Tumor-positive Axillary Lymph Nodes Research Articles

Diagnostic accuracy of sentinel lymph node biopsy in determining the axillary lymph node metastasis.

Sentinel lymph node biopsy (SLNB) is accepted as the standard procedure to determine the axillary lymph node metastasis in breast cancer at early stage. However, in many cases with sentinel lymph node positivity, the axilla does not contain any tumor cells. As a result, the accuracy of SLNB to predict axillary lymph node metastasis must be evaluated. Thousand hundred and fourteen women operated for breast cancer were retrospectively examined. Breast cancer patients without axillary metastasis on clinical examination who had undergone SLNB were included in the study. Sentinel lymph node positivity and axillary lymph node positivity were compared. Among 1114 women operated for breast cancer, 230 were clinically node negative preoperatively and undergone SLNB. Eighty-three (36%) of the patients were SLNB positive and undergone axillary dissection. Forty-three (51.8%) of them had tumor positive axillary lymph nodes and 40 (48.2%) of them had tumor negative axillary lymph nodes. In 48.2% of the patients, positive sentinel lymph node does not demonstrate a positive axilla. This finding supports sparing axillary dissection in patients with favorable prognostic factors even if the sentinel lymph node is found to be positive. Axillary lymph node dissection(ALND) may be spared even if there are macrometastatic sentinel lymph nodes in patients with favorable tumor types who will undergo breast-conserving surgery.

Feasibility of radioguided occult lesion localization of clip-marked lymph nodes for tailored axillary treatment in breast cancer patients treated with neoadjuvant systemic therapy

BackgroundSelective removal of initially tumor-positive axillary lymph nodes in breast cancer patients who underwent neoadjuvant systemic treatment (NST) improves the accuracy of nodal staging and provides the opportunity for more tailored axillary treatment. This study evaluated whether radioguided occult lesion localization (ROLL) of clip-marked lymph nodes is feasible in clinical practice.MethodsPrior to NST, a clip marker was placed inside a proven tumor-positive lymph node in all breast cancer patients (cTis-4N1-3 M0). After NST, technetium-99m-labeled macroaggregated albumin was injected in the clip-marked lymph nodes. The next day, these ROLL-marked nodes were selectively removed at surgery to evaluate the pathological response of the axilla.ResultsThirty-seven patients (38 axillae) underwent clip insertion. After NST, the clip was visible by ultrasound in 36 procedures (95%). In the other two patients, the ROLL-node injection was performed in a sonographically suspicious unclipped node (1), and near the clip under computed tomography guidance (1). Initial surgery successfully identified the ROLL-marked node with clip in 33 procedures (87%). Removed specimens in the other five procedures contained only the sonographically suspicious tumor-positive unclipped node (1), a node with signs of complete response but no clip (2), a clip without node (1), and tissue without node nor clip, and a second successful ROLL-node procedure was performed (1). Overall, 10 ROLL-marked nodes had no residual disease.ConclusionsThis study demonstrates that the ROLL procedure to identify clip-marked lymph nodes is feasible. This facilitates selective removal at surgery and may tailor axillary treatment in patients treated with NST.

Is ultrasound-guided fine-needle aspiration cytology of adequate value in detecting breast cancer patients with three or more positive axillary lymph nodes?

This study evaluated the accuracy of ultrasound-guided fine-needle aspiration cytology of the sonographically most suspicious axillary lymph node (US/FNAC) to select early breast cancer patients with three or more tumour-positive axillary lymph nodes. Between 2004 and 2014, a total of 2130 patients with histologically proven early breast cancer were evaluated and treated in the Noordwest Clinics Alkmaar. US/FNAC was performed preoperatively in all these patients. We analysed the results of US/FNAC retrospectively. Pathological axillary node status (sentinel node biopsy and/or axillary lymph node dissection) was used as reference standard. A total of 634 (29.8%) of 2130 patients had axillary lymph node metastases on final histology. 248 nodepositive patients (11.6%)had three or more positive lymph nodes. The accuracy of US/FNAC to detect three or more positive lymph nodes was 89.8%, sensitivity was 44.8%, specificity was 95.7%, PPV was 58.1%, and NPV was 92.9%. This study shows a more than adequate accuracy of preoperative US/FNAC to detect three or more positive lymph nodes (89.8%). However, when US/FNAC was chosen as the only axillary staging method, 6.4% of all patients (false negative group) would have been undertreated and 3.8% of all patients (false positive group) would have been overtreated according to the ACOSOG Z0011 criteria.

