Dutch Breast Cancer Trialists Research Articles

Abstract P2-01-03: Sentinel node procedure before or after neoadjuvant chemotherapy in clinically node negative or positive patients; results from 3 phase III studies of the Dutch breast cancer trialists' group (BOOG)

Abstract Background In breast cancer patients treated with neoadjuvant systemic therapy, the timing of the sentinel node (SN) procedure in patients with clinically node-negative disease (cN0) at diagnosis and the role of the SN procedure after neoadjuvant therapy in patients with initially clinical node-positive disease (cN+) still remains to be elucidated. Methods Between February 2006 and May 2012, 657 patients were enrolled in three clinical trials on neoadjuvant systemic therapy under the auspices of the Dutch Breast Cancer Research Group (BOOG). In the INTENS and NEO-ZOTAC study, patients were treated with TAC or AC-T neo-adjuvant chemotherapy (doxorubicin (A), cyclophosphamide (C) and docetaxel (T)). In the TEAM IIa trial, patients were treated with neoadjuvant endocrine therapy (exemestane for 6 months). Timing of the SN procedure in cN0 disease mainly depends on local policy and period of inclusion. We compared the pN0 rate after SN procedure performed before versus after neoadjuvant systemic therapy, in patients with cN0 disease at initial diagnosis. Further, we assessed the SN negative and the false-negative sentinel node rate in patients with initially cN+ breast cancer and conversion to cN0 when treated with neoadjuvant systemic therapy. The false-negative rate was obtained by dividing the number of patients who were SN-negative but non-SN positive by the number of patients who had a positive SN or a positive non-SN. Results In total, 271 patients (n=93 INTENS, n=107 NEOZOTAC, n= 71 TEAM IIa) underwent a SN procedure (n=233 cN0; n=38 cN+). Of patients with cN0 breast cancer at diagnosis, 131 (56%) underwent the SN procedure before and 102 (44%) after neoadjuvant systemic therapy, with ypN0(sn) or ypN0(i+)(sn) in 90/131 (69%) and 69/102 (68%) patients, respectively. Patients with initially cN+ disease who converted to cN0 disease after systemic therapy had a negative SN in 29% (11/38) of cases. The false-negative rate was 20% (6 of 30). More detailed analyses will be presented at the meeting. Conclusion To our knowledge, this is the first study comparing the impact of the timing of the sentinel procedure in patients with cN0 disease. We showed, that irrespective of the timing of the SN procedure - before or after neoadjuvant systemic therapy - in patients with cN0 breast cancer at diagnosis, two-third of patients had a negative sentinel node. In patients who converted after neoadjuvant chemotherapy from cN+ to cN0 the false negative sentinel node rate was 20%. Citation Format: Vivianne C Tjan-Heijnen, Birgitte E Vriens, Maureen J Aarts, Judith R Kroep, Cock J van de Velde, Gerrit-Jan Liefers, Ayoub Charehbili, Petronella G Peer, Maaike de Boer. Sentinel node procedure before or after neoadjuvant chemotherapy in clinically node negative or positive patients; results from 3 phase III studies of the Dutch breast cancer trialists' group (BOOG) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-01-03.

Chemotherapy for isolated locoregional recurrence of breast cancer (CALOR): a randomised trial

Patients with isolated locoregional recurrences (ILRR) of breast cancer have a high risk of distant metastasis and death from breast cancer. We aimed to establish whether adjuvant chemotherapy improves the outcome of such patients. The CALOR trial was a pragmatic, open-label, randomised trial that accrued patients with histologically proven and completely excised ILRR after unilateral breast cancer who had undergone a mastectomy or lumpectomy with clear surgical margins. Eligible patients were enrolled from hospitals worldwide and were centrally randomised (1:1) to chemotherapy (type selected by the investigator; multidrug for at least four courses recommended) or no chemotherapy, using permuted blocks, and stratified by previous chemotherapy, oestrogen-receptor and progesterone-receptor status, and location of ILRR. Patients with oestrogen-receptor-positive ILRR received adjuvant endocrine therapy, radiation therapy was mandated for patients with microscopically involved surgical margins, and anti-HER2 therapy was optional. The primary endpoint was disease-free survival. All analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00074152. From Aug 22, 2003, to Jan 31, 2010, 85 patients were randomly assigned to receive chemotherapy and 77 were assigned to no chemotherapy. At a median follow-up of 4·9 years (IQR 3·6-6 ·0), 24 (28%) patients had disease-free survival events in the chemotherapy group compared with 34 (44%) in the no chemotherapy group. 5-year disease-free survival was 69% (95% CI 56-79) with chemotherapy versus 57% (44-67) without chemotherapy (hazard ratio 0·59 [95% CI 0·35-0·99]; p=0·046). Adjuvant chemotherapy was significantly more effective for women with oestrogen-receptor-negative ILRR (pinteraction=0·046), but analyses of disease-free survival according to the oestrogen-receptor status of the primary tumour were not statistically significant (pinteraction=0·43). Of the 81 patients who received chemotherapy, 12 (15%) had serious adverse events. The most common adverse events were neutropenia, febrile neutropenia, and intestinal infection. Adjuvant chemotherapy should be recommended for patients with completely resected ILRR of breast cancer, especially if the recurrence is oestrogen-receptor negative. US Department of Health and Human Services, Swiss Group for Clinical Cancer Research (SAKK), Frontier Science and Technology Research Foundation, Australian and New Zealand Breast Cancer Trials Group, Swedish Cancer Society, Oncosuisse, Cancer Association of South Africa, Foundation for Clinical Research of Eastern Switzerland (OSKK), Grupo Español de Investigación en Cáncer de Mama (GEICAM), and the Dutch Breast Cancer Trialists' Group (BOOG).

