Giuseppe Renne

Chemotherapy Is More Effective in Patients with Breast Cancer Not Expressing Steroid Hormone Receptors A Study of Preoperative Treatment

Purpose: The purpose of this research was to identify factors predicting response to preoperative chemotherapy. Experimental Design: In a large volume laboratory using standard immunohistochemical methods, we reviewed the pretreatment biopsies and histologic specimens at final surgery of 399 patients with large or locally advanced breast cancer (cT2-T4, N0–2, M0) who were treated with preoperative chemotherapy. The incidence of pathological complete remission and the incidence of node-negative status at final surgery were assessed with respect to initial pathological and clinical findings. Menopausal status, estrogen receptor status, progesterone receptor status [absent (0% of the cells positive) versus expressed], clinical tumor size, histologic grade, Ki-67, Her-2/neu expression, and type and route of chemotherapy were considered. Results: High rates of pathological complete remission were associated with absence of estrogen receptor and progesterone receptor expression (P < 0.0001), and grade 3 (P = 0.001). Significant predictors of node-negative status at surgery were absence of estrogen receptor and progesterone receptor expression (P < 0.0001), clinical tumor size <5 cm (P < 0.001), and use of infusional regimens (P = 0.003). The chance of obtaining pathological complete remission or node-negative status for patients with endocrine nonresponsive tumors compared with those having some estrogen receptor or progesterone receptor expression was 4.22 (95% confidence interval, 2.20–8.09, 33.3% versus 7.5%) and 3.47 (95% confidence interval, 2.09–5.76, 42.9% versus 21.7%), respectively. Despite the significantly higher incidence of pathological complete remission and node-negative status achieved by preoperative chemotherapy for patients with estrogen receptor and progesterone receptor absent disease, the disease-free survival was significantly worse for this cohort compared with the low/positive expression cohort (4-year disease-free survival %: 41% versus 74%; hazard ratio 3.22; 95% confidence interval, 2.28–4.54; P < 0.0001). Conclusions: Response to preoperative chemotherapy is significantly higher for patients with endocrine nonresponsive tumors. New chemotherapy regimens or combinations should be explored in this cohort of patients with poor outcome. For patients with endocrine responsive disease, the role of preoperative endocrine therapies should be studied.

Stage migration after biopsy of internal mammary chain lymph nodes in breast cancer patients.

BackgroundInvolvement of the internal mammary chain lymph nodes (IMNs) is associated with worsened prognosis in breast cancer. Use of lymphoscintigraphy to visualize sentinel nodes reveals that IMNs often receive lymph from the area containing the tumor.MethodsWe biopsied IMNs in 182 patients because there was radiouptake to the IMNs or because the tumor was located in the medial portion of the breast. After tumor removal, pectoralis major fibers were divided to expose intercostal muscle. A portion of intercostal muscle adjacent to the sternum was removed. Lymph nodes and surrounding fatty tissue in the intercostal space were freed, removed, and analyzed histologically. The pleural cavity was breached in four cases (2.2%), with spontaneous resolution.ResultsIMNs were found in 160 (88%) of 182 patients; 146 (94.4%) were negative and 14 (8.8%) were positive. The latter received internal mammary chain radiotherapy. The axilla was negative in 4 of 14 cases and positive in 10.ConclusionsIMNs can be quickly and easily removed via the breast incision with insignificant risk and no increase in postoperative hospitalization. The patients with a positive IMN migrated from N0 (4 cases) or N1 (10 cases) to N3, prompting modification of both local (radiotherapy to internal mammary chain) and systemic treatment; without IMN sampling, they would have been understaged.

Axillary metastases in breast cancer patients with negative sentinel nodes: a follow-up of 3548 cases.

UNLABELLED PREMISES: Sentinel node biopsy (SNB) in patients with breast carcinoma accurately predicts the axillary node status. However, in some 4-7% of patients with negative sentinel nodes, the remaining axillary nodes harbour cancer cells. OBJECTIVE Our purpose was the long-term observation of a large number of patients who did not receive axillary dissection after a negative sentinel node biopsy, in order to evaluate the incidence of overt axillary metastases. METHODS Patients (3548) treated from 1996 to 2004, with negative sentinel nodes not submitted to axillary dissection, were followed up to 11 years with a median follow-up of 48 months. RESULTS Three hundred and sixteen unfavourable events occurred among the 3548 patients, 196 of which (5.5%) related to primary breast carcinoma. Thirty one cases of overt axillary metastases were found (0.9%): they received total axillary dissection and 27 of them are at present alive and well. The 5-year overall survival rate of the whole series was 98%. CONCLUSIONS Patients with negative sentinel node biopsy not submitted to axillary dissection show, at follow-up, a rate of overt axillary metastases lower than expected.