S100A14 is a novel independent prognostic biomarker in the triple-negative breast cancer subtype.

Triple-negative breast cancer (TNBC) represents a heterogeneous subgroup with generally poor outcome and lack of an effective targeted therapy. Prognostic or predictive biomarkers to guide treatment decisions for this group of patients are needed. To evaluate the potential of S100A14 protein as a novel biomarker in TNBC, the protein expression of S100A14 was correlated with clinical outcomes in a Pilot Sample set and a Danish cohort of predominantly TNBC patients. Kaplan-Meier analysis identified a prognostic impact of S100A14 on disease-free survival and overall survival, showing that tumors with high S100A14 protein expression levels were significantly correlated with poor outcome in TNBC patients (p = 0.017; p = 0.038), particularly those in the basal-like subgroup (p = 0.006; p = 0.037). Importantly, TNBC patients with high S100A14 expression, but tumor-negative axillary lymph nodes (N-), had equally poor outcomes as those with tumor-positive axillary lymph nodes (N+), while TNBC/N- patients with low S100A14 expression had a significantly better disease free survival (p = 0.013). Multivariate analysis revealed that S100A14 is an independent prognostic factor for TNBC patients (p = 0.024; p = 0.05). At the cellular level, S100A14 was found to be expressed in epithelial-like, but not in mesenchymal-like, TNBC cells in vitro. S100A14 is an independent prognostic factor in TNBC and a novel potential therapeutic target in TNBC.

Abstract P1-01-26: The feasibility of SNIPE trial; sentinel lymph node biopsy vs. no-SLNB In patients with early breast cancer

Abstract Background: The results of ZOO11 have shaken our longstanding approach for the axillary management of small invasive breast cancers where the incidence and burden of axillary metastasis would be much less than that of ZOO11 population. The traditional approach of sentinel lymph node biopsy (SLNB) for ‘‘all invasive cancers’’ is challenged due to the diminishing role of axillary lymph nodes (ALNs) status in guiding adjuvant systemic therapy. Certainly this raises the question of whether SLNB can be avoided in a select group of patients without compromising clinical outcomes? The aim was to identify a group of patients with a very low burden of axillary disease where SLNB is no longer required. The feasibility of the proposed SNIPE trial; Sentinel lymph node biopsy vs. No-SLNB In Patients with Early breast cancer was discussed and compared with SOUND trial, Sentinel node vs. Observation after axillary UltrasouND. Method: Patients with breast cancers ≤ 2 cm in size, clinically node negative who underwent breast conserving surgery and SLNB were identified. Patients were divided into different groups according to clinicopathological variables. The incidence of ALNs metastasis, further non-SLNs metastasis and ≥ 4 total number of tumour positive ALNs were determined. Results:194 patients met the inclusion criteria. The mean patient age was 58.5 y;75% were ≥ 50 y. The incidence of tumour positive ALNs is < 5% in T1b, G1-2 tumours where SLNB could be omitted without compromising the surgical outcomes. The burden of axillary nodal disease is shown below: Incidence and burden of axillary metastasis in different groups.GroupsT1 tumours(SOUND trial)T1, G1-2T1b tumoursT1b, G1-2(SNIPE trial)T1 and G1≤ 15mm G1-2≤ 15mm G1Total patients with T1 tumours and clinically negative axilla with no multifocality of tumour = 194Number of patients1941514943579243Incidence of ALNs mets30/194(15.5%)20/151(13.3%)6/49(12.4%)4/43(9.3%)8/57(14%)15/92(16.3%)7/43(16.3%)Incidence of ALNs mets excluding micromets13.4%11.9%6.1%4.6%10.5%13%11.6%OSM (Overall size of metastasis) mean, median, range.4.1,3(0.3-19)3.7,3(0.3-9)3.5,1.9(0.3-9)3.5,3(0.3-9)3.7,3(0.3-9)3.7,3(0.3-9)3.7,3(0.3-9)Incidence of non-SLNs metastasis9/30(30%)7/20(35%)1/6(16.7%)0%2/8(25%)3/15(20%)2/7(28.6%)Incidence of ≥ 4 total number of tumour positive ALNs5/194(2.5%)4/151(2.6%)1/49(2%)0%1/57(1.7%)1/92(1.1%)1/43(2.3%) Conclusion: It is possible to identify a group of patients where burden of axillary disease is acceptably low enough that SLNB can be avoided. Feasibility of a non-inferiority, multi-centres Randomized Controlled Trial in a select group of patients with or without SLNB has been explored to compare the distant disease free, disease free and overall survival and axillary relapse rate. Patients with 2 ≤ tumour positive SLNs would not have axillary node dissection inline with the recommendations of ZOO 11 trial. Overall, 1600 patients would be required to show that the group without SLNB is no more inferior in the outcomes to that with SLNB. Inclusion criteria and management of tumor positive SLNs in this proposed trial is open to discussion and should be debated intensively before starting such an important trial which may also improve accrual for this trial. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-01-26.

