Node-positive Invasive Breast Cancer Research Articles

Prediction of the MammaPrint Risk Group Using MRI Features in Women With Estrogen Receptor-Positive, HER2-Negative, and 1 to 3 Node-Positive Invasive Breast Cancer

BackgroundMammaPrint assigns chemotherapeutic benefits to patients with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative, and 1 to 3 node-positive invasive breast cancer. However, its cost and time-consuming nature limit its use in certain clinical settings. We aimed to develop and validate the prediction models for the low MammaPrint risk group using clinicopathologic and MRI features. Patients and MethodsOverall, 352 women with ER-positive, HER2-negative, and 1 to 3 node-positive invasive breast cancer were retrospectively reviewed and assigned to development (n = 235) and validation sets (n = 117). Univariate and multivariate analyses identified features associated with the low MammaPrint risk group. The area under the receiver operating characteristic curves (AUROCs) of models based on clinicopathologic, MRI, and combined features were evaluated. ResultsDevelopment set multivariate analysis showed that clinicopathologic features including low histologic grade (odds ratio [OR], 5.29; P = .02), progesterone receptor-positivity (OR, 3.23; P = .01), and low Ki-67 (OR, 6.05; P < .001) and MRI features, including peritumoral edema absence (OR, 2.24; P = .04) and a high proportion of persistent components (OR, 1.15; P = .004) were significantly associated with the low MammaPrint risk group. The AUROCs of models based on clinicopathologic, MRI, and combined features were 0.77, 0.64, and 0.80 in the development and 0.66, 0.60, and 0.70 in the validation sets, respectively. ConclusionThe combined model incorporating clinicopathologic and MRI features showed potential in predicting the low MammaPrint risk group, and may support decision-making in clinical settings with limited access to MammaPrint.

Association of mammography and ultrasound features with MammaPrint in patients with estrogen receptor-positive, HER2-negative, node-positive invasive breast cancer.

MammaPrint is a 70-gene signature microarray assay that predicts the likelihood of recurrence of breast cancer and chemotherapeutic benefits. To investigate the association between mammography and ultrasound (US) features and MammaPrint results in patients with estrogen receptor (ER)-positive, HER2-negative, node-positive invasive breast cancer, and to identify the predictive factors for high risk of recurrence. This retrospective study included 251 patients with ER-positive, HER2-negative, 1-3 node-positive invasive breast cancer. Mammography and US findings were reviewed according to the BI-RADS criteria. The association between MammaPrint results and the clinicopathological and imaging features was evaluated. Logistic regression analysis was performed to identify independent predictors for high risk of recurrence. Of the patients, 143 (57.0%) and 108 (43.0%) had low and high risks for recurrence on MammaPrint, respectively. Young age (odds ratio [OR] 1.08; 95% confidence interval (CI) 1.04-1.12; P<0.001), posterior enhancement on US (OR 2.45; 95% CI 1.16-5.20; P = 0.019), absence of posterior shadowing on US (OR 3.19; 95% CI 1.17-8.62; P = 0.023), high histologic grade (OR 113.36; 95% CI 6.79-1893.53; P = 0.001), and high Ki-67 level (OR 4.90; 95% CI 2.62-9.17; P<0.001) were independently associated with high risk of recurrence on multivariate logistic regression analysis. Posterior features in US may predict a high risk of recurrence in patients with ER-positive, HER2-negative, node-positive invasive breast cancer, which may be useful in enhancing the diagnostic value of MammaPrint and aid in the decision-making process regarding treatment.

Prospective surveillance model in the home for breast cancer-related lymphoedema: a feasibility study.

