OBJECTIVE:The MARI procedure marking the axillary lymph node with radioactive iodine (I) seeds is a new minimal invasive method to assess the pathological response of nodal metastases after ...neoadjuvant systemic treatment (NST) in patients with breast cancer. This method allows axilla-conserving surgery in patients responding well to NST.
METHODS:Prior to NST, proven tumor-positive axillary lymph nodes were marked with a I seed. This marked lymph node is the so-called MARI-node. After NST, the MARI node was selectively removed using a γ-detection probe. A complementary axillary lymph node dissection was performed in all patients to assess whether pathological response in the MARI node was indicative for the pathological response in the additional lymph nodes.
RESULTS:A tumor-positive axillary lymph node was marked with a I seed in 100 patients. The MARI node was successfully identified in 97 of these 100 patients (identification rate 97%). Two patients did not undergo subsequent axillary lymph node dissection, leaving 95 patients for further analysis. The MARI node contained residual tumor cells in 65 of these 95 patients. In the other 30 patients, the MARI node was free of tumor, but additional positive lymph nodes were found in 5 patients. Thus, the MARI procedure correctly identified 65 of 70 patients with residual axillary tumor activity (false negative rate 5/70 = 7%).
CONCLUSIONS:This study shows that marking and selectively removing metastatic lymph nodes after neoadjuvant systemic treatment has a high identification rate and a low false negative rate. The tumor response in the marked lymph node may be used to tailor further axillary treatment after NST.
Background
The added value of surgery in breast cancer patients with pathological complete response (pCR) after neoadjuvant systemic therapy (NST) is uncertain. The accuracy of imaging identifying ...pCR for omission of surgery, however, is insufficient. We investigated the accuracy of ultrasound-guided biopsies identifying breast pCR (ypT0) after NST in patients with radiological partial (rPR) or complete response (rCR) on MRI.
Methods
We performed a multicenter, prospective single-arm study in three Dutch hospitals. Patients with T1–4(N0 or N +) breast cancer with MRI rPR and enhancement ≤ 2.0 cm or MRI rCR after NST were enrolled. Eight ultrasound-guided 14-G core biopsies were obtained in the operating room before surgery close to the marker placed centrally in the tumor area at diagnosis (no attempt was made to remove the marker), and compared with the surgical specimen of the breast. Primary outcome was the false-negative rate (FNR).
Results
Between April 2016 and June 2019, 202 patients fulfilled eligibility criteria. Pre-surgical biopsies were obtained in 167 patients, of whom 136 had rCR and 31 had rPR on MRI. Forty-three (26%) tumors were hormone receptor (HR)-positive/HER2-negative, 64 (38%) were HER2-positive, and 60 (36%) were triple-negative. Eighty-nine patients had pCR (53%; 95% CI 45–61) and 78 had residual disease. Biopsies were false-negative in 29 (37%; 95% CI 27–49) of 78 patients. The multivariable associated with false-negative biopsies was rCR (FNR 47%; OR 9.81, 95% CI 1.72–55.89;
p
= 0.01); a trend was observed for HR-negative tumors (FNR 71% in HER2-positive and 55% in triple-negative tumors; OR 4.55, 95% CI 0.95–21.73;
p
= 0.058) and smaller pathological lesions (6 mm vs 15 mm; OR 0.93, 95% CI 0.87–1.00;
p
= 0.051).
Conclusion
The MICRA trial showed that ultrasound-guided core biopsies are not accurate enough to identify breast pCR in patients with good response on MRI after NST. Therefore, breast surgery cannot safely be omitted relying on the results of core biopsies in these patients.
The 70-gene signature (MammaPrint™) is a prognostic tool used to guide adjuvant treatment decisions. The aim of this study was to assess its value to predict chemosensitivity in the neoadjuvant ...setting. We obtained the 70-gene profile of stage II-III patients prior to neoadjuvant chemotherapy and classified the prognosis-signatures. Pathological complete remission (pCR) was used to measure chemosensitivity. Among 167 patients, 144 (86%) were having a poor and 23 (14%) a good prognosis-signature. None of the good prognosis-signature patients achieved a pCR (0/23), whereas 29/144 patients (20%) in the poor prognosis-signature group did (P = 0.015). All triple-negative tumors (n = 38) had a poor prognosis-signature. Within the non triple-negative subgroup, the response of the primary tumor remained associated with the classification of the prognosis-signature (P = 0.023). A pCR is unlikely to be achieved in tumors that have a good prognosis-signature. Tumors with a poor prognosis-signature are more sensitive to chemotherapy.
