Background and Objectives
No intraoperative imaging techniques exist for detecting tumor nodules or tumor scar tissues in patients treated with upfront or interval cytoreductive surgery (CS) after ...neoadjuvant chemotherapy (NAC). The aims of this study were to evaluate the role of indocyanine green (ICG) fluorescence imaging (FI) for the detection of peritoneal metastases (PM) and evaluate whether it can be used to detect remnant tumor cells in scar tissue.
Methods
Patients with PM from ovarian cancer admitted for CS were included. ICG, at 0.25 mg per kg of patient weight, was injected intraoperatively after explorative laparotomy before CS.
Results
A total of 108 peritoneal lesions, including 25 scars, were imaged in 20 patients. Seventy‐three were malignant (67.6%) and 35 benign (32.4%). The mean Tumor to Background Ratio (ex vivo) was 1.8 (SD 1.3) in malignant and 1.0 (SD 0.79) in benign nodules (P = 0.007). Of 25 post‐NAC scars, the mean Tumor to Background Ratio (TBR) (in vivo) was 2.06 (SD 1.15) in malignant and 1.21 (SD 0.50) in benign nodules (P = 0.26). The positive predictive value of ICG‐FI to detect tumor cells in scars was 57.1%.
Conclusions
ICG‐FI is accurate to demonstrate PM in ovarian cancer but unable to discriminate between benign and malignant post‐NAC.
Validated biomarkers predictive of response/resistance to anthracyclines in breast cancer are currently lacking. The neoadjuvant Trial of Principle (TOP) study, in which patients with estrogen ...receptor (ER) -negative tumors were treated with anthracycline (epirubicin) monotherapy, was specifically designed to evaluate the predictive value of topoisomerase II-α (TOP2A) and develop a gene expression signature to identify those patients who do not benefit from anthracyclines.
The TOP trial included 149 patients, 139 of whom were evaluable for response prediction analyses. The primary end point was pathologic complete response (pCR). TOP2A and gene expression profiles were evaluated using pre-epirubicin biopsies. Gene expression data from ER-negative samples of the EORTC (European Organisation for Research and Treatment of Cancer) 10994/BIG (Breast International Group) 00-01 and MDACC (MD Anderson Cancer Center) 2003-0321 neoadjuvant trials were used for validation purposes.
A pCR was obtained in 14% of the evaluable patients in the TOP trial. TOP2A amplification, but not protein overexpression, was significantly associated with pCR (P ≤ .001 v P ≤ .33). We developed an anthracycline-based score (A-Score) combining three signatures: a TOP2A gene signature and two previously published signatures related to tumor invasion and immune response. The A-Score was characterized by a high negative predictive value (NPV; NPV, 0.98; 95% CI, 0.90 to 1.00) overall and in the human epidermal growth factor receptor 2 (HER2) -negative and HER2-positive subpopulations. Its performance was independently confirmed in the anthracycline-based arms of the two validation trials (BIG 00-01: NPV, 0.83; 95% CI, 0.64 to 0.94 and MDACC 2003-0321: NPV, 1.00; 95% CI, 0.80 to 1.00).
Given its high NPV, the A-Score could become, if further validated, a useful clinical tool to identify those patients who do not benefit from anthracyclines and could therefore be spared the non-negligible adverse effects.
Abstract
Background
Intraoperative electron radiotherapy (IOERT) can be used to treat early breast cancer during the conservative surgery thus enabling shorter overall treatment times and reduced ...irradiation of organs at risk. We report on our first 996 patients enrolled prospectively in a registry trial.
Methods
At Jules Bordet Institute, from February 2010 onwards, patients underwent partial IOERT of the breast. Women with unifocal invasive ductal carcinoma, aged 40 years or older, with a clinical tumour size ≤ 20 mm and tumour-free sentinel lymph node (on frozen section and immunohistochemical analysis). A 21 Gy dose was prescribed on the 90% isodose line in the tumour bed with the energy of 6 to 12 MeV (Mobetron®-IntraOp Medical).
Results
Thirty-seven ipsilateral tumour relapses occurred. Sixteen of those were in the same breast quadrant. Sixty patients died, and among those, 12 deaths were due to breast cancer. With 71.9 months of median follow-up, the 5-year Kaplan–Meier estimate of local recurrence was 2.7%.