PurposeThe aim of this study was to assess the feasibility of delivering a prospective surveillance model in the home over 6 months for women at high risk of developing lymphoedema.MethodsA single-group, intervention study recruited 20 women who had surgical and medical treatment for confirmed node-positive invasive breast cancer and therefore at high risk of developing arm lymphoedema. Participants received a package including Bioimpedance Spectroscopy (BIS) monitoring, lymphoedema education and support to promote self-management and physical activity.ResultsParticipants adhered to BIS monitoring 74% of the time, and felt extremely confident in using the device. By 6 months, mean BIS L-Dex scores had increased from 3.5 (SD 5.6) to 8.4 (SD 11.1); five women (25%) who experienced > + 6.5 increase in L-Dex score were fitted with a compression garment. Self-reported symptoms and distress decreased by 0.4 out of 10 (95% CI 0.1 to 0.7); number of self-management strategies used increased by 0.6 (95% CI 0.1 to 1.2); and planned exercise increased by 2.8 h/week (95% CI 0.4 to 5.2).ConclusionsThese findings indicate a prospective surveillance model of care in the home with BIS is feasible and associated with increased self-management. A Phase II randomised trial is warranted as well as research exploring the costs associated with implementing this model of care for high-risk individuals.

Axillary reverse mapping (ARM) in clinically node positive breast cancer patients

BackgroundAxillary reverse mapping (ARM) is a technique to map and preserve upper extremity lymphatic drainage during axillary lymph node dissection (ALND) in breast cancer patients.We prospectively evaluated the metastatic involvement of ARM-nodes in patients who underwent an ALND for clinically node positive disease following (neo)adjuvant chemotherapy (NAC) in comparison to patients in whom primary ALND was performed without NAC. Patients and methodsPatients with clinically node positive invasive breast cancer, confirmed by fine needle aspiration cytology and scheduled for primary ALND were enrolled in the study. Patients were separated into two groups: one group treated with NAC (NAC+ group) and one group not treated with NAC (NAC− group). ARM was performed in all patients by injecting blue dye into the ipsilateral upper extremity. During ALND, ARM-nodes were first identified and removed separately, followed by a standard ALND. Results91 patients were included in the NAC+ and 21 patients in the NAC− group. There was no difference in the ARM visualization rate between the two groups (86.8% for NAC+ group versus 90.5% for NAC− group, P = 0.647). In the NAC+ group 16.5% of the patients had metastatic involvement of the ARM-nodes versus 36.8% of the patients in the NAC− group (P = 0.048). ConclusionThe risk of metastatic involvement of ARM-nodes in clinically node positive breast cancer patients is significantly lower in patients who have received NAC.

Lymph Node Ratio is More Predictive than Traditional Lymph Node Stratification in Lymph Node Positive Invasive Breast Cancer

To evaluate the relationships between lymph node ratio (LNR, the ratio of positive lymph nodes in excised axillary lymph nodes) and disease-free survival (DFS) by comparing with traditional absolute positive lymph node number (pN classification) for prediction of breast cancer (BC) progrnosis. We retrospectively reviewed patients who received comprehensive therapy in Department of Breast Surgery, Hubei Cancer Hospital, China from Jan 2002 to Dec 2006 (Group A), and Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, China from Jun 2008 to May 2012 (Group B). Patients were allocated to low-risk (≤0.20), intermediate-risk (> 0.20 but ≤ 0.65), high-risk (>0.65) groups by LNR. The primary endpoint was 5-DFS. A total of 294 patients were included in our study. LNR was verified as a negative prognostic factor for DFS (P= 0.002 in Group A, P< 0.0001 in Group B). Then we found the effects of pN and LNR delamination on disease-free survival (DFS) had statistical significance (P=0.012 for pN and P=0.031 for LNR stratification in Group A, both of them P<0.001 in Group B). Compared to pN staging, LNR staging displayed superior performance in prognosis, the adjusted hazard ratio of recurrence being 2.07 (95%CI, 1.07 to 4.0) for intermediate risk group (P=0.030) and 2.44 (95%CI, 1.21 to 4.92) for high risk group (P=0.013) in Group A. LNR stratification proved an adverse prognostic factor of DFS in lymph nodes positive invasive BC using cut-off values 0.20 and 0.65, and was more predictive than traditional pN classification for 5-DFS.