The feasibility of a randomised controlled trial for the axillary management of a select group of invasive breast cancer patients: SLNB vs. no-SLNB

The results of ZOO11 have shaken our thinking and approach for the axillary management of small invasive breast cancers where the incidence and burden of axillary metastasis would be much less than that of ZOO11 population. The traditional approach of sentinel lymph node biopsy (SLNB) for "all invasive cancers" is challenged because of the diminishing role of axillary lymph nodes (ALNs) status in guiding the adjuvant systemic therapy. Certainly this raises the question of whether SLNB can be avoided in a select group of patients without compromising clinical outcomes. The aim of this study was to identify such a group of patients in whom SLNB is no longer required. Patients with breast cancers ≤2 cm in size and clinically negative axilla who underwent breast conserving surgery (BCS) and SLNB were identified. Patients were divided into different groups; incidence of ALNs metastasis, further non-SLNs metastasis and a total number of tumour positive ALNs of ≥4 were determined. A total of 194 patients met the criteria; incidence of tumour positive SLNs, further non-SLNs metastasis and a total number of tumour positive ALNs of ≥4 varied between different groups and was 9.3-15.5 %, 0-35 % and 0-2.6 %, respectively. Patients with T1b, grade 1-2 tumours had less than 5 % risk of ALNs macrometastasis. It is possible to identify a group of patients whose burden of axillary disease is acceptably low enough that SLNB can be avoided. Feasibility of a non-inferiority randomised controlled trial (RCT) in a select group of patients with or without SLNB has been explored to compare the distant disease free, disease free and overall survival and axillary relapse rate (ARR).

International multicenter tool to predict the risk of four or more tumor-positive axillary lymph nodes in breast cancer patients with sentinel node macrometastases

Recently, many centers have omitted routine axillary lymph node dissection (ALND) after metastatic sentinel node biopsy in breast cancer due to a growing body of literature. However, existing guidelines of adjuvant treatment planning are strongly based on axillary nodal stage. In this study, we aim to develop a novel international multicenter predictive tool to estimate a patient-specific risk of having four or more tumor-positive axillary lymph nodes (ALN) in patients with macrometastatic sentinel node(s) (SN). A series of 675 patients with macrometastatic SN and completion ALND from five European centers were analyzed by logistic regression analysis. A multivariate predictive model was created and validated internally by 367 additional patients and then externally by 760 additional patients from eight different centers. All statistical tests were two-sided. Prevalence of four or more tumor-positive ALN in each center's series (P = 0.010), number of metastatic SNs (P < 0.0001), number of negative SNs (P = 0.003), histological size of the primary tumor (P = 0.020), and extra-capsular extension of SN metastasis (P < 0.0001) were included in the predictive model. The model's area under the receiver operating characteristics curve was 0.766 in the internal validation and 0.774 in external validation. Our novel international multicenter-based predictive tool reliably estimates the risk of four or more axillary metastases after identifying macrometastatic SN(s) in breast cancer. Our tool performs well in internal and external validation, but needs to be further validated in each center before application to clinical use.

Influence of Neoadjuvant Chemotherapy on HER2/neu Status in Invasive Breast Cancer

IntroductionReliably estimating HER2/neu expression in breast cancer is important for predicting patient prognosis and optimizing adjuvant therapeutic strategies. In this retrospective cohort study, effects of NAC on HER2/neu status in invasive breast cancer were evaluated, and the related factors were analyzed. Patients and MethodsOne hundred thirty-one patients with primary breast cancer were treated with anthracycline- and/or taxane-based NAC. HER2/neu status was evaluated by IHC on core needle biopsies of primary tumors before NAC and surgical resection specimens of post-NAC residual breast cancers or tumor-positive axillary lymph nodes. Thirty-two pairs of specimens with discordant HER2/neu IHC scores were analyzed by fluorescence in situ hybridization (FISH). ResultsA significant difference in HER2/neu status by IHC between core needle biopsies and surgical resection specimens in patients receiving NAC was observed. After NAC, 23.4% (29 of 124) of tumors showed downregulated HER2/neu expression by IHC. Alterations of HER2/neu IHC scores did not significantly correlate with tumor subtype, pathologic response to NAC, adjuvant regimen, or time interval from the last chemotherapy to surgery. HER2/neu protein overexpression level was associated with favorable pathologic response to anthracycline and taxane-based chemotherapy. However, tumors with altered HER2/neu IHC scores after NAC revealed stable HER2/neu gene amplification/nonamplification by FISH analysis. ConclusionNeoadjuvant chemotherapy for breast carcinoma resulted in the HER2/neu status alteration by IHC, but they have stable gene amplification status by FISH. HER2/neu protein overexpression indicated greater sensitivity to neoadjuvant anthracycline- and taxane-based chemotherapy. Thus, retesting HER2/neu IHC status in residual tumors after NAC should be considered in order to optimize adjuvant systemic therapy.

