Marie-Jeanne T. F. D. Vrancken Peeters

Magnetic Resonance Imaging Response Monitoring of Breast Cancer During Neoadjuvant Chemotherapy: Relevance of Breast Cancer Subtype

PURPOSE To evaluate the relevance of breast cancer subtypes for magnetic resonance imaging (MRI) markers for monitoring of therapy response during neoadjuvant chemotherapy (NAC). PATIENTS AND METHODS 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. RESULTS 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 (Pearsons 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. CONCLUSION 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.

Concordance of clinical and molecular breast cancer subtyping in the context of preoperative chemotherapy response

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.

Dynamic Contrast-Enhanced MRI for Prediction of Breast Cancer Response to Neoadjuvant Chemotherapy: Initial Results

OBJECTIVE The aim of this study was to establish changes in contrast-enhanced MRI of breast cancer during neoadjuvant chemotherapy that are indicative of pathology outcome. MATERIALS AND METHODS In 54 patients with breast cancer, dynamic contrast-enhanced MRI was performed before chemotherapy and after two chemotherapy cycles. Imaging was correlated with final histopathology. Multivariate analysis with cross-validation was performed on MRI features describing kinetics and morphology of contrast uptake in the early and late phases of enhancement. Receiver operating characteristic (ROC) analysis was used to develop a guideline that switches patients at high risk for incomplete remission to a different chemotherapy regimen while maintaining first-line therapy in 95% of patients who are not at risk (i.e., high specificity). RESULTS Change in largest diameter of late enhancement during chemotherapy was the single most predictive MRI characteristic for tumor response in multivariate analysis (A(z) [area under the ROC curve] = 0.73, p < 0.00001). Insufficient (< 25%) decrease in largest diameter of late enhancement during chemotherapy was most indicative of residual tumor at final pathology. Using this criterion, the fraction of unfavorable responders indicated by MRI was 41% (22/54). Approximately half (44%, 14/32) of the patients who showed favorable response at MRI achieved complete remission at pathology. Conversely, 95% (21/22) of patients who showed unfavorable response at MRI had residual tumor at pathology. CONCLUSION Reduction of less than 25% in largest diameter of late enhancement during neoadjuvant chemotherapy shows the potential to predict residual tumor after therapy with high specificity.

Detection of extra-axillary lymph node involvement with FDG PET/CT in patients with stage II-III breast cancer.

PURPOSE The aim of this prospective study was to assess the incidence of extra-axillary lymph node involvement on baseline FDG PET/CT in patients with stage II-III breast cancer scheduled for neo-adjuvant chemotherapy. METHODS Patients with invasive breast cancer of >3 cm and/or proven axillary lymph node metastasis were included for before neo-adjuvant chemotherapy. Baseline ultrasound of the infra- and supraclavicular regions was performed with fine-needle biopsy as needed. Subsequently FDG PET/CT was performed. All visually FDG-positive nodes were regarded as metastatic based on the previously reported high specificity of the technique. RESULTS Sixty patients were included. In 17 patients (28%) extra-axillary lymph nodes were detected by FDG PET/CT, localised in an intra-mammary node (1 lymph node in 1 patient), mediastinal (2 lymph nodes in 2 patients), internal mammary chain (9 lymph nodes in 8 patients), intra- and interpectoral (6 lymph nodes in 4 patients), infraclavicular (5 lymph nodes in 4 patients) and in the contralateral axilla (3 lymph nodes in 2 patients). Ultrasound-guided cytology had detected extra-axillary lymph node involvement in seven of these patients, but was unable to detect extra-axillary nodes in the other 10 patients with positive extra-axillary lymph nodes on FDG PET/CT. Radiotherapy treatment was altered in 7 patients with extra-axillary involvement (12% of the total group). CONCLUSIONS FDG PET/CT detected extra-axillary lymph node involvement in almost one-third of the patients with stage II-III breast cancer, including regions not evaluable with ultrasound. FDG PET/CT may be useful as an additional imaging tool to assess extra-axillary lymph node metastasis, with an impact on the adjuvant radiotherapy management.