3049 Antitumoral therapy within 30 days from death: clinical and prognostics evaluations in very advanced cancer patients died in palliative care unit (PCU)

To assess the safety, tolerability, and clinical outcomes of an adjuvant chemotherapy regimen designed to incorporate a non-cross-resistant agent (paclitaxel, T) with a maximally dose-intensified regimen of doxorubicin and cyclophosphamide (AC) in conjunction with hematopoietic growth factor support (recombinant human granulocyte-colony stimulating factor; G-CSF; Filgrastim). A secondary aim was to assess if a higher dose (10 mcg/kg/day) of G-CSF is more efficacious than the conventional dose (5 mcg/kg/day) in this setting.Female patients with early-stage, node-positive invasive breast cancer were eligible for this multicenter, cooperative group feasibility trial that was designed as the pilot study for a larger randomized clinical trial. The protocol treatment comprised five cycles of dose-intensified AC (75 and 2000 mg/m2/cycle, respectively, intravenously every three weeks) with G-CSF support, followed by an additional four cycles of T (175 mg/m2 by 3 h intravenous infusion, every three weeks). Patients were randomized to receive one of two dose levels of G-CSF (5 vs. 10 mcg/kg/day) during AC chemotherapy. Data on both short-term toxicity and long-term survival were collected.One hundred and seventy two node-positive patients with operable primary breast cancer were accrued to this trial between February 1993 and April 1994. 130 of the 172 patients (76%) completed all protocol-specified therapy. Of the 42 early study withdrawals, 23 were due to unacceptable acute treatment-related toxicity. No differences in toxicities or clinical outcomes were noted between the two different dose levels of G-CSF support. At 6.8 years median follow-up, relapse-free survival (RFS) and overall survival (OS) rates for all patients are 70% and 78%, respectively. Ten patients developed second malignancies during follow-up, including three cases with a hematologic malignancy (2% incidence).The delivery of dose-intensified AC followed by T was feasible in this large-scale pilot trial, although significant acute toxicities were commonly encountered. The data confirmed the acceptable tolerability of T after aggressive myelotoxic therapy in the adjuvant setting, leading to a larger randomized clinical trial comparing three dose levels of doxorubicin in AC with or without the addition of T (CALGB 9344). Supportive care using twice the conventional dose of G-CSF did not significantly improve the tolerability or change the toxicities of this regimen, and the occurrence of secondary malignancies is consistent with the emerging risk profile of dose-intensive regimens with growth factor support. With long-term follow-up, the clinical outcomes remain relatively favorable and correlate with such expected prognostic factors as the number of involved nodes and hormone receptor status.

Predictive implications of nucleoside metabolizing enzymes in premenopausal women with node-positive primary breast cancer who were randomly assigned to receive tamoxifen alone or tamoxifen plus tegafur-uracil as adjuvant therapy

Recent studies have demonstrated that tegafur-uracil (UFT) is useful for the adjuvant treatment of various types of cancers. To determine whether nucleoside metabolizing enzymes could be used to predict the response to UFT treatment in women with primary breast cancer, we retrospectively analyzed archived tumor tissue samples obtained from the 3rd Adjuvant Chemo-Endocrine Therapy for Breast Cancer (ACETBC) study, in which adjuvant treatment with tamoxifen (TAM) plus UFT for 2 years was compared with TAM alone for 2 years. Samples of tumor tissue were obtained from 192 premenopausal women with node-positive invasive breast cancer. The tissue samples were examined immunohistochemically to study the expression of thymidylate synthase (TS), thymidine phosphorylase (TP), and dihydropyrimidine dehydrogenase (DPD), as well as the expression of Her2 and p53. In patients with TS-positive tumors, the risk of relapse was significantly lower in the tamoxifen plus UFT group than in the tamoxifen alone group. After 2 years, however, there was a trend towards a decrease in the relative predictive value (RPV) of TS with time. No relationship to outcome was detected for TP or DPD. Expression of Her2 or p53 was a significant prognostic indicator in the tamoxifen alone group. TS, but not TP or DPD, may be a useful predictor of response to UFT therapy. After 2 years, the RPV of TS decreased with time, suggesting that 2 years of treatment with oral fluorouracil derivatives may be inadequate. Further studies are required to investigate this possibility.

Breast Cancer in Young Women after Treatment with Irradiation for Hodgkin's Lymphoma.