Ultrasound-guided vacuum-assisted core breast biopsy: experience with 406 cases

PurposeThe aim of this study was to determine the indications, accuracy and complications of vacuum-assisted breast biopsy (VABB) performed using ultrasonographic (US) guidance for non-palpable lesions.Materials and methodsThis was a prospective study in which results from consecutive US-guided VABB performed between January 1999 and April 2003 were subsequently compared to those from excisional biopsy or to long-term follow-up imaging.ResultsFour hundred and six lesions were submitted to VABB procedures. Out of those, 78.9% were benign, 18.8% were malignant, 1.7% was lobular neoplasia, and 0.4% was atypical duct hyperplasia. Underestimation occurred in 2.6% of the cases and false negative results in 0.6%. Sensitivity to VABB was 97%, specificity went up to 100%, negative predictive value was 99%, positive predictive value was 100%, and accuracy was 99%. Complications occurred in 9% of the patients.ConclusionUS-guided VABB is an accurate and safe procedure. The main indication is the non-palpable suspicious breast lesions (category 4). This new technique could be a good alternative for percutaneous and surgery biopsy.

Reverting estrogen-receptor-negative phenotype in HER-2-overexpressing advanced breast cancer patients exposed to trastuzumab plus chemotherapy

IntroductionThe amounts of estrogen receptor (ER) and progesterone receptor (PgR) in a primary tumor are predictive of the response to endocrine therapies of breast cancer. Several patients with ER-positive primary tumors relapse after adjuvant endocrine therapy with no ER expression in the recurrent tissue; much fewer with a recurrent disease after an ER-negative primary tumor may become endocrine responsive. These sequences of events indicate that a phenotype based on ER expression may not be a permanent feature of breast cancer.MethodsTen patients with advanced breast cancer whose tumors overexpressed HER-2, but not ER or PgR, were treated with weekly trastuzumab at standard doses with or without chemotherapy.ResultsThree out of 10 patients showed overexpression of ERs first appearing after 9, 12 and 37 weeks, respectively, from the initiation of trastuzumab. Two of these patients were subsequently treated with endocrine therapy alone: one of them received letrozole for 3 years without evidence of progression.ConclusionTherapeutic targets enabling the appearance of an endocrine responsive disease may increase treatment options for patients with breast cancer. Furthermore, these clinical data suggest that an ER-negative phenotype is a multi-step process with a reversible repression modality, and that some ER-negative tumors may either revert to an ER-positive phenotype, allowing an endocrine treatment to be effective.

The problem of the accuracy of intraoperative examination of axillary sentinel nodes in breast cancer.

Background: Sentinel node SN biopsy has become accepted as a reliable method of predicting the state of the axilla in breast cancer. The key issue, however, is the accuracy of the pathological evaluation of the biopsied node, which should be done intraoperatively whenever possible.Methods: In our initial experience on 192 patients using a conventional intraoperative frozen section method, the false-negative rate was 6.3%, and the negative predictive value was 93.7%. We devised a new and exhaustive intraoperative method, requiring about 40 minutes, in which pairs of sections are taken every 50 μ for the first 15 sections and every 100 μ thereafter, sampling the entire node. Sentinel node metastases were found in 143 of the 376 T1N0 cases examined 38%.Results: Metastases were always identified on hematoxylin and eosin sections, although in 4% of cases, cytokeratin immunostaining on adjacent sections was useful for confirming malignancy. In 233 patients the SNs were disease-free; of these patients, 222 had metastasis-free axillary nodes, and 11 4.7% had another metastatic node.Conclusion: Extensive intraoperative examination of frozen sentinel nodes correctly predicts an uninvolved axilla in 95.3% of cases negative predictive value. This method is, therefore, suitable for identifying patients in whom axillary dissection can be avoided.

Chronic stress in mice remodels lymph vasculature to promote tumour cell dissemination

Chronic stress induces signalling from the sympathetic nervous system (SNS) and drives cancer progression, although the pathways of tumour cell dissemination are unclear. Here we show that chronic stress restructures lymphatic networks within and around tumours to provide pathways for tumour cell escape. We show that VEGFC derived from tumour cells is required for stress to induce lymphatic remodelling and that this depends on COX2 inflammatory signalling from macrophages. Pharmacological inhibition of SNS signalling blocks the effect of chronic stress on lymphatic remodelling in vivo and reduces lymphatic metastasis in preclinical cancer models and in patients with breast cancer. These findings reveal unanticipated communication between stress-induced neural signalling and inflammation, which regulates tumour lymphatic architecture and lymphogenous tumour cell dissemination. These findings suggest that limiting the effects of SNS signalling to prevent tumour cell dissemination through lymphatic routes may provide a strategy to improve cancer outcomes.