Novel surgical technique to selectively remove metastatic axillary lymph nodes in breast cancer patients after neoadjuvant chemotherapy: The MARI procedure—Marking of the axilla with radioactive iodine seeds.

196 Background: An important benefit of neoadjuvant chemotherapy (NAC) is the increase in breast-conserving surgery. At present the response of axillary lymph node metastases to chemotherapy cannot be accurately assessed. Therefore axilla-conserving therapy is not yet a benefit. We aimed to assess a new surgical method to evaluate the axillary response: the MARI procedure, which stands for Marking of the Axillary lymph node with Radioactive Iodine seeds. Methods: Prior to NAC, proven tumor-positive axillary lymph nodes were marked with a Iodine-125 seed. After NAC, the marked lymph node was selectively removed with the use of a gamma-detection probe. A complementary axillary lymph node dissection was performed to assess whether pathological response in the marked node was indicative for the pathological response in the additional lymph nodes. Results: Tumor-positive axillary lymph nodes were successfully marked with Iodine-125 seeds in 68 patients. The marked lymph node (MARI-node) was surgically detected and selectively removed after NAC in all patients. The pathological response to chemotherapy in the MARI-node was indicative for the overall response in the additionally removed lymph nodes. In 47 patients the MARI-node contained residual disease (n=45 macrometastasis, n= 2 ITC). Thirty-five of them had macro- or micro metastases in the complementary axillary lymph node dissection specimen. In 21 patients the MARI-node was tumor negative. In 2 patients a macro metastasis was found in the additionally removed nodes, in 2 patients ITC were found and in the remaining 17 patients no residual tumor was found in the additionaly removed lymphnodes. (false negative rate of the MARI procedure: 9.5%). Conclusions: This study shows that marking and selectively removing metastatic lymph nodes after NAC is feasible. The tumor-response in the marked lymph node may be used to tailor further axillary treatment, and herewith enabling axilla-conserving surgery after neoadjuvant chemotherapy.

Factors associated with the prescription of antidepressive medication to breast cancer patients

We evaluated factors associated with use of antidepressant medication subsequent to a diagnosis of breast cancer. We also evaluated the effect of participation in a cancer rehabilitation program on use of antidepressants. Material and methods. We conducted a register-based cohort study of 1 247 women with breast cancer diagnosed between 1998 and 2006 who attended a week-long rehabilitation program and a comparison group of 2 903 women who did not attend the program matched through the registers of the Danish Breast Cancer Cooperative Group. The associations between breast cancer-related, treatment-related, and sociodemographic factors and use of antidepressants were evaluated in multivariate Cox proportional hazard models separated on use of antidepressants before diagnosis of breast cancer. Results. The mean follow-up for the 4 150 women in the study was 3.3 years (5–95% range, 0.3–7.0 years) and 1 020 (25%) were users of antidepressants after diagnosis of breast cancer. Among women who had not used antidepressants before their breast cancer, the diagnosis of a new primary cancer increased the adjusted hazard ratio (HR) to 3.34 (95% CI, 1.50–7.76), and recurrence of breast cancer increased the HR for first use of antidepressants to 2.56 (95% CI, 1.86–3.52). Unemployment was associated significantly with use of antidepressants, whereas having no children living at home, lower income, and the number of tumor-positive axillary lymph nodes were of borderline significance. No effect of the rehabilitation program was observed on first use of antidepressants after breast cancer. Discussion. Diagnosis of a new cancer or recurrence of breast cancer considerably increased the rate of use of antidepressants. Sociodemographic rather than disease- or treatment-related characteristics at the time of diagnosis were associated with first use of antidepressants after a breast cancer diagnosis.

