be evaluated prospectively in phase II trials. Identification of various risk groups may also be useful for interpretation and design of clinical trials.

Prognostic value of cytokeratin 19 fragment (CYFRA 21-1) and cytokeratin-positive cells in bone marrow samples of breast cancer patients.

The aim of this study was to investigate the relationship between the detection of micrometastatic cells by immunocytochemistry (ICC) with an anticytokeratin antibody and cytokeratin fragment (CYFRA 21-1) expression detected by an immunofluorescent assay in bone marrow of breast cancer patients. Micrometastatic CK+ cells were screened with a pancytokeratin antibody A45 B/B3 from bone marrow aspiration samples of 102 breast cancer patients (65 primary tumors, 10 local recurrences and 27 distant metastases). CYFRA 21-1 levels were assessed in bone marrow supernatant of these patients before collection of the mononucleated interface cells on a Ficoll-Hypaque density gradient and in 20 control patients. CYFRA 21-1 and CK+ cell detection by ICC were both correlated with clinical stage. CYFRA 21-1 was significantly elevated in patients with micrometastatic disease detected by ICC: 4.77 ng/mL (+/- 10.87 SD) versus 1.00 ng/mL (+/-1.36 SD) in patients with negative ICC (p=0.01). In univariate analysis, a CYFRA 21-1 value > or =1 ng/mL and the presence of CK+ cells were associated with a poorer survival for patients with stage I to III breast cancer (n=65). On multivariate analysis, only pathological nodal status and presence of CK+ cells in bone marrow were independent prognostic factors for overall survival. In conclusion, in this series CYFRA 21-1 was correlated with detection of CK+ cells by ICC in bone marrow, but cannot replace ICC. The presence of CK+ cells in bone marrow remains a strong independent prognostic factor in primary breast cancer.

Are ipsilateral breast tumour invasive recurrences in young (≤40 years) women more aggressive than their primary tumours?

The characteristics of ipsilateral breast tumour recurrences (IBTRs) relative to those of their primary tumours (PTs) remain scarcely studied. Of 70 young (⩽40 years) premenopausal women with IBTRs, we studied a series of 63 with paired histological data. Median follow-up since IBTR was 10 years. Rates of histological types, grades or hormonal receptors were not significantly different in PTs and in IBTRs. The concordance between IBTRs and their PTs was good for histological types. IBTRs with conserved histological types tended to occur more locally, but not significantly sooner than others. These IBTRs had good concordance for hormone receptors. In discordant cases there were as many losses as appearances of the receptors. The concordance was weak for grades, with equivalent numbers of IBTRs graded lower as higher than their PTs. The 10-year overall survival rate was 70%. Neither the conservation of histological type, location, nor of the two combined were associated with deaths. Early (<2 years) IBTRs, tended to be associated with poorer survival (HR=2.24 (0.92–5.41); P=0.08). IBTRs did not display features of higher aggressiveness than PTs. Neither clinical nor histological definition of a true recurrence could be established other than the conservation of the histological type.

Dose-intense salvage therapy after neoadjuvant chemotherapy: feasibility and preliminary results

Abstract Breast cancer patients who, following treatment with primary chemotherapy (FAC 50) present an axillary node involvement of more than 4 nodes together with clinically palpable residual disease (minor response to chemotherapy) and the presence of tumour cell emboli in lymphatics have a very poor outcome. DFS rates of 50 patients treated between 1990 and 1994 were 31% at 5 years. Our aim was therefore to evaluate an entirely different therapeutic regime in these very high risk patients. 32 patients selected for these criteria entered a pilot study consisting in treatment with 3 four weekly cycles of vinorelbine, ifosfamide, cisplatinum followed by a high dose chemotherapy (HDCT) course and rescue by peripheral hematopoietic stem cells which had been collected by cytapheresis after the second course of chemotherapy. HDCT consisted of thiotepa, L-Pam, CBDCA (800 mg/m2 d1), ifosfamide and mesna. Following primary chemotherapy, 14 patients had breast conservation and 18 had a modified mastectomy. Median number of involved lymph nodes was 11 (range 4–26). 29 patients received the complete HDCT course. Median age was 40 (range 24–59). Engraftment was prompt with a median of 10 days to leucocyte recovery to 1000/μl and 9 days to platelet recovery. One patient developed reversible renal failure, and subsequently died of Gram–septicemia. To date, with a median follow up of 20 months (range 14–36), 6 patients have relapsed and 2 patients have died. It is too early to make any firm conclusions, but we feel that this alternative regime is feasible and may prove superior to the classical optimal dose anthracycline-containing regimes in patients who have a tendency to rapidly develop resistance to anthracyclines.