To evaluate the relevance of breast cancer subtypes for magnetic resonance imaging (MRI) markers for monitoring of therapy response during neoadjuvant chemotherapy (NAC).
MRI examinations were ...performed in 188 women before and during NAC. MRI interpretation included lesion morphology at baseline, changes in morphology, size, and contrast uptake kinetics (initial and late enhancement). By using immunohistochemistry, tumors were divided into three subtypes: triple negative, human epidermal growth factor receptor 2 (HER2) positive, and estrogen receptor (ER) positive/HER2 negative. Tumor response was assessed dichotomously (ie, presence or absence of residual tumor in the surgical specimen). Complementary, a continuous scale assessment was used (the breast response index BRI, representing the relative change in tumor stage). Multivariate regression analysis and receiver operating characteristic analysis were employed to establish significant associations.
Residual tumor at pathology was present in 31 (66%) of 47 triple-negative tumors, 23 (61%) of 38 HER2-positive tumors, and 96 (93%) of 103 ER-positive/HER2-negative tumors. Multivariate analysis of residual disease showed significant associations between breast cancer subtype and MRI (area under the curve AUC, 0.84; P < .001). BRI also showed significant correlation among breast cancer subtype, MRI, and age (Pearson's r = 0.465; P < .001). In subset analysis, this was only significant for triple-negative tumors (P < .001) and HER2-positive tumors (P < .05). Residual tumor after NAC in the triple-negative and HER2-positive group is significantly associated with the change in largest diameter of late enhancement during NAC (AUC, 0.76; P < .001). No associations were found for ER-positive/HER2-negative tumors.
MRI during NAC to monitor response is effective in triple-negative or HER2-positive disease but is inaccurate in ER-positive/HER2-negative breast cancer.
The optimal chemotherapy backbone for dual HER2 blockade in the neoadjuvant setting for early breast cancer is unknown. We investigated whether the addition of anthracyclines would improve ...pathological complete response compared with a carboplatin–taxane regimen, when given in combination with the HER2-targeted agents trastuzumab and pertuzumab.
The TRAIN-2 study is an open-label, randomised, controlled, phase 3 trial being done in 37 hospitals in the Netherlands. We recruited patients aged 18 years or older with previously untreated, histologically confirmed stage II–III HER2-positive breast cancer. Patients were randomly allocated using central randomisation software (1:1 ratio) with minimisation without a random component, stratified by tumour stage, nodal stage, oestrogen receptor status, and age, to receive 5-fluorouracil (500 mg/m2), epirubicin (90 mg/m2), and cyclophosphamide (500 mg/m2) every 3 weeks for three cycles followed by paclitaxel (80 mg/m2 on days 1 and 8) and carboplatin (area under the concentration–time curve AUC 6 mg/mL per min on day 1 or optionally, as per hospital preference, AUC 3 mg/mL per min on days 1 and 8) every 3 weeks for six cycles, or to receive nine cycles of paclitaxel and carboplatin at the same dose and schedule as in the anthracycline group. Patients in both study groups received trastuzumab (6 mg/kg, loading dose 8 mg/kg) and pertuzumab (420 mg, loading dose 840 mg) concurrently with all chemotherapy cycles. The primary endpoint was the proportion of patients who achieved a pathological complete response in breast and axilla (ypT0/is ypN0) in the intention-to-treat population. Safety was analysed in patients who received at least one treatment cycle according to actual treatment received. This trial is registered with ClinicalTrials.gov, number NCT01996267, and follow-up for long-term outcome is ongoing.