The indocyanine green method is equivalent to the 99mTc-labeled radiotracer method for identifying the sentinel node in breast cancer: A concordance and validation study

AIMS The aim of this study was to assess concordance between the indocyanine green (ICG) method and (99m)Tc-radiotracer method to identify the sentinel node (SN) in breast cancer. Evidence supports the feasibility and efficacy of the ICG to identify the SN, however this method has not been prospectively compared with the gold-standard radiotracer method in terms of SN detection rate. METHODS Between June 2011 and January 2013, 134 women with clinically node-negative early breast cancer received subdermal/peritumoral injection of (99m)Tc-labeled tracer for lymphoscintigraphy, followed by intraoperative injection of ICG for fluorescence detection of SNs using an exciting light source combined with a camera. In all patients, SNs were first identified by the fluorescence method (ICG-positive) and removed. A gamma ray-detecting probe was then used to determine whether ICG-positive SNs were hot ((99m)Tc-positive) and to identify and remove any (99m)Tc-positive (ICG-negative) SNs remaining in the axilla. The study was powered to perform an equivalence analysis. RESULTS The 134 patients provided 246 SNs, detected by one or both methods. 1, 2 and 3 SNs, respectively, were detected, removed and examined in 70 (52.2%), 39 (29.1%) and 17 (12.7%) patients; 4-10 SNs were detected and examined in the remaining 8 patients. The two methods were concordant for 230/246 (93.5%) SNs and discordant for 16 (6.5%) SNs. The ICG method detected 99.6% of all SNs. CONCLUSIONS Fluorescent lymphangiography with ICG allows easy identification of axillary SNs, at a frequency not inferior to that of radiotracer, and can be used alone to reliably identify SNs.

Relationship between histologic thickness of tongue carcinoma and thickness estimated from preoperative MRI

Several studies have shown that the thickness of tongue carcinoma is related to prognosis and to the likelihood of cervical node metastases. We investigated whether preoperative estimates of tumor thickness and volume, as determined from magnetic resonance imaging (MRI), correlated with histologic thickness and might therefore predict the presence of neck metastases. We assessed relationships between histologic tumor thickness and MRI tumor thickness and volume in a retrospective series of 33 patients with squamous cell carcinoma of the tongue. Thicknesses were determined by direct measurement and by considering corrections for ulceration or tumor vegetation (reconstructed thickness). Relationships between MRI thickness and the presence or absence of homolateral and contralateral nodal metastases were also investigated. We found that MRI thicknesses correlated strongly and directly with histologic tumor thicknesses, although mean MRI thicknesses were significantly greater than histologic thicknesses. MRI thicknesses were significantly greater in patients with contralateral neck involvement than in those with no neck involvement. We conclude that MRI provides an accurate and reproducible means of estimating the thickness of tongue carcinomas, paving the way for further studies on more extensive series of patients to determine whether preoperatively determined MRI thickness can reliably predict homolateral and bilateral neck involvement.

Positive predictive value for malignancy on surgical excision of breast lesions of uncertain malignant potential (B3) diagnosed by stereotactic vacuum-assisted needle core biopsy (VANCB): A large multi-institutional study in Italy

Percutaneous core biopsy (CB) has been introduced to increase the ability of accurately diagnosing breast malignancies without the need of resorting to surgery. Compared to conventional automated 14 gauge needle core biopsy (NCB), vacuum-assisted needle core biopsy (VANCB) allows obtaining larger specimens and has recognized advantages particularly when the radiological pattern is represented by microcalcifications. Regardless of technical improvements, a small percentage of percutaneous CBs performed to detect breast lesions are still classified, according to European and UK guidelines, in the borderline B3 category, including a group of heterogeneous lesions with uncertain malignant potential. We aimed to assess the prevalence and positive predictive values (PPV) on surgical excision (SE) of B3 category (overall and by sub-categories) in a large series of non-palpable breast lesions assessed through VANCB, also comparison with published data on CB. Overall, 26,165 consecutive stereotactic VANCB were identified in 22 Italian centres: 3107 (11.9%) were classified as B3, of which 1644 (54.2%) proceeded to SE to establish a definitive histological diagnosis of breast pathology. Due to a high proportion of microcalcifications as main radiological pattern, the overall PPV was 21.2% (range 10.6%-27.3% for different B3 subtypes), somewhat lower than the average value (24.5%) from published studies (range 9.9%-35.1%). Our study, to date the largest series of B3 with definitive histological assessment on SE, suggests that B3 lesions should be referred for SE even if VANCB is more accurate than NCB in the diagnostic process of non-palpable, sonographically invisible breast lesions.