Abstract OT1-1-01: Optimizing neoadjuvant systemic treatment in HER2 positive breast cancer - The TRAIN-2 study

Abstract Background Anthracycline-based regimens are still commonly used in HER2 positive (HER2+) breast cancer (BC), despite added toxicity compared to non-anthracycline containing regimens. The benefit of antracyclines in the era of trastuzumab containing regimens is controversial. Moreover, the value of anthracyclines in combination with dual-HER2 blockade is uncertain. We recently showed high pathologic complete response (pCR) rates with a weekly neoadjuvant paclitaxel-trastuzumab-carboplatin (PTC) regimen. We now aim to evaluate the effect of replacing 3 PTC cycles in this regimen with 3 FE90C-trastuzumab cycles, while adding pertuzumab to all cycles in both arms. Secondly, combined blockade of the estrogen-receptor (ER) pathway and the HER2-pathway in the presence of chemotherapy has not previously been investigated in HER2+/ER+ tumors. Trial design This is a randomized comparative trial evaluating pCR rate (ypT0/is ypN0) at surgery as primary endpoint after neoadjuvant systemic therapy with 9 cycles PTC plus pertuzumab q3w (paclitaxel 80mg/m2 day 1, 8 – trastuzumab 6mg/kg (loading dose 8mg/kg) day 1 – carboplatin AUC = 6 day 1 – pertuzumab 420mg (loading dose 840mg) day 1) versus 3 cycles FE90C-T plus pertuzumab q3w followed by 6 cycles PTC plus pertuzumab q3w. An optional second randomization (2×2 factorial design) will compare concurrent endocrine treatment with an aromatase inhibitor (and ovarian function suppression in premenopausal women and men) during neoadjuvant chemotherapy in combination with dual HER2-blockade, in patients with HER2+/ER+ tumors. Eligibility criteria Patients aged ≥18 year with histologically confirmed invasive HER2+ BC, stage II or III. Eligible patients have a performance status of 0 to 1 and adequate cardiac and organ function. Specific aims The primary objective is to compare the efficacy of 6 cycles neoadjuvant PTC plus pertuzumab preceded by either 3 cycles FE90C-T plus pertuzumab or 3 cycles PTC plus pertuzumab in stage II and III HER2+ BC. Secondary objectives are to describe the efficacy of combined HER2 and ER pathway blockade in HER2+/ER+ BC, to describe the safety of the various regimens and to identify prognostic and predictive biomarkers for pCR. Statistical methods The sample size of the study will be based on the primary objective. To detect an increase in pCR rate from 44% in the PTC arm to 58% in the FE90C-T arm at the 5% (2-sided) level of significance with an 80% power 437 patients need to be randomized (assuming ∼10% of patients will be not evaluable). Target accrual Recruitment will start in the summer of 2013 across ∼30 sites in the Netherlands. Unrestricted research support and pertuzumab are kindly provided by Roche Netherlands. The trial is sponsored by the Dutch Breast Cancer Trialists’ Group (BOOG). Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT1-1-01.

Abstract P1-06-04: The predictive value of tumor-stroma ratio for radiological and pathological response to neoadjuvant chemotherapy in breast cancer (BC): A Dutch breast cancer trialists’ group (BOOG) side-study

Abstract Background Intra-tumoral stroma interacts with tumor cells and has a profound effect on tumor behavior. The tumor-stroma ratio (TSR) is of prognostic value in BC and other types of solid tumors. However, the predictive value of this parameter for achieving pathological complete response (pCR) after neoadjuvant chemotherapy is unknown. Methods We evaluated the relation between TSR and neoadjuvant treatment response in a retrospective cohort of 69 patients (pts) treated with various regimens of neoadjuvant chemotherapy at our institution who were diagnosed with BC between 1991 and 2007 and of whom radiological response was recorded. The percentage of intra-tumoral stroma was visually estimated on diagnostic sections from primary tumor tissue by two observers. The cut-off point between stroma-rich and stroma-poor tumors was set to 50% (as determined in previous investigations). These results were validated in a cohort from the NEOZOTAC trial: a national, multicenter, randomized study comparing the efficacy of TAC (docetaxel, adriamycin and cyclophosphamide i.v. day 1) chemotherapy with or without zoledronic acid 4 mg i.v., q 3 weeks, 6 times in 250 pts with stage II/III, measurable, HER2-negative BC. Radiological response (complete or partial) was evaluated following RECIST 1.1 criteria. pCR was centrally revised and defined as absence of residual tumor cells in the original tumor bed. Results In the retrospective cohort (n = 69) 62.3% of the specimens were classified as stroma-rich. In univariate analysis TSR was significantly associated with radiological response (76.0% stroma-poor vs. 48.8% stroma-rich, P = 0.03). This finding persisted after multivariate analysis for T-status, N-status and ER-status (Odds Ratio [OR] 0.17, 95% C.I.: 0.04-0.78). In the validation set, in which 47.9% of the specimens were stroma-rich (211 cases evaluated), TSR did not predict for radiological response (79.5% stroma-poor vs. 79.2%, P = 0.96). However, when validation data were split on basis of ER-status, TSR was a significant and independent predictor for radiological response in ER-negative pts. (89.5% vs. 50%, P = 0.048, 95% C.I.: 0.01 - 0.98). In the validation set, TSR predicted for pCR with greater pCR rates in stroma-poor tumors (P = 0.03, 22.7% vs 10.3%). Final response results of the pilot and the enlarged sample size of all 250 pts of the validation set will be presented. Conclusions TSR might be a marker for radiological and pathological response to neoadjuvant chemotherapy, especially for the ER- tumor subgroup. Considering the simplicity and low cost of TSR assessment, it should be further evaluated and will be prospectively studied in the next neoadjuvant chemotherapy trial of the BOOG. Contact information: Dr. J.R. Kroep, M.D., Ph.D., Department of Medical Oncology, email:j.r.kroep@lumc.nl or T.J.A. Dekker, MSc. Department of Surgery and Medical Oncology, email: t.j.a.dekker@lumc.nl or LUMC datacenter, Department of Surgery, phone +31(0)71-5263500, fax +31(0)71-5266744, email: datacenter@lumc.nl, Leiden University Medical Center (LUMC), Leiden, The Netherlands. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-06-04.

Abstract P1-08-19: Changes in circulating vitamin D levels as a predictor for pathological response to neoadjuvant chemotherapy (NAC) in breast cancer (BC): A Dutch breast cancer trialists group (BOOG) side-study