Between Dec 9, 2013, and Jan 14, 2016, 438 patients were enrolled and randomly assigned to the two treatment groups (219 patients to each group), of whom 418 were evaluable for the primary endpoint (212 in the anthracycline group and 206 in the non-anthracycline group). The median follow-up for all patients was 19 months (IQR 16–23 months). A pathological complete response was recorded in 141 (67%, 95% CI 60–73) of 212 patients in the anthracycline group and in 140 (68%, 61–74) of 206 in the non-anthracycline group (p=0·95). One patient randomly allocated to the non-anthracycline group did receive anthracyclines and was thus included in the anthracycline group for safety analyses; therefore, for the safety analyses there were 220 patients in the anthracycline group and 218 in the non-anthracycline group. Serious adverse events were reported in 61 (28%) of 220 patients in the anthracycline group and in 49 (22%) of 218 in the non-anthracycline group. The most common adverse events of any cause were grade 3 or worse neutropenia (in 131 60% of 220 patients in the anthracycline group vs 118 54% of 218 in the non-anthracycline group), grade 3 or worse diarrhoea (26 12% vs 37 18%), and grade 2 or worse peripheral neuropathy (66 30% vs 68 31%), with no substantial differences between the groups. Grade 3 or worse febrile neutropenia was more common in the anthracycline group than in the non-anthracycline group (23 10% vs three 1%, p<0·0001). Symptomatic left ventricular systolic dysfunction was rare in both groups (two 1% of 220 vs 0 of 218). One patient in the anthracycline group died because of a pulmonary embolism, which was possibly treatment related.
In view of the high proportion of pathological complete responses recorded in both groups and the fact that febrile neutropenia was more frequent in the anthracycline group, omitting anthracyclines from neoadjuvant treatment regimens might be a preferred approach in the presence of dual HER2 blockade in patients with early HER2-positive breast cancer. Long-term follow-up is required to confirm these results.
Roche Netherlands.
With current advances in neoadjuvant systemic therapy (NST) and improved breast imaging, the potential of nonoperative therapy for invasive breast cancer has emerged as a viable option when utilizing ...meticulous image-guided percutaneous biopsy to document pathologic complete response. Feasibility clinical trials utilizing this approach are being performed by teams of investigators from single and multicenter/cooperative groups around the world. Imaging alone after NST lacks sufficient sensitivity and specificity in predicting pCR and therefore cannot be utilized for clinical selection of patients for omission of surgery. Imaging with adequate sampling after NST of the residual lesions (or around the remaining clip if a complete radiologic response occurs) appears to be essential in selecting patients with pCR to lower the false-negative rates based on initial reported feasibility studies to identify pCR without surgery that range from 5 to 49%. In this manuscript, recently completed, ongoing, and planned clinical feasibility trials and a new omission of surgery trial are described. Drastic rethinking of all diagnostic and therapeutic management strategies that are ordinarily utilized for patients who receive standard breast cancer surgery is required. A roadmap of essential questions and issues that will have to be resolved as the field of nonoperative breast cancer management advances is described in detail.
Invasive lobular carcinoma (ILC) has been reported to be less responsive to neoadjuvant chemotherapy (NAC) than invasive ductal carcinoma (IDC). We sought to determine whether ILC histology indeed ...predicts poor response to NAC by analyzing tumor characteristics such as protein expression, gene expression, and imaging features, and by comparing NAC response rates to those seen in IDC after adjustment for these factors. We combined datasets from two large prospective NAC trials, including in total 676 patients, of which 75 were of lobular histology. Eligible patients had tumors ≥3 cm in diameter or pathologic documentation of positive nodes, and underwent serial biopsies, expression microarray analysis, and MRI imaging. We compared pathologic complete response (pCR) rates and breast conservation surgery (BCS) rates between ILC and IDC, adjusted for clinicopathologic factors. On univariate analysis, ILCs were significantly less likely to have a pCR after NAC than IDCs (11 vs. 25 %,
p
= 0.01). However, the known differences in tumor characteristics between the two histologic types, including hormone receptor (HR) status, HER2 status, histological grade, and p53 expression, accounted for this difference with the lowest pCR rates among HR+/HER2− tumors in both ILC and IDC (7 and 5 %, respectively). ILC which were HR− and/or HER2+ had a pCR rate of 25 %. Expression subtyping, particularly the NKI 70-gene signature, was correlated with pCR, although the small numbers of ILC in each group precluded significant associations. BCS rate did not differ between IDC and ILC after adjusting for molecular characteristics. We conclude that ILC represents a heterogeneous group of tumors which are less responsive to NAC than IDC. However, this difference is explained by differences in molecular characteristics, particularly HR and HER2, and independent of lobular histology.