Conclusions
The rate of breast cancer local recurrence after IOERT is low and comparable to published results for IORT and APBI. IOERT is highly operator-dependent, and appropriate applicator sizing according to tumour size is critical. When used in a selected patient population, IOERT achieves a good balance between tumour control and late radiotherapy-mediated toxicity morbidity and mortality thanks to insignificant irradiation of organs at risk.
Background
The size and focality of the primary tumor in breast cancer (BC) influence therapeutic decision making. The purpose of this study was to evaluate whether preoperative breast magnetic ...resonance imaging (MRI) is helpful for the assessment of tumor size and surgical planning in early BC.
Methods
We performed a retrospective review of a prospectively collected database of 174 patients treated at a single institution for invasive BC who had complete documentation of the tumor size from mammography (MMG), ultrasonography (US), and MRI.
Results
A total of 186 breast tumors were analyzed. Mean tumor size varied by imaging method: 14.7 mm by MMG, 13.8 mm by US, and 17.9 mm by MRI. The concordance between breast imaging techniques (BIT) and final pathology with a cutoff ≤ 2 mm was 34.8% for MRI, 32.1% for US, and 27.2% for MMG. US and MMG underestimated while MRI and MMG overestimated the real tumor size. Concordance was the same in premenopausal women for MRI and US at 35%, while concordance was higher in postmenopausal women for MRI. Correlations between size determined by BIT and histopathological size were best with MRI (0.59), compared to US (0.56) or MMG (0.42). Intrinsic subtypes of BC had different concordances according to imaging method, but no significant associations were found. MRI examination revealed additional lesions in 13.8% of patients, 69% of these lesions were malignant. MRI changed the surgical plan in 15 patients (8.6%), and the rate of mastectomy increased by 6.9%.
Conclusions
MRI estimates BC tumor size more accurately than US or MMG, but a significant overestimation exists. Complementary MRI examination improved the concordance for tumor size between BIT and final pathology in 16.7%. MRI did not alter surgical planning for most patients and allowed more appropriate treatment for 8% of them.
Objective
To compare in a multicenter randomized controlled trial the benefits in terms of anxiety regulation of a 15‐session single‐component group intervention (SGI) based on support with those of ...a 15‐session multiple‐component structured manualized group intervention (MGI) combining support with cognitive‐behavioral and hypnosis components.
Methods
Patients with nonmetastatic breast cancer were randomly assigned at the beginning of the survivorship period to the SGI (n = 83) or MGI (n = 87). Anxiety regulation was assessed, before and after group interventions, through an anxiety regulation task designed to assess their ability to regulate anxiety psychologically (anxiety levels) and physiologically (heart rates). Questionnaires were used to assess psychological distress, everyday anxiety regulation, and fear of recurrence. Group allocation was computer generated and concealed till baseline completion.
Results
Compared with patients in the SGI group (n = 77), patients attending the MGI group (n = 82) showed significantly reduced anxiety after a self‐relaxation exercise (P = .006) and after exposure to anxiety triggers (P = .013) and reduced heart rates at different time points throughout the task (P = .001 to P = .047). The MGI participants also reported better everyday anxiety regulation (P = .005), greater use of fear of recurrence–related coping strategies (P = .022), and greater reduction in fear of recurrence–related psychological distress (P = .017) compared with the SGI group.
Conclusions
This study shows that an MGI combining support with cognitive‐behavioral techniques and hypnosis is more effective than an SGI based only on support in improving anxiety regulation in patients with breast cancer.
Previous analyses of the Breast International Group (BIG) 1-98 four-arm study compared initial therapy with letrozole or tamoxifen including patients randomly assigned to sequential treatment whose ...information was censored at the time of therapy change. Because this presentation may unduly reflect early events, the present analysis is limited to patients randomly assigned to the continuous therapy arms and includes protocol-defined updated results.
Four thousand nine hundred twenty-two of the 8,028 postmenopausal women with receptor-positive early breast cancer randomly assigned (double-blind) to the BIG 1-98 trial were assigned to 5 years of continuous adjuvant therapy with either letrozole or tamoxifen; the remainder of women were assigned to receive the agents in sequence. Disease-free survival (DFS) was the primary end point.