Abstract Background: Vitamin D (vit D) status is suggested to be of prognostic value for treatment outcome in women with breast cancer. However, there are no data of the predictive value of vit D status and changes of vit D levels for response to neoadjuvant chemotherapy (NAC). Methods: A subset of patients (pts) from the NEOZOTAC trial in whom vit D data were available was evaluated. NEOZOTAC is a randomized phase III study comparing the efficacy of NCT with or without zoledronic acid (ZA) in pts with stage II/III, measurable, HER2-negative BC. Vit D deficiency and severe deficiency were defined as vit D levels of ≤ 50 and ≤25 nmol/L, respectively. Baseline vit D levels were available for correlation to pathological response of 165 pts (83 ZA-arm), while 67 pts (35 ZA arm) could be evaluated for changes in vit D levels between baseline and cycle 6. Pts who were allocated to the ZA arm should by protocol receive daily supplements of calcium/vit D 500/400 IU. Pathological response was assessed using the Miller and Payne scoring system; pathological complete response (pCR) was defined as absence of tumor cells in the tumor bed and good response was defined as ≥90% decrease of tumor cellularity. Results: Vit D was measured in 168 pts and was done in 75% of pre/perimenopausal pts and 51.3% of postmenopausal pts. There was no significant relation between baseline vit D deficiency (< 50 nmol/L) and pCR (pCR 25.8% for deficient pts vs. 14.1% for non-deficient pts, P = 0.06). Pts with severe vit D deficiency (<25 nmol/L) tended to respond less (pCR 10.5 vs 19.9%, p = 0.53). At the end of chemotherapy, good pathological responders seemed to have a slight increase in vit D levels compared to non-responders who rather showed a decrease (mean 1.11 vs. -9.71, P = 0.08). After multivariate analysis correcting for menopausal status and treatment arm, this result was significant (P = 0.03, 95% C.I. 1.004-1.055). When pts in the ZA arm were analyzed separately, again, good response was rather associated with an increase than a decrease (mean = 9.8 vs. -1.6, P = 0.12). From 17 out of 35 ZA treated pts who were vit D deficient at baseline, only 5 (29.4%) reached levels >50 nmol/L at the end of treatment. Conclusions: Baseline vit D status was not predictive for pCR. However, increase in vit D levels during therapy tended to be associated with better pathological response. Therefore, achieving higher vit D levels can be important. Daily suppletion with calcium/ vitamin D 500/400 might be inadequate for achieving sufficient levels after NAC. Contact information: Dr. J.R. Kroep, M.D., Ph.D., Department of Medical Oncology, email:j.r.kroep@lumc.nl or A. Charehbili, BSc. Department of Surgery and Medical Oncology, email: a.charehbili@lumc.nl or LUMC datacenter, Department of Surgery, phone +31(0)71-5263500, fax +31(0)71-5266744, email: datacenter@lumc.nl, Leiden University Medical Center (LUMC), Leiden, The Netherlands. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-08-19.

Baseline comprehensive geriatric assessment is associated with toxicity and survival in elderly metastatic breast cancer patients receiving single-agent chemotherapy: Results from the OMEGA study of the Dutch Breast Cancer Trialists' Group

AimTo evaluate the association between baseline comprehensive geriatric assessment (CGA) or the Groningen Frailty Indicator (GFI) and toxicity in elderly metastatic breast cancer (MBC) patients treated with first-line palliative chemotherapy. Patients and methodsMBC patients (≥65 years) were randomized between pegylated liposomal doxorubicine or capecitabine. CGA included instrumental activities of daily living (IADL), cognition using the mini-mental state examination (MMSE), mood using the geriatric depression scale (GDS), comorbidity using the Charlson index, polypharmacy and nutritional status using the body mass index. Frailty on CGA was defined as one or more of the following: IADL ≤ 13, MMSE ≤ 23, GDS ≥ 5, BMI ≤ 20, ≥5 medications or Charlson ≥2. The cut-off for frailty on the GFI was ≥4. ResultsOf the randomized 78 patients (median age 75.5 years, range 65.8–86.8 years), 73 were evaluable for CGA; 52 (71%) had one or more geriatric conditions. Grade 3–4 chemotherapy-related toxicity was experienced by 19% of patients without geriatric conditions compared to 56% of patients with two geriatric conditions and 80% of those with three or more (p = 0.002). Polypharmacy was the only individual factor significantly associated with toxicity (p = 0.001). GFI had a sensitivity of 69% and a specificity of 76% for frailty on CGA, and was not significantly associated with survival or toxicity. ConclusionIn this study of elderly patients with MBC, the number of geriatric conditions correlated with grade 3-4 chemotherapy-related toxicity. Therefore, in elderly patients for whom chemotherapy is being considered, a CGA could be a useful addition to the decision-making process.

NEOZOTAC: Efficacy results from a phase III randomized trial with neoadjuvant chemotherapy (TAC) with or without zoledronic acid for patients with HER2-negative large resectable or stage II or III breast cancer (BC)—A Dutch Breast Cancer Trialists’ Group (BOOG) study.

1028 Background: The role of bisphosphonates when added to the neoadjuvant treatment of BC in enhancing the efficacy of therapy is still unknown. Methods: NEOZOTAC is a national, multicenter, randomized study comparing the efficacy of TAC (docetaxel, Adriamycin and cyclophosphamide i.v.) CT followed by G-CSF on day 2 with or without ZA 4 mg i.v. ,q 3 weeks in patients (pts) with stage II/III, measurable, HER2-negative BC and absence of prior bisphosphonate usage. The primary endpoint is the pathologic complete response (pCR) rate in the resection specimen and positive lymph nodes. 228 pts are needed to show an improvement of the pCR rates from 17% to 34% in the experimental arm using a 5% significance level based on the two-sided Fisher’s exact test with a power of 80%. Randomization was done by using the Pocock’s minimisation technique stratified by cT, cN and estrogen receptor status. pCR rate was analyzed using the Cochran-Mantel-Haenszel test, adjusting for the stratification factors. Analysis was based on intent-to-treat. An unplanned subgroup analysis of postmenopausal women (PMW; FSH >20 and estradiol <110) and baseline vitamin D levels was performed. Results: From July 2010 to April 2012, 250 patients from 25 participating sites were randomized. Pathologic response data of 228 patients are currently available. pCR rate did not differ between the two study arms (17% vs 16%, p = 0.81). However, a trend in benefit in favor of ZA was observed in PMW (18% vs 11%, OR 1.90, 95% C.I. 0.52 – 6.88). Patients with severe vitamin D insufficiency (<25 nmol/L) seemed to respond worse to CT numerically (6% vs. 18%). At ASCO pCR and clinical response data of all patients will be reported. Conclusions: Previously, we have shown that adding ZA to neoadjuvant CT is safe with good compliance.In this study, treatment with ZA did not result in a pCR benefit in the total study population. However our findings suggest that addition of ZA to neoadjuvant CT might be effective for enhancing response in PMW with BC. Clinical trial information: NCT01099436.