Diagnosis of breast cancer using diffuse optical spectroscopy from 500 to 1600 nm: comparison of classification methods

We report on the use of diffuse optical spectroscopy analysis of breast spectra acquired in the wavelength range from 500 to 1600 nm with a fiber optic probe. A total of 102 ex vivo samples of five different breast tissue types, namely adipose, glandular, fibroadenoma, invasive carcinoma, and ductal carcinoma in situ from 52 patients were measured. A model deriving from the diffusion theory was applied to the measured spectra in order to extract clinically relevant parameters such as blood, water, lipid, and collagen volume fractions, β-carotene concentration, average vessels radius, reduced scattering amplitude, Mie slope, and Mie-to-total scattering fraction. Based on a classification and regression tree algorithm applied to the derived parameters, a sensitivity-specificity of 98%-99%, 84%-95%, 81%-98%, 91%-95%, and 83%-99% were obtained for discrimination of adipose, glandular, fibroadenoma, invasive carcinoma, and ductal carcinoma in situ, respectively; and a multiple classes overall diagnostic performance of 94%. Sensitivity-specificity values obtained for discriminating malignant from nonmalignant tissue were compared to existing reported studies by applying the different classification methods that were used in each of these studies. Furthermore, in these reported studies, either lipid or β-carotene was considered as adipose tissue precursors. We estimate both chromophore concentrations and demonstrate that lipid is a better discriminator for adipose tissue than β-carotene.

Prophylactic mastectomy in BRCA1 and BRCA2 mutation carriers: very low risk for subsequent breast cancer.

Aim:To examine the outcome of prophylactic mastectomy in a hospital-based series of BRCA1/2 gene mutation carriers with and without a history of breast cancer. Patients and Methods:A center-based consecutive series of 254 BRCA1/2 gene mutation carriers that had prophylactic mastectomy after a normal surveillance round including breast-magnetic resonance imaging were identified. One hundred forty-seven asymptomatic carriers underwent bilateral mastectomy and 107 symptomatic women had contralateral mastectomy after a mean cancer free interval of 3.6 years. All removed breasts were histopathologically examined. Results:In one asymptomatic BRCA2 carrier (0.7%) an occult small invasive breast cancer was diagnosed, while in 6 asymptomatic carriers (4.0% BRCA1 and 4.3% BRCA2) and in 5 symptomatic carriers (2.5% BRCA1 and 10.7% BRCA2) DCIS was detected at prophylactic mastectomy. No breast cancer occurred in the asymptomatic group after a postprophylactic follow-up period of 778 women-years. In the symptomatic carriers 1 invasive breast cancer was detected after 580 follow-up years. From age-, cohort-, and gene-specific reference data we calculated that 15 invasive first cancers in the asymptomatic carriers were prevented during follow-up. Conclusion:One invasive breast cancer in 147 bilateral prophylactic mastectomies (0.7%) was detected, this makes a sentinel node procedure redundant and preoperative imaging vital. The prophylactic procedure is highly effective in preventing invasive breast cancer in BRCA1/2 mutation carriers. Since the remaining risk is less than 0.2%/woman-year, continued surveillance of the asymptomatic carriers is not warranted.

Radioactive Seed Localization of Breast Lesions: An Adequate Localization Method without Seed Migration

Abstract:  Preoperative localization is important to optimize the surgical treatment of breast lesions, especially in nonpalpable lesions. Radioactive seed localization (RSL) using iodine‐125 is a relatively new approach. To provide accurate guidance to surgery, it is important that the seeds do not migrate after placement. The aim of this study was to assess short‐term and long‐term seed migration after RSL of breast lesions. In 45 patients, 48 RSL procedures were performed under ultrasound or stereotactic guidance. In the first 12 patients, the lesion was localized with two markers: an iodine‐125 seed and a reference marker. In 33 patients, 36 RSL procedures were performed using a single iodine‐125 seed. All patients received control mammograms after seed placement and prior to surgery. In the patients with two markers, migration was defined as the difference in the largest distance between the markers observed in the mammograms. For single‐marked lesions, migration was assessed by comparing distances between anatomical landmarks in the mammograms. RSL was successful in all patients. Seeds were in‐situ for 59.5 days on average (3–136 days). The detection rate during surgery was 100%. Overall, an average seed migration of 0.9 mm (standard deviation 1.0 mm) was observed. Neither differences in lesion type, nor days in situ, type of surgery or radiologic localization method were found to have impact on seed migration. RSL is an accurate preoperative localization method for breast lesions with negligible seed migration, independent of time in‐situ.