BACKGROUND: Women who are survivors of Hodgkin's Lymphoma (HL) are at increased risk of developing breast cancer (BCa) as a long-term complication due to the use of extended field (mantle) irradiation (RT) of disease above the diaphragm. Many young women are at significantly increased risk of BCa prior to the age at which routine screening mammography is recommended for the general population. The sensitivity of mammography is lower in these women, in part due to increased breast tissue density characteristic of young pre-menopausal women. Currently, there is a paucity of information on the optimal screening modality and surveillance frequency for these women.METHODS: We reviewed the current BCa screening strategies used for this high risk group at our centre and described the incidence, method of detection, and characteristics of secondary BCas in a cohort of 115 women who received supradiaphragmatic RT for HL before age 30 between 1965 and 2000 at Princess Margaret Hospital (PMH) and who subsequently accepted long-term follow-up in a high-risk screening clinic.RESULTS: Median age at treatment was 22 (range 9–30). Radiation fields were mantle in 106 women, modified mantle in 6, and involved field in 3 (median dose delivered: 35 Gy, range 15–60). RT alone was used for 44 patients while 71 received combined modality therapy, of which 45 (65%) received MOPP. Treatment induced amenorrhea occurred in 15 women (median age 38); hormone replacement therapy was subsequently used by 9. Of the 107 women who participated in annual radiographic BCa screening, 95 were screened with mammogram alone, 1 with breast MRI alone, 8 with mammogram and MRI, and 3 with mammogram and ultrasound. Median age at first mammogram was 36; however, median age decreased with more recent year of HL diagnosis (age 40 for women diagnosed before 1985 compared to age 33 for women diagnosed after 1985, p<0.0001). Women with high breast density received MRI screening more often (p=0.02); however, breast density was not significantly associated with previous breast radiation dose or age at last follow-up. Twelve women were diagnosed with BCa in this cohort, following active breast surveillance for a median of 5 years (representing 584 person-years). The 20-year cumulative incidence of breast cancer was 10.9% (95% CI 5.3–18.8%) in this group of women. This was comparable to the 20-year cumulative incidence of breast cancer of 12% (95% CI 8–17%) in all 448 women with HL treated with supradiaphragmatic radiation before age 30 at PMH during the same time period. BCa occurred after a median of 17 years after treatment for HL (range 13–28). Median age at BCa diagnosis was 40 (range 31–51). Seven cancers were detected by physical exam (6 node-positive invasive BCas, 1 in-situ BCa) and 5 were detected on annual mammograms (1 node-positive invasive BCa, 4 in-situ BCas).CONCLUSIONS: Although women in the more recent treatment cohort are receiving their first mammogram at a younger age, the majority of BCas were still detected clinically, and these BCas had less favorable pathological characteristics. More frequent breast imaging should be considered in women who have had supradiaphragmatic RT for HL. Prospective evaluation of breast MRI as a screening strategy for HL survivors has been initiated at PMH in an effort to detect BCa at an earlier stage.

VEGF-C expressing tumor-associated macrophages in lymph node positive breast cancer: impact on lymphangiogenesis and survival

The ability of malignant tumors to metastasize presents a severe challenge in cancer treatment. Lymphatic vessels provide one of the main routes for tumor-metastasis on the way to regional lymph nodes. Increasing evidence suggests that inflammatory cells play an important role in tumor-associated angiogenesis and lymphangiogenesis. Recent data show that a specialized sub fraction of tumor-associated macrophages (TAMs) expressing the lymphoangiogenic growth factors vascular endothelial growth factor-C and -D (VEGF-C/D) at the tumor site, is related to lymphangiogenesis, lymphovascular invasion, and lymph node metastasis. Aim of this study was to clear the role of VEGF-C/D expressing TAMs in invasive breast cancer. One hundred-seven cases of lymph node positive invasive breast cancer were included into the study. Lymphatic microvessel density (LMVD), lymphovascular invasion (LVI), peritumoral inflammatory reaction (PI), and VEGF-C expression in tumors (VEGF-C(T)) and TAMs (VEGF-C(C)) were evaluated by immunohistochemistry and in situ hybridization. Significant associations were seen between LMVD and LVI, LMVD and VEGF-C(T), and between VEGF-C(T) and VEGF-C(C). Further significant correlations were evaluated between VEGF-C(C)/VEGF-C(T) and PI as well as between PI and LVI. LVI remained an independent prognostic factor for disease-free survival and overall survival. Our data provide evidence that the peritumoral inflammatory reaction and VEGF-C expressing TAMs may play an important role in tumor lymphangiogenesis and lymphovascular invasion in invasive breast cancer, implying new potential anti-tumor targets.