A combined EpCAM and MCAM circulating tumor cell (CTC) CellSearch enrichment to improve CTC capture rate in stage II/III breast cancer: A Dutch Breast Cancer Trialists' Group (BOOG) side study.

e22106 Background: Using the CellSearch System (Veridex, USA), ≥1 CTC/7.5 mL of peripheral blood is found in ~20% of primary breast cancer (BC) patients. However, epithelial cell adhesion molecule (EpCAM)-negative CTCs may be missed. We previously showed that a subset of BC cell lines lacks EpCAM, but does express melanoma cell adhesion molecule (MCAM) and that MCAM-positive CTCs (M-CTCs) do occur in metastatic breast cancer patients. In a side-study of the NEOZOTAC trial, a randomized study comparing neoadjuvant chemotherapy (NAC) with or without zoledronic acid in stage II/III BC, we investigated whether combined enrichment with EpCAM and MCAM increases the CTC detection rate. Besides, we hypothesized that CTC counts would correlate with pathological complete response (pCR) to NAC. Additionally, as exploratory study, circulated endothelial cells (CECs) were measured. Methods: At baseline and after the 1st chemotherapy cycle, blood was drawn from all patients in the NEOZOTAC trial who gave additional informed consent. The CellSearch System was used to count EpCAM-positive CTCs (E-CTCs) and M-CTCs. For the latter, the anti-EpCAM-ferrofluid was replaced by an anti-MCAM-ferrofluid (both Veridex). CECs were measured using flow cytometry. Results: At baseline, blood was received from 73 patients; ≥1 E-CTCs and M-CTCs were detected in 14/73 (19%, median 1) and 8/68 (12%, median 1), respectively. Combining both counts, ≥1 CTCs were detected in 17/68 (25%) of patients (p=0.01). After 1 chemotherapy cycle, E-CTCs, M-CTCs and overall CTCs were detected in 9/47 (19%), 7/45 (16%), and 13/44 (30%; p<0.01) patients. Median CEC count was 43 at baseline and 142 after cycle 1 (p<0.001). No differences in CTC and CEC count were found between the treatment arms. Baseline CTC counts, nor changes in counts, were associated with pCR. Conclusions: Combined enrichment of CTCs with EpCAM and MCAM significantly increased CTC detection rates in stage II/III BC with about 10%. CTC counts were not associated with pCR to NAC. Associations with disease free survival will follow when available.

Abstract P1-14-07: Neoadjuvant chemotherapy and pathologic complete response in relation to the clinical response, results from a phase III study (INTENS) of the Dutch breast cancer trialists' group (BOOG).

Abstract Background Taxanes have an established role as (neo-)adjuvant treatment of breast cancer. In the present study, we compared 4 AC–4 T with 6 cycles of TAC in the neoadjuvant setting (A = adriamycine, C = cyclophosphamide, T = docetaxel). Previously, we reported that AC-T resulted in a trend for improved outcome (odds ratio of the pathologic complete response (pCR) of the breast 1.60; 95% CI 0.90–3.21). This present analysis focuses on the results of treatment and pCR in the breast in relation to clinical response. Methods Women with breast cancer, eligible for neoadjuvant chemotherapy, were randomized to AC (60/600 mg/m2 q3wk × 4 cycles) followed by T (100 mg/m2 q3wk × 4 cycles), or to TAC (75/50/500 mg/m2 q3wk × 6 cycles). If indicated, trastuzumab and/or endocrine therapy were given as adjuvant treatment. Physical examination, ultrasound of breast and axillary lymph nodes and breast MRI were performed before start of chemotherapy, halfway and after completion of chemotherapy. These results together determined the clinical response (c) halfway and after chemotherapy. The clinical response was classified as cCR (complete response), cPR (partial response), cSD (stable disease) or cPD (progressive disease). pCR was defined as no invasive tumor in the breast at surgery. Results In total, 201 patients (n = 100 AC-T, n=101 TAC) were enrolled between February 2006 and April 2009. Baseline characteristics (AC-T/TAC) were well balanced. The clinical overall response rate (cCR and cPR) to 4 AC was comparable to that seen with 3 cycles TAC (48% versus 54%). Also, the clinical overall response rate to 8 AC-T was comparable to that seen with 6 TAC (81% versus 72%). In the AC-T arm, a third of the patients with cSD halfway reached a cCR or cPR after 8 cycles, whereas in the TAC arm only 18% of patients with cSD halfway reached a cCR or cPR after chemotherapy. In the sequential AC-T arm, 16% of the patients with cSD halfway reached a pCR after switching to docetaxel monotherapy. In contrast, in the TAC arm cSD halfway rarely resulted in pCR after 6 cycles. Patients with a cCR after chemotherapy had a pCR in 58% and 49% of cases, respectively. For patients with cPR these rates were 29% and 18%, respectively, and for patients with cSD 6% and 0%, respectively. Conclusion: Clinical response rates are related to pCR rates. The meaning of cSD halfway should be differently interpreted for sequential versus concurrent chemotherapy. In concurrent chemotherapy schedules, a switch to a non-cross resistant drug may be worthwhile. Early clinical response may be used as a decision aid during neoadjuvant chemotherapy to recognize non-responders. Support: Unrestricted grants from sanofi-aventis NL BV and Amgen BV. Dutch breast cancer trialists' group (BOOG). Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-14-07.

Abstract P1-12-05: First-line chemotherapy with pegylated liposomal doxorubicin versus capecitabine in elderly patients with metastatic breast cancer: results of the phase III OMEGA study of the Dutch Breast Cancer Trialists' Group (BOOG)