FDG PET/CT during neoadjuvant chemotherapy may predict response in ER-positive/HER2-negative and triple negative, but not in HER2-positive breast cancer

BACKGROUND Response monitoring with MRI during neoadjuvant chemotherapy (NAC) in breast cancer is promising, but knowledge of breast cancer subtype is essential. The aim of the present study was to evaluate the relevance of breast cancer subtypes for monitoring of therapy response during NAC with 18F-FDG PET/CT. METHODS Evaluation included 98 women with stages II and III breast cancer. PET/CTs were performed before and after six or eight weeks of NAC. FDG uptake was quantified using maximum standardized uptake values (SUVmax). Tumors were divided into three subtypes: HER2-positive, ER-positive/HER2-negative, and triple negative. Tumor response at surgery was assessed dichotomously (presence or absence of residual disease) and ordinally (breast response index, representing relative change in tumor stage). Multivariate regression and receiver operating characteristic (ROC) analyses were employed to determine associations with pathological response. RESULTS A (near) complete pathological response was seen in 19 (76%) of 25 HER2-positive, 7 (16%) of 45 ER-positive/HER2-negative, and 20 (71%) of 28 triple negative tumors. Multivariate regression of pathological response indicated a significant interaction between change in FDG uptake and breast cancer subtype. The area under the ROC curve was 0.35 (0.12-0.64) for HER2-positive, 0.90 (0.76-1.00) for ER-positive/HER2-negative, and 0.96 (0.86-1.00) for triple negative tumors. We found no association between age, stage, histology, or baseline SUVmax and pathological response. CONCLUSION Response monitoring with PET/CT during NAC in breast cancer seems feasible, but is dependent on the breast cancer subtype. PET/CT may predict response in ER-positive/HER2-negative and triple negative tumors, but seems less accurate in HER2-positive tumors.

Heading toward radioactive seed localization in non-palpable breast cancer surgery? A meta-analysis.

Wire‐guided localization is the most commonly used technique for intraoperative localization of non‐palpable breast cancer. Radioactive seed localization (RSL) is becoming more popular and seems to be a reliable alternative for intraoperative lesion localization. The purpose of the present meta‐analysis was to evaluate the use of RSL. Primary study outcomes were irradicality and re‐excision rates. In total 3168 patients were included. The clinical adaptation shows growing confidence in RSL and further growth is expected. J. Surg. Oncol. 2015 111:185–191.

On the feasibility of MRI‐guided navigation to demarcate breast cancer for breast‐conserving surgery

PURPOSE The aim of this study was to investigate the feasibility of image-guided navigation approaches to demarcate breast cancer on the basis of preacquired magnetic resonance (MR) imaging in supine patient orientation. METHODS Strategies were examined to minimize the uncertainty in the instrument-tip position, based on the hypothesis that the release of instrument pressure returns the breast tissue to its predeformed state. For this purpose, four sources of uncertainty were taken into account: (1) Uligaments: Uncertainty in the reproducibility of the internal mammary gland geometry during repeat patient setup in supine orientation; (2) Ur_breathing: Residual uncertainty in registration of the breast after compensation for breathing motion using an external marker; (3) Ureconstruction: Uncertainty in the reconstructed location of the tip of the needle using an optical image-navigation system (phantom experiments, n=50); and (4) Udeformation: Uncertainty in displacement of breast tumors due to needle-induced tissue deformations (patients, n=21). A Monte Carlo study was performed to establish the 95% confidence interval (CI) of the combined uncertainties. This region of uncertainty was subsequently visualized around the reconstructed needle tip as an additional navigational aid in the preacquired MR images. Validation of the system was performed in five healthy volunteers (localization of skin markers only) and in two patients. In the patients, the navigation system was used to monitor ultrasound-guided radioactive seed localization of breast cancer. Nearest distances between the needle tip and the tumor boundary in the ultrasound images were compared to those in the concurrently reconstructed MR images. RESULTS Both Ureconstruction and Udeformation were normally distributed with 0.1±1.2mm (mean±1SD) and 0.1±0.8mm, respectively. Taking prior estimates for Uligaments (0.0±1.5mm) and Ur_breathing (-0.1±0.6mm) into account, the combined impact resulted in 3.9 mm uncertainty in the position of the needle tip (95% CI) after release of pressure. The volunteer study showed a targeting accuracy comparable to that in the phantom experiments: 2.9±1.3 versus 2.7±1.1mm, respectively. In the patient feasibility study, the deviations were within the 3.9 mm CI. CONCLUSIONS Image-guided navigation to demarcate breast cancer on the basis of preacquired MR images in supine orientation appears feasible if patient breathing is tracked during the navigation procedure, positional uncertainty is visualized and pressure on the localization instrument is released prior to verification of its position.