Occult breast cancer presenting as axillary lymph node metastases: a single-institution experience with a challenging diagnostic and therapeutic dilemma

Background: Occult breast cancer with axillary lymph node metastases but without evidence of primary tumor on clinical examination and conventional imaging is a rare but serious scenario. Due to diagnostic difficulties and prognostic uncertainties, evidence to guide the management of such patients is lacking. Here, we review the cases of occult breast cancer treated at our institution and discuss recent advances in its management. Methods: We searched our database for patients with occult breast cancer operated on between 2002 and 2011. The following data were extracted: clinical presentation; diagnostic work-up; surgical treatment; adjuvant management; and duration of follow-up. Results: Out of 1405 patients operated on for breast cancer, 7 (0.5%) had occult breast cancer. The mean age at diagnosis was 60.5 years. Six patients were postmenopausal. All patients had one or more metastatic axillary lymph nodes but no signs of malignancy at either conventional imaging (mammography and ultrasonography) or clinical examination. Magnetic resonance imaging revealed the primary breast tumor in 1 patient. Histopathology showed positive estrogen receptors in 3 patients. After preoperative staging, neoadjuvant chemotherapy and subsequent mastectomy was performed in 1 patient with N3 disease, primary surgical treatment in 5 patients (4 mastectomies, 1 breast-conserving procedure), and chemotherapy alone in 1 patient. Postoperative management included chemotherapy in 5 patients, endocrine therapy in 2, and radiation therapy in 5. An infiltrating carcinoma was found in 5 mastectomy specimens (4 ductal histotype and 1 lobular histotype). The mean tumor size was 11 mm (range, 7-17). At a mean follow-up of 51 months, 6 patients were disease-free, and 1 patient died of pulmonary embolism. Conclusions: Occult breast cancer poses difficult management issues, especially when estrogen receptor status is negative. No consensus exists on the need for breast surgery in such patients, as recent literature suggests that breast irradiation might be an alternative treatment. Management decisions should be taken on an individual basis with a multidisciplinary approach. Considering the results of this series, we believe that breast surgery should be proposed to patients with occult breast cancer.</br

Fluorouracil and dose-dense adjuvant chemotherapy in patients with early-stage breast cancer (GIM2): end-of-study results from a randomised, phase 3 trial

Background Previous analyses of the GIM (Gruppo Italiano Mammella) 2 study showed that addition of fluorouracil to epirubicin, cyclophosphamide, and paclitaxel in patients with node-positive early breast cancer does not improve outcome, whereas dose-dense chemotherapy induces a significant improvement in both disease-free survival and overall survival as compared with a standard schedule. Here, we present long-term results of the study.Methods In this 2 x 2 factorial, open-label, randomised, phase 3 trial, we enrolled patients aged 18-70 years with operable, node-positive, breast cancer with Eastern Cooperative Oncology Group performance status of 0-1 from 81 hospitals in Italy. Eligible patients were randomly allocated (1:1:1:1) to one of the four following study groups: four cycles of standard-interval intravenous EC (epirubicin 90 mg/m(2) and cyclophosphamide 600 mg/m(2)) on day 1 every 3 weeks, followed by four cycles of intravenous paclitaxel (175 mg/m(2)) on day 1 every 3 weeks (q3EC-P group); four cycles of intravenous FEC (fluorouracil 600 mg/m(2), epirubicin 90 mg/m(2), and cyclophosphamide 600 mg/m(2)) on day 1 every 3 weeks, followed by four cycles of intravenous paclitaxel (175 mg/m(2)) on day 1 every 3 weeks (q3FEC-P group); dose-dense EC-P regimen, with the same doses and drugs as the q3EC-P group but administered every 2 weeks (q2EC-P group); and the dose-dense FEC-P regimen, with the same doses and drugs as the q3FEC-P group but given every 2 weeks (q2FEC-P). Randomisation, with stratification by centre, with permuted blocks of size 12, was done with a centralised, interactive, internet-based system that randomly generated the treatment allocation. The primary endpoint was disease-free survival in the intentionto-treat population, comparing different chemotherapy schedule (dose-dense vs standard-dose intervals) and regimen (FEC-P vs EC-P). Safety population included all patients that received at least one dose of any study drug according to the treatment received. This trial is registered with ClinicalTrials.gov, NCT00433420, and is now closed.Findings Between April 24, 2003, and July 3, 2006, 2091 patients were randomly assigned to treatment: 545 to q3EC-P, 544 to q3FEC- P, 502 to q2EC-P, and 500 to q2FEC-P. 88 patients were enrolled in centres providing only standard interval schedule and were assigned only to q3FEC-P and q3EC-P; thus, 2091 patients were included in the intention-to-treat analysis for the comparison of EC-P (1047 patients) versus FEC-P (1044 patients) and 2003 patients were included in the intention-to-treat analysis for the comparison of dose-dense (1002 patients) versus standard interval analysis (1001 patients). After a median follow-up of 15 center dot 1 years (IQR 8 center dot 4-16 center dot 3), median diseasefree survival was not significantly different between FEC-P and EC-P groups (17 center dot 09 years [95% CI 15 center dot 51-not reached] vs not reached [17 center dot 54-not reached]; unadjusted hazard ratio 1 center dot 12 [95% CI 0 center dot 98-1 center dot 29]; log-rank p=0 center dot 11). Median disease-free survival was significantly higher in the dose-dense interval group than the standard-interval group (not reached [95% CI 17 center dot 45-not reached] vs 16 center dot 52 [14 center dot 24-17 center dot 54]; 0 center dot 77 [95% CI 0 center dot 67-0 center dot 89]; p=0 center dot 0004). The most common grade 3-4 adverse events were neutropenia (200 [37%] of 536 patients in the q3EC-P group vs 257 [48%] of 533 in the q3FEC-P group vs 50 [10%] of 496 q2EC-P vs 97 [20%] of 492) and alopecia (238 [44%] vs 249 [47%] vs 228 [46%] vs 235 [ 48%]). During extended follow-up, no further grade 3-4 adverse events or deaths related to toxic-effects were reported. Treatment-related serious adverse events were reported in nine (2%) patients in the q3EC-P group, seven (1%) in the q3FEC-P group, nine (2%) in the q2EC-P group, and nine (2%) in the q2FEC-P group. No treatment-related deaths occurred.Interpretation Updated results from the GIM2 study support that optimal adjuvant chemotherapy for patients with high-risk early breast cancer should not include fluorouracil and should use a dose-dense schedule.Copyright (c) 2022 Published by Elsevier Ltd. All rights reserved