Hypoxia inducible factor-1α correlates with VEGF-C expression and lymphangiogenesis in breast cancer

The transcription factor Hypoxia inducible factor-1alpha (HIF-1alpha) plays a crucial role in tumor progression by regulating angiogenesis, cell survival and drug resistance. HIF-1alpha is also implicated in biological functions under normoxic conditions and recent data provide evidence for a possible role in tumor lymphangiogenesis by regulating the lymphatic vascular endothelial growth factor-C (VEGF-C). In breast cancer, lymphatic vessel invasion (LVI) by tumor cells and subsequent metastasis to axillary lymph nodes is a critical point in progression of the disease with severe therapeutical and prognostic implications. Aim of this study is to investigate the role of HIF-1alpha in VEGF-C expression, lymphangiogenesis, and LVI in lymph node positive breast cancer. Lymphatic microvessel density (LMVD), LVI, HIF-1alpha and VEGF-C protein-expression were evaluated by immunohistochemistry in 119 cases of lymph node positive invasive breast cancer. There was a significant correlation between HIF-1alpha and VEGF-C (p = 0.026, r = 0.204, Spearman's coefficient of correlation). Further a significant association between HIF-1alpha-expression and the amount of peritumoral lymphangiogenesis LMVD was seen (p = 0.014, Mann-Whitney test). LMVD correlated significantly with LVI (p<0.001, Mann-Whitney test). HIF-1alpha was an independent prognostic factor for overall and disease free survival in uni- and multivariate analysis (p = 0.027, 0.029, 0.025, respectively, Cox regression). Our data provide evidence for a possible role of HIF-1alpha as regulator of tumor-associated lymphangiogenesis in human breast cancer and emphasizes the promising status of HIF-1alpha as a therapeutical target against tumor progression and metastasis.

Prognostic Significance of Immunohistochemical Expression of p53 Gene Product in Operable Breast Cancer

The aim of this study was to investigate the prognostic significance of the expression of p53 gene product in operable invasive breast cancer by performing immunohistochemical analysis. Between January 1993 and December 2001, 440 operable invasive breast cancer patients underwent immunohistochemical staining for p53, and we retrospectively analyzed these results together with the clinical outcomes. The overexpression of p53 was detected in 51.6% of the cases. The overexpression of p53 was inversely correlated with lymph node metastasis (p=0.005). The tumor size, tumor histology, histologic grade, hormonal receptor status and tumor stage were not related to the overexpression of p53. Multivariate Cox regression analysis indicate that lymph node metastasis, tumor size and the p53 expression were the significant prognostic factors for overall survival; lymph node metastasis, the estrogen receptor status and the p53 expression were the significant prognostic factors for relapse free survival. On the subgroup analysis, the p53 non-expressors showed better 7-year overall survival (92.7% vs. 76.7%, respectively, p=0.011) and relapse free survival (74.9% vs. 57.8%, respectively, p=0.032) than did the p53 overexpressors for the patients with lymph node metastasis. However, for the patients without lymph node metastasis, the survival rates were not different for both the p53 non-expressors and the p53 overexpressors. Immunohistochemical staining of the p53 gene product was an independent prognostic factor for predicting survival of the lymph node positive invasive breast cancer patients.