The aim of the present study was to investigate if 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) outperforms conventional imaging techniques for excluding ...distant metastases prior to neoadjuvant chemotherapy (NAC) treatment in patients with stage II and III breast cancer. Second, we assessed the clinical importance of false positive findings. One hundred and fifty four patients with stage II or III breast cancer, scheduled to receive NAC, underwent an 18F-FDG PET/CT scan and conventional imaging, consisting of bone scintigraphy, ultrasound of the liver, and chest radiography. Suspect additional lesions at staging examination were confirmed by biopsy and histopathology and/or additional imaging. Metastases that were detected within 6 months after the PET/CT scan were considered evidence of occult metastasis, missed by staging examination. Forty-two additional distant lesions were seen in 25 patients with PET/CT and could be confirmed in 20 (13%) of 154 patients. PET/CT was false positive for 8 additional lesions (19%) and misclassified the presence of metastatic disease in 5 (3%) of 154 patients. In 16 (80%) of 20 patients, additional lesions were exclusively seen with PET/CT, leading to a change in treatment in 13 (8%) of 154 patients. In 129 patients with a negative staging PET/CT, no metastases developed during the follow-up of 9.0 months. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of PET/CT in the detection of additional distant lesions in patients with stage II or III breast cancer are 100, 96, 80, 100, and 97%, respectively. FDG PET/CT is superior to conventional imaging techniques in the detection of distant metastases in patients with untreated stage II or III breast cancer and is associated with a low false positive rate. PET/CT may be of additional value in the staging of breast cancer prior to NAC.
Complete tumor removal during cancer surgery remains challenging due to the lack of accurate techniques for intraoperative margin assessment. This study evaluates the use of hyperspectral imaging for ...margin assessment by reporting its use in fresh human breast specimens.
Hyperspectral data were first acquired on tissue slices from 18 patients after gross sectioning of the resected breast specimen. This dataset, which contained over 22,000 spectra, was well correlated with histopathology and was used to develop a support vector machine classification algorithm and test the classification performance. In addition, we evaluated hyperspectral imaging in clinical practice by imaging the resection surface of six lumpectomy specimens. With the developed classification algorithm, we determined if hyperspectral imaging could detect malignancies in the resection surface.
The diagnostic performance of hyperspectral imaging on the tissue slices was high; invasive carcinoma, ductal carcinoma
, connective tissue, and adipose tissue were correctly classified as tumor or healthy tissue with accuracies of 93%, 84%, 70%, and 99%, respectively. These accuracies increased with the size of the area, consisting of one tissue type. The entire resection surface was imaged within 10 minutes, and data analysis was performed fast, without the need of an experienced operator. On the resection surface, hyperspectral imaging detected 19 of 20 malignancies that, according to the available histopathology information, were located within 2 mm of the resection surface.
These findings show the potential of using hyperspectral imaging for margin assessment during breast-conserving surgery to improve surgical outcome.
ER, PR and HER2 status in breast cancer are important markers for the selection of drug therapy. By immunohistochemistry (IHC), three major breast cancer subtypes can be distinguished: Triple ...negative (TNIHC), HER2+IHC and LuminalIHC (ER+IHC/HER2−IHC). By using the intrinsic gene set defined by Hu et al. five molecular subtypes (BasalmRNA, HER2+mRNA, Luminal AmRNA, Luminal BmRNA and Normal-likemRNA) can be defined. We studied the concordance between analogous subtypes and their prediction of response to neoadjuvant chemotherapy. We classified 195 breast tumors by both IHC and mRNA expression analysis of patients who received neoadjuvant treatment at the Netherlands Cancer institute for Stage II-III breast cancer between 2000 and 2007. The pathological complete remission (pCR) rate was used to assess chemotherapy response. The IHC and molecular subtypes showed high concordance with the exception of the HER2+IHC group. 60% of the HER2+IHC tumors were not classified as HER2+mRNA. The HER2+IHC/Luminal A or BmRNA group had a low response rate to a trastuzumab-chemotherapy combination with a pCR rate of 8%, while the HER2+mRNA group had a pCR rate of 54%. The Luminal AmRNA and Luminal BmRNA groups showed similar degrees of response to chemotherapy. Neither the PR status nor the endocrine responsiveness index subdivided the ER+IHC tumors accurately into Luminal AmRNA and Luminal BmRNA groups. Molecular subtyping suggests the existence of a HER2+IHC/LuminalmRNA group that responds poorly to trastuzumab-based chemotherapy. For LuminalIHC and triple negativeIHC tumors, further subdivision into molecular subgroups does not offer a clear advantage in treatment selection.
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