Abstract PD06-06: Novel Surgical Technique To Assess the Response of Metastatic Axillary Lymph Nodes to Neoadjuvant Chemotherapy in Breast Cancer Patients

Abstract Background: An important benefit of neoadjuvant chemotherapy (NAC) is the increase in breast-conserving surgery. At present the response of axillary lymph node metastases to chemotherapy is not assessed accurately, since SN biopsy either before or after NAC will not provide an accurate answer. Therefore a reliable axilla-conserving therapy is not yet a benefit. We developed a new surgical technique to evaluate the axillary nodal response by Marking of the Axillary lymph node with Radioactive Iodine seeds (= the MARI procedure) Method: Prior to NAC, tumor positive axillary lymph nodes were marked with a Iodine-125 seed under ultrasound guidance (the MARI node). After NAC, the marked lymph node was selectively removed with the use of a gamma-detection probe. A complementary axillary lymph node dissection was performed to assess whether the pathological response in the marked node was indicative for the pathological response in the additional lymph nodes. Results: In 44 patients who were scheduled for NAC the MARI procedure was attempted. In 42 patients the tumor-positive axillary lymph node was successfully marked with a radioactive Iodine-125 seed. Two patients appeared to have overt distant metastasis and did not undergo complete axillary dissection. Thus, in 40 patients the MARI node was selectively removed after NAC. In all these patients a complementary axillary lymph node dissection was performed. In 24 patients the MARI node contained a macrometastasis after NAC. In 4 patients only isolated tumor cells (ITC) were present in the MARI node. In 24 of these 28 patients further nodal involvement was found. More importantly: in 12 patients (=30%) no residual tumor was present in the MARI node (pathological complete response= pCR) and 10 of them also showed a pCR in the complementary axillary lymph node dissection. In one patient a macrometastasis, and in one, ITC were found in one of the additional nodes. Conclusion: In this study we present the first results of a new surgical technique to assess the response of metastatic lymph nodes in the context of NAC for breast cancer; the MARI procedure. We conclude that marking tumor-positive lymph nodes before NAC and selectively removing them after NAC is feasible. Moreover we report that this MARI node is indicative for the response to NAC in the other axillary nodes: in 30% of the treated patients an axillary pCR was found which was correctly indicated by a negative MARI node in all but one patient. Thus the MARI procedure will enable us to select patients in which axillary lymph node dissection can be avoided after NAC. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD06-06.

Factors associated with the prescription of antidepressive medication in breast cancer patients: A rehabilitation perspective.

e19646 Background: This study evaluated factors associated with use of antidepressant medication (AD) subsequent to a diagnosis of breast cancer (BC). Further, we evaluated the effect of participation in a cancer rehabilitation program on use of AD. Methods: A register-based cohort study included 1,247 women diagnosed with BC from 1998 until 2006 and who attended a week-long rehabilitation program as well as a matched comparison group of 2,903 women who did not attend the program. The associations between BC-related, treatment related and socio-demographic factors with use of AD were evaluated in multivariate Cox proportional hazard models separated on use of AD prior to diagnosis of BC. Results: In women who were not users of AD prior to BC, a relapse increased the hazard ratio (HR) of first use of AD to 2.53 (95% CI, 1.16-2.09) whereas a diagnosis of a new primary cancer increased the HR to 3.36 (95% CI 1.48 to 7.65). Further, number of tumor-positive axillary lymph nodes and unemployment was associated with significantly increased HRs for use of AD, whereas having children living at home, education and income was borderline associated with AD use. No effect of the rehabilitation program was observed on first use of AD after BC. Conclusions: Sociodemographic rather than disease and treatment characteristics at time of diagnosis were associated with first time use of AD following a breast cancer. No significant financial relationships to disclose.

Marking the axilla with radioactive iodine seeds (MARI procedure) may reduce the need for axillary dissection after neoadjuvant chemotherapy for breast cancer

An important benefit of neoadjuvant chemotherapy is the increased potential for breast-conserving surgery. At present the response of axillary lymph node metastases to chemotherapy is not easily assessed, rendering axilla-conserving treatment difficult. The aim was to assess a new surgical method for evaluating the axillary response to chemotherapy. Before neoadjuvant chemotherapy, proven tumour-positive axillary lymph nodes were localized using ultrasound-guided insertion of iodine-125-labelled (I-125) seeds. After neoadjuvant chemotherapy, the marked lymph nodes were removed selectively with the use of a gamma probe. A complete axillary lymph node clearance was carried out to determine whether the pathological response in the marked node was indicative of that in the other lymph nodes. Tumour-positive axillary lymph nodes were localized successfully with I-125 seeds in 15 patients. The marked lymph node was detected and removed selectively after neoadjuvant chemotherapy in all patients. The pathological response to chemotherapy in the marked lymph node was indicative of the overall response in other removed lymph nodes. This study showed that marking and selectively removing metastatic lymph nodes after neoadjuvant chemotherapy was feasible. The tumour response in the marked lymph node may be used to tailor further axillary treatment, making axilla-conserving surgery a possibility.