Adjuvant anastrozole versus exemestane versus letrozole, upfront or after 2 years of tamoxifen, in endocrine-sensitive breast cancer (FATA-GIM3): a randomised, phase 3 trial

Background: Uncertainty exists about the optimal schedule of adjuvant treatment of breast cancer with aromatase inhibitors and, to our knowledge, no trial has directly compared the three aromatase inhibitors anastrozole, exemestane, and letrozole. We investigated the schedule and type of aromatase inhibitors to be used as adjuvant treatment for hormone receptor-positive early breast cancer. Methods: FATA-GIM3 is a multicentre, open-label, randomised, phase 3 trial of six different treatments in postmenopausal women with hormone receptor-positive early breast cancer. Eligible patients had histologically confirmed invasive hormone receptor-positive breast cancer that had been completely removed by surgery, any pathological tumour size, and axillary nodal status. Key exclusion criteria were hormone replacement therapy, recurrent or metastatic disease, previous treatment with tamoxifen, and another malignancy in the previous 10 years. Patients were randomly assigned in an equal ratio to one of six treatment groups: oral anastrozole (1 mg per day), exemestane (25 mg per day), or letrozole (2·5 mg per day) tablets upfront for 5 years (upfront strategy) or oral tamoxifen (20 mg per day) for 2 years followed by oral administration of one of the three aromatase inhibitors for 3 years (switch strategy). Randomisation was done by a computerised minimisation procedure stratified for oestrogen receptor, progesterone receptor, and HER2 status; previous chemotherapy; and pathological nodal status. Neither the patients nor the physicians were masked to treatment allocation. The primary endpoint was disease-free survival. The minimum cutoff to declare superiority of the upfront strategy over the switch strategy was assumed to be a 2% difference in disease-free survival at 5 years. Primary efficacy analyses were done by intention to treat; safety analyses included all patients for whom at least one safety case report form had been completed. Follow-up is ongoing. This trial is registered with the European Clinical Trials Database, number 2006-004018-42, and ClinicalTrials.gov, number NCT00541086. Findings: Between March 9, 2007, and July 31, 2012, 3697 patients were enrolled into the study. After a median follow-up of 60 months (IQR 46–72), 401 disease-free survival events were reported, including 211 (11%) of 1850 patients allocated to the switch strategy and 190 (10%) of 1847 patients allocated to upfront treatment. 5-year disease-free survival was 88·5% (95% CI 86·7–90·0) with the switch strategy and 89·8% (88·2–91·2) with upfront treatment (hazard ratio 0·89, 95% CI 0·73–1·08; p=0·23). 5-year disease-free survival was 90·0% (95% CI 87·9–91·7) with anastrozole (124 events), 88·0% (85·8–89·9) with exemestane (148 events), and 89·4% (87·3 to 91·1) with letrozole (129 events; p=0·24). No unexpected serious adverse reactions or treatment-related deaths occurred. Musculoskeletal side-effects were the most frequent grade 3–4 events, reported in 130 (7%) of 1761 patients who received the switch strategy and 128 (7%) of 1766 patients who received upfront treatment. Grade 1 musculoskeletal events were more frequent with the upfront schedule than with the switch schedule (924 [52%] of 1766 patients vs 745 [42%] of 1761 patients). All other grade 3–4 adverse events occurred in less than 2% of patients in either group. Interpretation: 5 years of treatment with aromatase inhibitors was not superior to 2 years of tamoxifen followed by 3 years of aromatase inhibitors. None of the three aromatase inhibitors was superior to the others in terms of efficacy. Therefore, patient preference, tolerability, and financial constraints should be considered when deciding the optimal treatment approach in this setting. Funding: Italian Drug Agency