Abstract Background The efficacy and feasibility of chemotherapy in elderly metastatic breast cancer (MBC) patients (pts) have been studied in various phase II studies. However, results of prospective randomized studies in elderly MBC pts are scarce. Methods In this phase III multicenter study, MBC pts ≥ 65 years eligible for first-line chemotherapy were randomized between pegylated liposomal doxorubicin (PEGdoxo) (45mg/m2, IV, q 4 wks) or capecitabine (Cape) (1000 mg/m2 PO bid, days 1–14, q 3 wks). Other eligibility criteria were ECOG performance status (PS) ≤ 2 (3 allowed if due to pain or pre existing comorbidity), adequate bone marrow and organ functions. Stratification factors were PS (0–1 vs 2–3), HER2 status, visceral/non-visceral disease, adjuvant hormonal therapy (HTx), and HTx for MBC. Baseline geriatric assessment (GA) included functional status, instrumental activities of daily living, cognition, mood, comorbidity, polypharmacy and nutritional status. Chemotherapy was continued for 24 wks in the absence of progressive disease (PD) or unacceptable toxicity. Primary endpoint was progression-free survival (PFS), secondary endpoints were response rate, overall survival (OS), toxicity (CTC criteria) and compliance. Results Between April 2007 and August 2011, 78 pts were randomized to PEGdoxo (n = 40) or Cape (n = 38). The study was prematurely closed due to slow accrual and supply problems with PEGdoxo. Mean age was 74 years (range 65–86; 75+ 54%; 80+ 13%). Pt characteristics were balanced between the two arms: PS 0–1 77%, ER+ 68%, HER2+ 5%, visceral/non-visceral disease 76%/24%, adjuvant HTx 46%, HTx for MBC 56%, ≥ 3 metastatic sites 50%. Only 22 out of 75 pts with a baseline GA had no geriatric condition (29%), while 32 pts (43%) and 21 pts (28%) had one or ≥ 2 geriatric conditions, respectively. Chemotherapy was given for 6 months in 38%, with a mean dose intensity of 84% in both arms. Reasons for early treatment discontinuation were: PD (31%), toxicity (28%), pt withdrawal (3%). After a median follow up of 32 months, 74 pts had PD and 56 pts had died. The median PFS was 5.7 and 7.7 months with PEGdoxo and Cape (HR 0.68, 95% CI: 0.42–1.11, p = 0.12) and the median OS was 13.8 and 16.8 months, respectively (HR 0.84, 95% CI: 0.49–1.42, p = 0.51). Response was evaluable in 64 pts, with a partial response (PR) in 7 (21%) and 6 pts (19%), and stable disease in 21 (64%) and 17 pts (55%) for PEGdoxo and Cape, respectively. Toxicity was acceptable, mainly being grade 1–2, with for PEGdoxo/Cape grade 1 alopecia in 14/4 pts (grade 2 in 1 PEGdoxo pt), grade 3 fatigue in 5/5 pts, grade 3 HFS in 4/6 pts and grade 3 mucositis in 4/1 pts, respectively. Pts with ≥ 1 geriatric condition more frequently experienced grade 3–4 toxicity, after correcting for type of chemotherapy, age and PS (HR 2.24, 95% CI: 1.21–4.16). Pts aged 75+ had a twofold higher risk of dying, irrespective of treatment arm (HR 2.31, 95% CI: 1.31–4.07). Conclusions First-line chemotherapy with either PEGdoxo or Cape was feasible in elderly MBC pts, with adequate dose intensity and acceptable toxicity, even in non-fit pts or pts aged 75+. Baseline GA correlated with toxicity. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-12-05.

Baseline comprehensive geriatric assessment to predict for toxicity of single-agent chemotherapy in elderly metastatic breast cancer patients: Results from the OMEGA study of the Dutch Breast Cancer Trialists’ Group.

1080 Background: A comprehensive geriatric assessment (CGA) systematically appraises the somatic, psychosocial and functional health status of elderly patients. If CGA can predict toxicity of chemotherapy in elderly cancer patients, this assessment could be useful in deciding on optimal treatment. In this analysis, we evaluated the association between frailty on CGA or Groningen Frailty Index (GFI), and grade 3/4 toxicity in metastatic breast cancer (MBC) patients treated with first-line chemotherapy. Methods: In the OMEGA study, MBC patients (≥ 65 years) were randomized between PEGdoxo 45mg/m2every 4 weeks or capecitabine 2000 mg/m2 on days 1-14 every 3 weeks. Baseline geriatric assessment included functional status (ECOG performance status (PS), IADL), cognition (MMSE), mood (GDS), comorbidity (Charlson), polypharmacy and undernutrition (BMI) and GFI. Frailty on CGA was defined as one or more of the following: IADL≤13, MMSE ≤23, GDS ≥5, BMI ≤20, ≥5 medications or Charlson ≥2. GFI score for frailty was ≥4. Results: In total, 78 patients were randomized (PEGdoxo 38, capecitabine 40), median age 75 years (range 65-86). ECOG PS was 0-1 in 78% of patients and 2-3 in 22%. So far, 72 patients were evaluable for toxicity and baseline CGA. Overall, 50 patients (70%) were frail on CGA, and 40 (55%) according to GFI. Grade 3/4 toxicity related to chemotherapy was reported in 30 patients (42%) and 50% of CGA-frail patients experienced grade 3/4 toxicity, compared to 20% of CGA-fit patients (p=0.02). Grade 3/4 toxicity was experienced by 44% of GFI-frail patients, compared to 38% of GFI-fit patients (p=0.39). After correcting for type of chemotherapy and age, toxicity was associated with CGA-frailty (odds ratio (OR) 4.00, 95% confidence interval (CI) 1.77-13.59, p=0.03) while GFI-frailty was not associated with toxicity (OR 1.11, 95% CI 0.85-1.46, p=0.43). Conclusions: In this randomized study on first-line single-agent chemotherapy in elderly MBC patients, baseline CGA demonstrated a good predictive value for grade 3/4 toxicity of chemotherapy but GFI did not.

249 Feasibility and Toxicities Associated with PEG Doxo Versus Capecitabine as First-line Chemotherapy in Elderly Metastatic Breast Cancer (MBC) Patients; Results From the Randomized OMEGA Study of the Dutch Breast Cancer Trialists’ Group (BOOG)

249 Feasibility and Toxicities Associated with PEG Doxo Versus Capecitabine as First-line Chemotherapy in Elderly Metastatic Breast Cancer (MBC) Patients; Results From the Randomized OMEGA Study of the Dutch Breast Cancer Trialists’ Group (BOOG)

PD04-02: Recovery of Ovarian Function in Breast Cancer Patients with Chemotherapy-Induced Amenorrhea Receiving Anastrozole in the Dutch DATA Study.