Postmastectomy Radiation and Mortality in Women With T1-2 Node-Positive Breast Cancer

To determine the relationship between postmastectomy radiotherapy (PMRT) and mortality in a population-based cohort of women with T1-2 node-positive breast cancer. Using data from the Surveillance, Epidemiology, and End Results program, we identified 18,038 women with T1-2 node-positive invasive breast cancer who were treated with mastectomy between 1988 and 1995. The relationship between PMRT and mortality was determined using proportional hazards multivariate modeling and propensity score matched case-control analysis. Median follow-up was 8.1 years. Only 2,648 women (15%) received PMRT. After adjusting for covariates, PMRT use was not associated with mortality (hazard ratio [HR] = 0.96; 95% CI, 0.90 to 1.03). However, the interaction term for PMRT use and number of involved regional lymph nodes was significant (P = .002), suggesting that, above a certain threshold of involved nodes, a mortality benefit from PMRT may exist. Adjusted analysis stratified by number of involved nodes revealed that patients with seven or more involved nodes treated with PMRT experienced a significant reduction in all-cause (HR = 0.84; 95% CI, 0.76 to 0.93) and cause-specific mortality (HR = 0.86; 95% CI, 0.77 to 0.96). Propensity score matched case-control analysis confirmed that PMRT was associated with reduced mortality only in the subset of patients with seven or more involved nodes (HR = 0.81; 95% CI, 0.73 to 0.91 for all-cause mortality; and HR = 0.82; 95% CI, 0.72 to 0.93 for cause-specific mortality). For women with T1-2 breast cancer, PMRT is associated with a 15% to 20% relative reduction in mortality for patients with seven or more involved regional lymph nodes.

Angiogenesis sustains tumor dormancy in patients with breast cancer treated with adjuvant chemotherapy.

Experimental studies performed in Folkman laboratories suggest that angiogenesis is involved in the biology of tumor dormancy. We determined the vascular index in a series of 190 women operated of node-positive invasive breast cancer treated with adjuvant chemotherapy (CMF schedule) and we studied the relationship between vascularity of primary tumors with the behaviour in time of metastasis. The study of the hazard function of recurrence (in any site) was performed resorting to a generalized linear modelling approach with a binominal error according to Efron. A total of 80 cases developed recurrences during the period of observation. We found that the hazard function of metastasis in time presented two peaks of incidence at 20 and 60 months, respectively. We also plotted the curves of the hazard function by considering three values of microvessel counts corresponding to the quartiles of their distribution. The risk of first recurrence was associated with vascular index, and the patients of the third quartile of distribution of microvessels had the highest risk. In the final full model for the risk of recurrence at 5 years vascular index provided the highest prognostic contribution followed by the number of involved axillary lymph nodes. The observation that the patients with highly angiogenic tumors are at high risk of recurrence coupled with the identification of the second peak of incidence after 5 years which was also mainly sustained by angiogenic tumors suggest that a fraction of breast cancers promote metastasis after a period of tumor dormancy. The clinical and therapeutic implications of our results are discussed.

Behaviour of metastasis in relation to vascular index in patients with node-positive breast cancer treated with adjuvant tamoxifen.

Some experimental studies suggested that one possible oestrogen-receptor-unrelated mechanism of action of tamoxifen involves inhibition of angiogenesis. We evaluated the correlation of the degree of vascularisation of the primary tumour and we assessed it by using the panendothelial marker anti-CD31 and immunohistochemistry with microvessels count, performed at the vascular 'hot spot' of each single cancer, with the risk of recurrence in time. A cohort of 176 consecutive patients with node-positive invasive breast cancer treated with adjuvant tamoxifen (30 mg/daily for 3 years) and a median follow-up of 72 months was studied. Sixty-two patients developed metastasis (30 visceral, 18 skeletal and 14 in soft tissues) during the time of observation. The study of the hazard function for metastasis was performed by a generalized linear modelling approach with a binomial error according to Efron. The risk of first recurrence was strictly associated with vascular index, having the patients with the highest microvessel counts the highest risk of metastasis during all the period of observation. We did not find an interaction of vascularity with oestrogen receptor (ER) status. However, in the subgroup of patients with ER-positive tumours the hazard of metastasis was almost constant in time, while in that with ER-negative tumours it increased rapidly up to 20 months and, thereafter, decreased sharply. The results of our study are an indirect evidence that the patients with highly vascularized breast cancers may gain poor benefit of adjuvant tamoxifen and, therefore. that this antioestrogen is unlikely to retain a clinically relevant antiangiogenic activity in human breast cancer. Our data need confirmation by a prospective randomized clinical trial.