Discordance of Intraoperative Frozen Section Analysis with Definitive Histology of Sentinel Lymph Nodes in Breast Cancer Surgery: Complementary Axillary Lymph Node Dissection is Irrelevant for Subsequent Systemic Therapy

BackgroundIn breast cancer surgery, intraoperative frozen section (FS) analysis of sentinel lymph nodes (SLNs) enables axillary lymph node dissection (ALND) during the same operative procedure. In case of discordance between a “negative” FS analysis and definitive histology, an ALND as a second operation is advocated since additional lymph node metastases may be present. The clinical implications of the subsequent ALND in these patients were evaluated.Materials and MethodsBetween November 2000 and May 2008, 879 consecutive breast cancer patients underwent surgery including sentinel lymph node biopsy (SLNB) with intraoperative FS analysis of 2 central cuts from axillary SLNs. Following fixation and serial sectioning, SLNs were further examined postoperatively with hematoxylin and eosin (H&E) and immunohistochemical techniques. For patients with a discordant FS examination, the effect of the pathology findings of the subsequent ALND specimen on subsequent nonsurgical therapy were evaluated.ResultsFS analysis detected axillary metastases in the SLN(s) in 200 patients (23%), while the definitive pathology examination detected metastases in SLNs in another 151 patients (17%). A complementary ALND was performed in 108 of the 151 patients with discordant FS. Additional tumor positive axillary lymph nodes were found in 17 patients (16%), leading to “upstaging” in 7 (6%). Subsequent nonsurgical treatment was adjusted in 4 patients (4%): all 4 had more extensive locoregional radiotherapy; no patient received additional hormonal and/or chemotherapy.ConclusionDiscordance between intraoperative FS analysis and definitive histology of SLNs is common. In this selection of patients, a substantial proportion had additional lymph node metastases, but postsurgical treatment was rarely adjusted based on the findings of the complementary ALND.

High-dose sequential chemotherapy (HDSC) with peripheral blood progenitor cells (PBPC) support for high-risk breast cancer (BC)

11026 Background: Recent reports suggest that intensified adjuvant chemotherapy with stem cell support improve disease free (DFS) and overall survival (OS) in subgroups of patients with high risk BC. We retrospectively analyzed the efficacy, safety and feasibility of a program of HDSC with PBPC support (according to the Milan protocol, ASCO 2001) in patients with BC at high risk of recurrence Methods: Between February 1995 and January 2001, 201 non-consecutive patients with more than 3 positive axillary nodes at surgery, median age 46 (range 27–62), has been evaluated. Median number of involved nodes was 15 (range 3–48), 38% and 49% pts had ER and PgR negative tumors, respectively. Fourty-sevent percent of pts had tumors with a high proliferative activity. HDSC consisted of sequential administration of cyclosphosphamide 7 g/m2 (day 0) plus filgrastim 5 μg/kg s.c. daily and stem cell collection, methotrexate 8 g/m2 plus vincristine 2 mg/m2 (day +16), and two consecutive courses of epidoxorubicin 120 mg/m2 (days +23 and + 38) plus filgrastim 5 μg/kg s.c. daily. Myeloablative therapy (day +58) consisted of thiotepa 600 mg/m2 and melphalan 160 mg/m2 plus PBPCs and filgrastim 5 μg/kg s.c. daily. Results: Three pts discontinued the program permanently because of toxicity. A median of 9,35x106/kg (range 3.35–35.62) CD34+ cells was infused. Engraftment for neutrophils (&gt; 500/μl) and platelets (&gt; 20.000/μl) was observed a median of 9 days (range 7–17) and 10 days (range 7–18) after PBPC infusion, respectively. No treatment-related deaths were recorded. After a median follow-up of 79 months, 108 (54%) pts are disease- free. Ninety-three patients experienced disease recurrence [9/93 (10%) pts had loco regional disease recurrence and 84/93 (90%) pts distant recurrence], of whom 58/93 (63%) have died. Five-year DFS and OS from the start of treatment are 55% and 71%, respectively. No poor marrow function, myelodysplastic syndrome or secondary tumors were observed. In 2-sided log-rank tests, hormone-receptor status and the number of tumor-positive axillary lymph nodes were significant prognostic factors for DFS. Conclusions: Our results confirm that HDSC is a safe procedure and is associated with favorable outcome in patients with high-risk BC. No significant financial relationships to disclose.