Abstract Background: In early stage hormone receptor positive breast cancer, aromatase inhibitors (AIs) are established as adjuvant therapy for postmenopausal women. In daily practice AIs are also offered to patients with chemotherapy-induced amenorrhea (CIA). The impact of AIs on estrogen (E2) levels in these patients has not extensively been studied, although this could be very relevant for the efficacy and safety of the adjuvant hormonal treatment. The Dutch phase III DATA study is assessing the impact on disease-free survival of 3 vs. 6 years of anastrozole after 2–3 years of tamoxifen (N=1900 patients in total), and has included both postmenopausal patients and patients with CIA. The current analysis reports on the hormonal data in the CIA group. Patients and methods: We identified patients from the DATA study < 55 years of age at randomization who had received adjuvant chemotherapy and developed CIA, and excluded patients with ovariectomy or use of LHRH agonist. Patients were considered as having CIA if they were in amenorrhea since 3 months before start of chemotherapy up to 6 months after start of chemotherapy, and did not resume menses during tamoxifen therapy. Patients were eligible if postmenopausal E2 levels were confirmed within the last three months before randomization. Plasma FSH and E2 levels were serially determined at 6-month intervals. Results: A total of 285 patients with CIA were identified in the DATA study. Median age was 50.8 years (range 35.9 - 54.9). Results on E2 and FSH levels are presented in the Table. During treatment with anastrazole, FSH levels tended to increase over time and E2 levels didn't decline. Of note, FSH increased in nearly all patients with significantly elevated (premenopausal) E2 levels, in contrast to the pattern seen in spontaneous recovery of ovarian function. During follow-up, 4 patients had vaginal bleeding, 2 of them having postmenopausal E2 levels. In 8 (2.8%) patients E2 levels became ≥ 200 pmol/l (considered premenopausal) after 12–30 months use of AI. Using a more strict cutoff value of E2 (≥ 100 pmol/l), 62 (21.8%) patients had elevated levels of E2 during AI treatment. With 70 pmol/l as cutoff value, 117 (41.0%) patients had at some point during treatment an increased E2 level. Updated and detailed analyses will be presented at the meeting. Conclusion: In this first series of a large number of CIA patients with available data on E2 and FSH levels during anastrozole therapy, we observed high E2 levels in a substantial number of patients. The combination of increased E2 and FSH levels may indicate continuous stimulation of remaining ovarian follicles. The efficacy of AIs in women with CIA without strict E2 monitoring and adequate treatment modification in the presence of increasing E2 can be questioned. Further data hereon are warranted. Supported by: AstraZeneca NL and the Dutch Breast Cancer Trialists’ Group (BOOG). Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD04-02.

PD07-07: Combination of Paclitaxel and Bevacizumab without or with Capecitabine as First-Line Treatment of HER2−Negative Locally Recurrent or Metastatic Breast Cancer (LR/MBC): First Results from a Randomized, Multicenter, Open-Label, Phase II Study of the Dutch Breast Cancer Trialists' Group (BOOG).

Abstract Background: First-line treatment of HER2−negative LR/MBC with paclitaxel (T) and bevacizumab (A) has demonstrated improved progression-free survival (PFS) and overall response rate (ORR) when compared with T alone (E2100). We determined whether addition of capecitabine (X) to AT is safe and would be better effective than AT in women with HER2−negative LR/MBC. Methods: Eligibility criteria were age ≥18 & ≤75 years, measurable or non-measurable HER2−negative LR/MBC, ECOG PS 0–1 and no prior chemotherapy for LR/MBC. Patients were randomized in 1:1 ratio to receive AT (4-week cycle of T 90 mg/m2 on days 1, 8, 15 and A 10 mg/kg on days 1, 15 for 6 cycles, followed by A 15 mg/kg on day 1 given 3-weekly for subsequent cycles) or ATX (3-week cycle of T 90 mg/m2 on days 1, 8, A 15 mg/kg on day 1 and X 825 mg/m2 bid on days 1–14 for 8 cycles, followed by A 15 mg/kg on day 1 and X 825 mg/m2 bid on days 1–14 given 3-weekly for subsequent cycles). Treatment was discontinued at disease progression, unmanageable toxicity or withdrawal of consent. The primary endpoint was PFS. Secondary endpoints were overall survival, ORR, duration of response and toxicity. Efficacy was evaluated according to RECIST 1.0 and toxicity was assessed according to NCI CTCAE 3.0. Results: From June 2007 till December 2010, 312 patients were recruited at 36 sites. The median age was 56 years (range 32–76). Among all patients, 52% had ECOG 0, 85% were hormone-receptor positive, 86% had measurable disease and 8% had bone-only metastases. These factors were well balanced between both arms. A total of 48% and 33% of patients, respectively, received prior hormonal therapy or radiotherapy for LR/MBC. At the data cut-off of 1st June 2011, the median follow-up duration was 23 months. 311 patients received at least one cycle of treatment and were evaluable for safety. The median number of treatment cycles in AT was 9 and in ATX was 11 (both 33 weeks). An ORR of ≥40% was reached in patients with measurable disease in both groups. The incidence of serious adverse events (SAEs) was 47% and 40% for AT and ATX, respectively, while that of treatment-related SAEs was 12% and 19%, respectively. Treatment-related deaths were 2% for AT and 2% for ATX. The overall rate of AEs grade 3 or 4 was similar in both arms as shown in Table 1, except for hand-foot syndrome grade 3 and neutropenia grade 3 in ATX. In addition, 6 patients with pulmonary embolism were reported in ATX. Conclusions: ATX was well tolerable, although more patients experienced hand-foot syndrome grade 3 and thromboembolic events than patients treated with AT. The efficacy data will be presented at the meeting. Support: This study was supported by Roche. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD07-07.

P3-14-02: Sequential Versus Upfront Intensified Neoadjuvant Chemotherapy in Patients with Large Resectable or Locally Advanced Breast Cancer (INTENS), Toxicity Results from a Phase III Study of the Dutch Breast Cancer Trialists' Group (BOOG).

Abstract Background Taxanes have an established role as (neo-)adjuvant treatment of breast cancer. In the present study, we compared 4 AC - 4 T with 6 cycles of TAC in the neo-adjuvant setting (A=adriamycine, C=cyclophosphamide, T=docetaxel). Previously, we reported that AC-T resulted in a trend for improved outcome (odds ratio pCR of the breast 1.61; 95% CI 0.79−3.33). Now we report the safety data. Methods Women presenting with breast cancer, cT2≥3cm, cT3, cT4 and/or cN+, with measurable disease and no prior treatment, age ≥18 and ≤70 years and Karnofsky Score ≥70% were eligible. Patients were randomized to AC (60/600 mg/m2 q3wk x 4 cycles) followed by T (100 mg/m2 q3wk x 4 cycles) without primary G-CSF prophylaxis, or to TAC (75/50/500 mg/m2 q3wk x 6 cycles) with primary G-CSF prophylaxis. If indicated, trastuzumab and/or endocrine therapy were given as adjuvant treatment. This present analysis focuses on the toxicity profile of the two treatment arms. Results In total, 201 patients (n=100 AC-T, n=101 TAC) were included between February 2006 and April 2009. Baseline characteristics (AC-T/TAC) were well balanced. Patients in the AC-T arm had more frequently grade 3 / 4 toxicities as compared to the TAC arm, respectively in 57% and 28% (p=0.001). Grade 3 / 4 neutropenia without fever was more frequently reported with AC-T (35% vs. 4%; p=0.001). Grade 3 / 4 febrile neutropenia was also more frequent with AC-T (17% versus 5%; p=0.0062) and significantly increased during docetaxel treatment after AC. Notably, diarrhea was also more frequently seen in the AC-T arm (4% versus 0%, p=0.0423). Other grade 3 / 4 toxicities more frequently reported in the AC-T arm were neuropathy - sensory (5% vs. 0%; p=0.229) and pain other than muscle or bone pain (4% vs. 0%; p=0.0423). There were no grade 3 / 4 toxicities more frequently observed in the TAC arm. Conclusion In the comparison of two taxane-anthracycline-cyclophosphamide regimens in the neo-adjuvant setting, it is observed that the sequential approach with a lower cumulative dose tends to have a slightly better efficacy outcome, but at the cost of increased grade 3 / 4 toxicity. However, considering the use of primary G-CSF prophylaxis in the TAC arm, and the fact that the incidence of febrile neutropenia was higher during taxane containing chemotherapy in the AC-T arm, the difference might (partly) disappear if primary G-CSF prophylaxis would be used in the sequential arm. Primary G-CSF prophylaxis may be considered during docetaxel if used sequentially after anthracycline-containing chemotherapy. Support: Unrestricted grants from sanofi-aventis NL BV and Amgen BV. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-14-02.