At a median follow-up time of 51 months, we observed 352 DFS events among 2,463 women receiving letrozole and 418 events among 2,459 women receiving tamoxifen. This reflected an 18% reduction in the risk of an event (hazard ratio, 0.82; 95% CI, 0.71 to 0.95; P = .007). No predefined subsets showed differential benefit. Adverse events were similar to previous reports. Patients on tamoxifen experienced more thromboembolic events, endometrial pathology, hot flashes, night sweats, and vaginal bleeding. Patients on letrozole experienced more bone fractures, arthralgia, low-grade hypercholesterolemia, and cardiovascular events other than ischemia and cardiac failure.
The present updated analysis, which was limited to patients on monotherapy arms in BIG 1-98, yields results similar to those from the previous primary analysis but more directly comparable with results from other trials of continuous therapy using a single endocrine agent.
Response to neoadjuvant chemotherapy (NACT), particularly pathologic complete response (pCR), is an independent predictor of favorable clinical outcome in breast cancer (BC). The accuracy of residual ...disease measurement and reporting is of critical importance in treatment planning and prognosis for these patients. Currently, gross pathological evaluation of the residual tumor bed is the greatest determinant for accurate reporting of NACT response. Fluorescence imaging (FI) is a new technology that is being evaluated for use in the detection of tumors in different oncological conditions.
The aim of this study was to evaluate whether indocyanine green fluorescence imaging (ICG-FI) is able to detect residual breast tumor tissue after NACT in breast surgical operative specimens.
Patients who underwent NACT for BC and were admitted for breast surgery were selected for participation in this study. Free ICG (0.25 mg/kg) was injected intraoperatively. Tumor-to-background fluorescence ratio (TBFR) was calculated on ex vivo samples from the surgical specimen.
One hundred and seventy-two samples from nine breast surgical specimens were evaluated for their fluorescence intensity. Among them, 52 were malignant (30.2%) and 120 were benign (69.8%). The mean TBFR was 3.3 (SD 1.68) in malignant samples and 1.9 (SD 0.97) in benign samples (p = 0.0002). With a TBFR cut-off value of 1.3, the sensitivity, specificity, negative predictive value, false negative rate, and false positive rate of ICG-FI to predict residual tumoral disease in breast surgical samples post-NACT were 94.2%, 31.7%, 92.7%, 5.8%, and 68.3%, respectively. If we restricted our analysis to only patients who achieved pCR, the negative predictive value for ICG-FI was 100%.
These first observations indicate that ex vivo ICG-FI is sensitive but not sufficiently specific to discriminate between benign breast tissue and malignant residual tissue. Nevertheless, its negative predictive value seems sufficiently accurate to exclude the presence of residual breast tumor tissue on the operative specimen of patients treated by NACT, representing a potential tool to assist pathologists in the assessment of breast surgical specimens.
Near-infrared fluorescence imaging (NIRFI) of breast cancer (BC) after the intravenous (IV) injection of free indocyanine green (fICG) has been reported to be feasible. However, some questions ...remained unclarified.
To evaluate the distribution of fICG in BC and the axillary lymph nodes (LNs) of women undergoing surgery with complete axillary LN dissection (CALND) and/or selective lymphadenectomy (SLN) of sentinel LNs (NCT no. 01993576 and NCT no. 02027818).
An intravenous injection of fICG (0.25 mg/kg) was administered to one series of 20 women undergoing treatment with mastectomy, the day before surgery in 5 (group 1) and immediately before surgery in 15 (group 2: tumor localization, 25; and pN+ CALND, 4) as well as to another series of 20 women undergoing treatment with tumorectomy (group 3). A dedicated NIR camera was used for
fluorescence imaging of the 45 BC lesions and the LNs.
In group 1, two of the four BC lesions and one large pN+ LN exhibited fluorescence. In contrast, 24 of the 25 tumors in group 2 and all of the tumors in group 3 were fluorescent. The sentinel LNs were all fluorescent, as well as some of the LNs in all CALND specimens. Metastatic cells were found in the fluorescent LNs of the pN+ cases. Fluorescent BC lesions could be identified
on the surface of the lumpectomy specimen in 14 of 19 cases.
When fICG is injected intravenously just before surgery, BC can be detected using NIRFI with high sensitivity, with metastatic axillary LNs also showing fluorescence. Such a technical approach seems promising in the management of BC and merits further investigation.