Ultrasonography and Fine-Needle Aspiration Cytology Can Spare Breast Cancer Patients Unnecessary Sentinel Lymph Node Biopsy

Some 30% to 40% of the breast cancer patients scheduled for sentinel node biopsy have axillary metastasis. Pilot studies suggest that ultrasonography is useful in the preoperative detection of such nodes. The aims of this study were to evaluate the sensitivity of preoperative ultrasonography and fine-needle aspiration cytology for detecting axillary metastases and to assess how often sentinel node biopsy could be avoided. Between October 1999 and December 2003, 726 patients with clinically negative lymph nodes were eligible for sentinel node biopsy. A total of 732 axillae were examined. Preoperative ultrasonography with subsequent fine-needle aspiration cytology in case of suspicious lymph nodes was performed in all patients. The sentinel node procedure was omitted in patients with tumor-positive axillary lymph nodes in lieu of axillary lymph node dissection. Ultrasound and fine-needle aspiration cytology established axillary metastases in 58 (8%) of the 726 patients. These 58 were 21% of the total of 271 patients who were proven to have axillary metastasis in the end. Of the patients with ultrasonographically suspicious lymph nodes and negative cytology, 31% had tumor-positive sentinel nodes. Patients with preoperatively established metastases by ultrasonography and fine-needle aspiration cytology had more tumor-positive lymph nodes (P < .001) than patients with metastases established later on. The sensitivity of ultrasonography and fine-needle aspiration cytology is 21%, and unnecessary sentinel node biopsy is avoided in 8% of the patients. This approach improves the selection of patients eligible for sentinel node biopsy.

Efficacy of high-dose alkylating chemotherapy in the adjuvant treatment of HER2/neu-negative primary breast cancer: update of the Dutch randomized trial

The role of high-dose chemotherapy in the adjuvant treatment of high-dose breast cancer has not been established. Results have been reported from six randomized studies with a symmetrical study design (Table ​(Table1).1). All show a lower relapse rate in the high-dose arm, but in only one study was this result statistically significant. Table 1 Randomized studies evaluating the role of high-dose chemotherapy in high-risk breast cancer Methods Patients below 56 years of age who had undergone surgery for stage II or III breast cancer were eligible if they had at least four tumor-positive axillary lymph nodes. Patients in the conventional dose (CD) arm received five courses of FEC (fluorouracil 500 mg/m2, epirubicin 90 mg/m2 and cyclophosphamide 500 mg/m2; every 3 weeks) followed by radiation therapy and tamoxifen. The high-dose (HD) arm was identical, except that high-dose chemotherapy (CTC [cyclophosphamide 6 g/m2, thiotepa 480 mg/m2 and carboplatin 1600 mg/m2]) with peripheral blood progenitor cell reinfusion was given instead of the fifth FEC course.

Randomized trial of high-dose chemotherapy and hematopoietic progenitor-cell support in operable breast cancer with extensive lymph node involvement: final analysis with 7 years of follow-up

BackgroundThe aim of this study was to present an update of overall (OS) and disease-free survival (DFS) and to evaluate the correlation between outcome and pathological findings at surgery in a randomized trial of high-dose chemotherapy following neoadjuvant chemotherapy and surgery in high-risk breast cancer patients. Patients and methodsNinety-seven women <60 years of age with breast cancer and extensive axillary lymph node involvement received three courses of FE120C (5-fluorouracil 500 mg/m2, epirubicin 120 mg/m2, cyclophosphamide 500 mg/m2) followed by surgery. Eighty-one patients were randomized to receive either a fourth FE120C course alone or a fourth FE120C course followed by high-dose chemotherapy (cyclophosphamide 6 g/m2, thiotepa 480 mg/m2, carboplatin 1600 mg/m2). We performed a univariate analysis on possible prognostic factors and analyzed the sites of relapse. ResultsAfter a median follow-up of 6.9 years, 47 (48%) patients were alive, of whom 36 (38%) were without disease. Sixty patients relapsed after treatment. One patient died of myelodysplastic syndrome, without a relapse. In intention-to-treat analysis, the 5-year DFS rates were 47.5% in the conventional treatment arm and 49% in the high-dose arm, and the 5-year OS rates were 62.5% and 61%, respectively. In the univariate analysis, the clinical T-stage before chemotherapy and the number of tumor-positive axillary lymph nodes after induction chemotherapy (P = 0.027) were significant prognostic factors for OS. The same factors (both P = 0.06) plus the estrogen receptor (P = 0.08) were borderline significant factors for DFS. ConclusionsAfter a median follow-up of 6.9 years there was no difference in OS or DFS rates between the two treatment groups. The number of tumor-positive axillary lymph nodes after induction chemotherapy and the clinical T-stage before chemotherapy were significant factors for OS.