Abstract P1-11-10: Sequential Versus Upfront Intensified Neoadjuvant Chemotherapy in Patients with Large Resectable or Locally Advanced Breast Cancer (INTENS), First Results from a Phase III Study of the Dutch Breast Cancer Trialists’ Group (BOOG)

Abstract Background: Taxanes have an established role as (neo)-adjuvant treatment of breast cancer. In the NSABP-B30 and the BCIRG 005, adriamycin and cyclophosphamide followed by docetaxel (AC-T) was compared with docetaxel in combination with adriamycin and cyclophosphamide (TAC) in the adjuvant setting. AC-T outperformed TAC if TAC was given for 4 cycles (B-30). However, AC-T was not significantly different from TAC if TAC was given for 6 cycles (BCIRG 005). In the present study, we compared AC-T with 6 cycles of TAC in the neo-adjuvant setting. Methods: Women presenting with breast cancer, cT2≥3cm, cT3, cT4 and/or cN+, with measurable disease and no prior treatment, age ≥18 and ≥70 years and Karnofsky-Score ≥70% were eligible. Patients were randomized to AC (60/600 mg/m2 q3wk x 4 cycles) followed by T (100 mg/m2 q3wk x 4 cycles) or TAC (75/50/500 mg/m2 q3wk x 6 cycles). If indicated, trastuzumab and/or endocrine therapy were given as adjuvant treatment. The primary endpoint of this study was the pathologic complete response (pCR) rate to neoadjuvant chemotherapy at surgery. Safety data will be presented separately at a later date. Results: In total, 201 patients (n=100 AC-T, n=101 TAC) were included between February 2006 and April 2009. Baseline characteristics (ACT/TAC) were well balanced for age (median 49/49y), T-status (cT1-2 51/49%), N-status (cN0 37/40%), hormone receptor status (positive in 65/66%) and HER2 (positive in 28/18%). AC-T resulted in pCR of the breast in 28% of patients and TAC in 19% of patients (Odds ratio (OR) 1.61; 95% CI 0.79-3.33). In patients with positive lymph nodes in situ at start of chemotherapy (no sentinel node procedure), combined pCR of the breast and axilla was 19 % (n=42) and 13% (n=38). Conclusion: AC followed by T resulted in a higher pCR rate, though not statistically significant. Support: Unrestricted grants from sanofi-aventis NL BV and Amgen BV Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-11-10.

Abstract P3-15-01: Primary G-CSF Prophylaxis during the First Two Cycles Only or Throughout All Chemotherapy Cycles in Breast Cancer Patients at Risk of Febrile Neutropenia: Final Results from a Phase III Trial of the Dutch Breast Cancer Trialists Group (BOOG)

Abstract Background: In patients at risk of febrile neutropenia (FN), the highest incidence of FN is seen during the first chemotherapy cycles. This observation questions the effectiveness of continued G-CSF prophylaxis during later chemotherapy cycles. Methods: We conducted a multicenter phase III study in breast cancer. Patients were randomized to primary G-CSF prophylaxis during the first two chemotherapy cycles only (experimental arm) or to primary G-CSF prophylaxis throughout all chemotherapy cycles (standard arm). Patients were eligible if treated with 3-weekly chemotherapy, being at risk of FN according to criteria of international guidelines. This was an equivalence study, aimed to include 230 patients, with FN as primary endpoint. Results: An independent Data Safety Monitoring Board recommended premature closure of the study because of an unacceptable increase in FN rate in the experimental arm. In total, 85 patients enrolled the experimental arm and 84 patients the standard arm till 15 th December 2009. Baseline characteristics were well belanced: age ≥65years in 93% versus 95%, ECOG PS of zero in 82% versus 88%, treated with docetaxel containing chemotherapy in (neo)-adjuvant setting in 97% versus 100%, respectively. At least one episode of FN was seen in 27 (32%) patients of the experimental arm compared with 4 (5%) patients in the standard arm (P<0.0001). Notably, in the experimental arm FN occurred predominantly in the third cycle, whereas in the standard arm FN was seen throughout all cycles. Fever, infection and/or mucositis led to serious adverse events in 31 (36%) patients in the experimental arm versus in 11 (13%) patients in the standard arm (P<0.001). In both arms, 5% of patients stopped or changed treatment because of toxicity. Most patients experienced only one FN episode. In these, chemotherapy was mostly given as planned, but in 61 % of patients with secondary G-CSF prophylaxis and in 21% of patients with secondary antibiotic prophylaxis (in the experimental arm). Conclusion: We conclude that in patients at risk of FN, primary G-CSF prophylaxis cannot be limited to the first chemotherapy cycles, despite the well known increased FN incidence in the first cycles without prophylaxis. With only 2 cycles protected, FN risk is increased in the third cycle. Support: The Netherlands organization for health research and development (ZonMw) and sanofi-aventis Netherlands B.V. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-15-01.

Isolated Tumor Cells in Axillary Lymph Nodes of Breast Cancer Patients: Differential Prognostic Impact of Single Tumor Cell(s) Versus Tumor Cell Clusters, and Microanatomic Location. New Results from the Dutch MIRROR Study.