EndoTAG-1, a tumor endothelial targeting agent has shown activity in metastatic triple-negative breast cancer (BC) in combination with paclitaxel.
HER2-negative BC patients candidates for neoadjuvant ...chemotherapy were scheduled to receive 12 cycles of weekly EndoTAG-1 22mg/m2 plus paclitaxel 70mg/m2 followed by 3 cycles of FEC (Fluorouracil 500mg/m2, Epirubicin 100mg/m2, Cyclophosphamide 500mg/m2) every 3 weeks followed by surgery. Primary endpoint was percent (%) reduction in Magnetic Resonance Imaging (MRI) estimated Gadolinium (Gd) enhancing tumor volume at the end of EndoTAG-1 plus paclitaxel administration as compared to baseline. Safety, pathological complete response (pCR) defined as no residual tumor in breast and axillary nodes at surgery and correlation between % reduction in MRI estimated tumor volume and pCR were also evaluated.
Fifteen out of 20 scheduled patients were included: Six patients with estrogen receptor (ER)-negative/HER2-negative and 9 with ER-positive/HER2-negative BC. Nine patients completed treatment as per protocol. Despite premedication and slow infusion rates, grade 3 hypersensitivity reactions to EndoTAG-1 were observed during the 1st, 2nd, 3rd and 6th weekly infusion in 4 patients, respectively, and required permanent discontinuation of the EndoTAG-1. Moreover, two additional patients stopped EndoTAG-1 plus paclitaxel after 8 and 9 weeks due to clinical disease progression. Two patients had grade 3 increases in transaminases and 1 patient grade 4 neutropenia. pCR was achieved in 5 of the 6 ER-/HER2- and in none of the 9 ER+/HER2- BC patients. The mean % reduction in MRI estimated tumor volume at the end of EndoTAG-1 plus paclitaxel treatment was 81% (95% CI, 66% to 96%, p<0.001) for the 15 patients that underwent surgery; 96% for patients with pCR and 73% for patients with no pCR (p = 0.04).
The EndoTAG-1 and paclitaxel combination showed promising preliminary activity as preoperative treatment, especially in ER-/HER2- patients. Further studies are warranted with need of premedication optimization.
ClinicalTrials.gov NCT01537536.
In cancer follow-up, in addition to the evaluation of survival probabilities, there is a fundamental need of assessing recurrence dynamics for optimal disease management. Although the time-dependent ...effect of the oestrogen receptor (ER) status of the tumour has already been described, so far no factor has proven to disentangle the multi-peak behaviour observed for breast cancer recurrences. Here, we aimed at investigating whether adiposity at diagnosis, reflected by increased patient's body mass index (BMI), could be associated with breast cancer recurrence patterns over time after primary cancer therapy.
We retrieved BMI from 734 of 777 patients with node-positive breast cancer from a phase III randomised clinical trial, which compared different chemotherapy regimens and had a median follow-up of 15.4 years. Cumulative incidence estimation as well as piecewise exponential models were carried out to estimate the distant recurrence dynamics, in all patients, as well as in subgroups based on the ER status, with the ER-positive group being further split according to the menopausal status.
In patients with ER-negative breast cancer, time-dependent analyses revealed that the hazard of late relapses could mainly be attributed to the overweight and obese patients. Within the subgroup of premenopausal patients with ER-positive tumours, obesity was associated with an early high narrow peak of distant recurrences followed by another main peak after 5 years of follow-up. The risk for overweight patients was intermediate between obese and normal-weight patients. In the postmenopausal subgroup of patients with ER-positive tumours, the distant recurrence rate was significantly more elevated in the overweight patients compared to the other BMI categories, and a second late peak of recurrences was also observed for the obese patients.
These results demonstrate that the patient's BMI at diagnosis is associated with cancer recurrence dynamics. Patient adiposity should therefore be central to the exploration of late adjuvant treatment modalities.
•The body mass index (BMI) at diagnosis is influencing breast cancer recurrence patterns over time.•Late relapses could mainly be attributed to the overweight and obese patients in the oestrogen-receptor negative disease.•Obese patients display a first high peak of recurrence followed by a delayed clustering of late distant events.•These findings support the consideration of patient's BMI for adequate treatment management over time.
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