Acute and Late Toxicity Following Adjuvant High-Dose Chemotherapy for High-Risk Primary Operable Breast Cancer A Quality Assessment Study

From 1996 to 2000, high-dose chemotherapy with haematopoietic stem-cell support was used as an adjuvant treatment strategy for management of primary high-risk breast cancer patients with more than five positive nodes. This single institution study included 52 women aged h 56 years with primary operable breast cancer and S 6 tumour-positive axillary lymph nodes. The treatment regimen consisted of at least three initial courses of FEC (5-fluorouracil, epirubicin, cyclophosphamide) followed by high-dose chemotherapy (cyclophosphamide, thiotepa, carboplatin) supported by autologous peripheral blood stem-cell reinfusion. This study focuses on quality control including evaluation of toxicity, supportive therapy and assessment of the stem-cell products. Cytokeratin 19 positive cells were found in the stem-cell product from 3/37 patients. Data regarding organ toxicity were used for evaluation of short- and long-term side effects. Substantial acute toxicity and frequent catheter-related infections were found. Long-term toxicities included reduced lung diffusion capacity (n=36), fatigue (n=14), arthralgia/myalgia (n=10), neurotoxicity (n=9) and memory loss (n=4). However, most toxicities were grade 1-2 and reversible within two years. No treatment-related death occurred. Within a median follow-up of 30 months (range, 11-57), 25% of the patients had relapsed. Recurrence-free survival was 75% and overall survival was 88% three years after the start of treatment. Overall, high-dose chemotherapy was relatively well tolerated, with manageable toxicity and an acceptable requirement of supportive therapy. Until now, high-dose chemotherapy has not proven superior to conventional-dose adjuvant chemotherapy, therefore it is necessary in the future to focus on well-designed randomized studies.

Stage III and oestrogen receptor negativity are associated with poor prognosis after adjuvant high-dose therapy in high-risk breast cancer.

We report on the efficacy and toxicity of a sequential high-dose therapy with peripheral blood stem cell (PBSC) support in 85 patients with high-risk stage II/III breast cancer. There were 71 patients with more than nine tumour-positive axillary lymph nodes. An induction therapy of two cycles of ifosfamide (total dose, 7.5 g m−2) and epirubicin (120 mg m−2) was given, and PBSC were harvested during G-CSF-supported leucocyte recovery following the second cycle. The PBSC-supported high-dose chemotherapy consisted of two cycles of ifosfamide (total dose, 12 000 mg m−2), carboplatin (900 mg m−2) and epirubicin (180 mg m−2). Patients were autografted with a median number of 3.7 × 106 CD34+ cells kg−1 (range, 1.9–26.5 × 106) resulting in haematological reconstitution within approximately 2 weeks following high-dose therapy. The toxicity was moderate in general, and there was no treatment-related toxic death. Twenty-one patients relapsed between 3 and 30 months following the last cycle of high-dose therapy (median, 11 months). The probability of disease-free and overall survival at 4 years were 60% and 83%, respectively. According to a multivariate analysis, patients with stage II disease had a significantly better probability of disease-free survival (74%) in comparison to patients with stage III disease (36%). The probability of disease-free survival was also significantly better for patients with oestrogen receptor-positive tumours (70%) compared to patients with receptor-negative ones (40%). Bone marrow samples collected from 52 patients after high-dose therapy were examined to evaluate the prognostic relevance of isolated tumour cells. The proportion of patients presenting with tumour cell-positive samples did not change in comparison to that observed before high-dose therapy (65% vs 71%), but a decrease in the incidence and concentration of tumour cells was observed over time after high-dose therapy. This finding was true for patients with relapse and for those in remission, which argues against a prognostic significance of isolated tumour cells in bone marrow. In conclusion, sequential high-dose chemotherapy with PBSC support can be safely administered to patients with high-risk stage II/III breast cancer. Further intensification of the therapy, including the addition of non-cross resistant drugs or immunological approaches such as the use of antibodies against HER-2/NEU, may be envisaged for patients with stage III disease and hormone receptor-negative tumours. © 1999 Cancer Research Campaign