Abstract BackgroundThe MIRROR study is the largest breast cancer cohort study on pN0(i+) and pN1mi in the sentinel node era, with central pathology review plus restaging according to the 6th AJCC classification, and separate analyses on the impact of systemic adjuvant therapy. In patients not receiving systemic therapy, pN0(i+) as final N-status was shown to be an equally independent prognosticator for disease-free survival as pN1mi compared with pN0 (SABCS 2008, #23, oral). However, pN0(i+) is a heterogeneous group, consisting of single tumor cell(s) and clusters of cells, and consisting of locations in either sinus or parenchyma. We determined the differential impact of size and microanatomic location of nodal involvement on disease-free survival.MethodsWomen operated for breast cancer in all Dutch hospitals in the years 1998-2005, with favorable characteristics (tumor size 1-3 cm and differentiation grade I-II OR tumor size <=1 cm irrespective of grade), having undergone a sentinel node procedure were selected. For this present analysis, only patients with pN0(i+) as final nodal status who had not received systemic adjuvant therapy were included (n=513). Presence of single tumor cell(s) versus tumor cell clusters, and the microanatomic location (sinus versus parenchyma) were recorded. In addition, metastatic size was measured. The primary endpoint was 5-year disease-free survival.ResultsThe 5-year disease-free survival of patients with lymph nodes containing single tumor cell(s) (n=93) was 78.6%, as compared to a 5-year disease-free survival of 77.1% of patients with small clusters of cells (n=404). After adjustment for age, log tumor size, grade, axillary treatment, and hormone receptor status, the adjusted hazard ratio for events was 1.10 (95% CI 0.67-1.78, NS) for the presence of tumor cell clusters as compared to the presence of single tumor cell(s). When including log metastasis size within the pN0(i+) group as a continuous variable in the Cox regression model, increasing metastatic size was borderline significantly associated with reduced 5-years disease-free survival with an adjusted hazard ratio of 1.27 (95% CI 1.00 – 1.61, p=0.05). The adjusted hazard ratio for events was 0.93 (95% CI 0.57-1.51, NS) for the parenchymal (n=112) versus sinusoidal microanatomic location (n=395).ConclusionSingle tumor cell(s) bear similar prognostic information as small tumor cell clusters, even though results do suggest that within the pN0(i+) group increasing size of nodal involvement is associated with reduced survival. Microanatomic location does not seem to have prognostic relevance.Support: The Netherlands organization for health research and development (ZonMw) and the Dutch Breast Cancer Trialists' Group (BOOG) Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 306.

Impact of omission of completion axillary lymph node dissection (cALND) or axillary radiotherapy (ax RT) in breast cancer patients with micrometastases (pN1mi) or isolated tumor cells (pN0[i+]) in the sentinel lymph node (SN): Results from the MIRROR study

CRA506 Background: The Dutch MIRROR study is the largest cohort study on pN1mi and pN0(i+) in the SN era with long-term follow-up, central pathology review (6th AJCC-classification), and separate analyses on the use of adjuvant systemic therapy (AST). In patients not receiving AST, pN1mi and pN0(i+) as final N-stage were shown to be independent prognosticators for disease-free survival (SABCS 2008, #23, oral). As a substantial number of patients in the MIRROR study did not undergo cALND or ax RT, we questioned whether this policy was safe in patients with pN1mi(sn) or pN0(i+)(sn). Methods: Patients operated for breast cancer in all Dutch hospitals in the years 1998–2005, having favorable primary tumor characteristics, and having undergone an SN biopsy without macrometastases as final N-stage were included. For this present research question, patients were categorized by their SN-stage. Median follow-up was 4.7 years. The Kaplan-Meier method was used to estimate 5-year axillary recurrence (AR) rates, and Cox regression was used to estimate the hazard ratios (HR). In the analyses, the effect of AST was taken into account. Results: In total, 835 patients with pN0(i-)(sn), 799 patients with pN0(i+)(sn), and 958 patients with pN1mi(sn) were included. AR rates, and HRs on AR are displayed below. Conclusions: Omission of cALND or ax RT in patients with pN1mi(sn) resulted in a significantly higher 5-year AR rate, even after correction for AST, and other patient and tumor characteristics. This indicates that patients with pN1mi(sn) should undergo cALND or ax RT to prevent AR. Support: The Netherlands Organization for Health Research and Development (ZonMw) and the Dutch Breast Cancer Trialists’ Group (BOOG). [Table: see text] No significant financial relationships to disclose.

Micrometastases and isolated tumor cells: relevant and robust or rubbish? (MIRROR): preliminary results of the MIRROR study from the Dutch breast cancer trialists' group (BOOG).

Abstract Abstract #23 Background
 The sentinel lymph node procedure (SNP) has largely replaced axillary lymph node dissection (ALND) in patients with early breast cancer (BC). Intensified examination of the sentinel node (SN) results in the detection of isolated tumor cells (ITCs) and micrometastases, whereas its relevance is still debated. This retrospective cohort study is the first study on this topic which includes only patients who underwent a SNP, with central review of all SN slides, and with separate analyses for the impact of administration of adjuvant systemic therapy.
 Methods
 Patients operated for BC in all Dutch hospitals in the years 1998-2005, having favourable tumor characteristics (> 35 year; tumor size 1-3 cm and differentiation grade I-II OR tumor size ≤ 1 cm irrespective of grade), having undergone a SNP with pN0(i-), pN0(i+), or pN1mi as final N-stage were selected. Patients were classified in cohort I in case of pN0(i-) and no adjuvant systemic therapy (AST), in cohort II in case of pN0(i+)/pN1mi and no AST, and in cohort III in case of pN0(i+)/pN1mi with AST. SNs were centrally reviewed and restaged according to 6th TNM classification. The 5-year disease-free survival (DFS) was analysed for the 3 different cohorts.
 Results
 So far, data are available for 1,744 of the 3,240 selected patients (cohort I n=935; cohort II n=340, cohort III n=469) with a median follow-up of 5.5 years. At diagnosis median age was 58, 56 and 56 years (p < 0.01) and median tumor size was 1.2, 1.4 and 1.5 cm (p < 0.0001). Differentiation grade and hormone receptor status were equally distributed among the three cohorts. Adjuvant systemic therapy in cohort III consisted of chemotherapy (10%), hormonal therapy (63%), or both (27%). The 5-yr DFS is 84% in cohort I, 73% in cohort II, and 86% in cohort III (p = 0.003 cohort I vs II; p < 0.0001 cohort II vs III). Correction for baseline characteristics did not lead to a relevant change in the results.
 Conclusion
 BC patients with ITCs or micrometastases as final N-stage after SNP have a significantly worse 5-yr DFS as compared to patients having no ITCs or micrometastases, independent of primary tumor characteristics. Adjuvant systemic therapy significantly improves the 5-yr DFS in the group of patients with ITCs or micrometastases in the lymph node(s). At the meeting, updated analyses will be available for the entire MIRROR study population.
 Support: The Netherlands organization for health research and development (ZonMw) and all Dutch CCCs. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 23.