Subsequent Distant Metastasis Research Articles

The loss of E-cadherin, α- and β-catenin expression is associated with metastasis and poor prognosis in invasive breast cancer

Loss of E-cadherin and catenin expression may be associated with distant and lymph node metastases in breast cancer. Heterogeneity of E-cadherin expression is associated with poor prognosis, suggesting that E-cadherin and catenins may serve as useful prognostic markers for invasive breast carcinoma. Reduction or loss of expression of either E-cadherin or catenins is associated with invasion, metastasis and poor prognosis in several types of human malignancies. We investigated the expression of E-cadherin, and alpha- and beta-catenins by immunohistochemistry in 171 cases of primary invasive breast cancer, and compared the expression with clinicopathological parameters to define the relationship between expression and prognosis. E-cadherin immunoreactive protein was shown to be expressed in 97 cases. Reduction or lack of expression of E-cadherin was associated with distant metastasis. Based on immunohistochemical heterogeneity, E-cadherin-positive tumors were classified into heterogeneous, homogeneous and intermediate types. Interestingly, although patients with heterogeneous type demonstrated the lowest incidence of distant metastasis at diagnosis, they showed a higher incidence of subsequent distant metastasis, after surgery, and a lower survival rate than those with homogeneous type (p<0.05). E-cadherin expression was reduced or negative in metastatic axillary lymph nodes regardless of the expression in the primary tumor, suggesting that changes in E-cadherin expression are associated with not only distant metastasis but also lymph node metastasis. Tumors negative for either alpha- or beta-catenin expression demonstrated a higher incidence of distant metastasis than those expressing both catenins, suggesting that the expression of catenins is involved in breast cancer metastasis. Reduction or loss of E-cadherin and catenin expression may be associated with distant and lymph node metastases in invasive breast cancer, and the heterogeneous type may be associated with poor prognosis.

Internal mammary node irradiation neither decreases distant metastases nor improves survival in stage I and II breast cancer

Purpose: To compare outcome for ipsilateral breast tumor recurrence (IBTR), or regional node recurrence, initial and subsequent distant metastases, and overall and cause-specific survival in women treated with conservative surgery and radiation based on whether or not radiation was targeted to the internal mammary nodes (IMN). Methods and Materials: From 1979–1994, 1383 women with Stage I–II breast cancer underwent wide excision, axillary node dissection with ≥10 nodes removed, and radiation. Median follow-up was 6 years; median age was 55 years. A total of 114 women had radiation targeted to the IMN with deep tangents and 1269 did not. Women who received IMN treatment were more often axillary node–positive (40% vs. 25%, p = 0.002), had central or inner quadrant tumors (61% vs. 40%, p = 0.001), and had T2 tumors (47% vs. 31%, p = 0.001). All axillary node–positive women received adjuvant chemotherapy and/or tamoxifen. For axillary node–negative women, 13% of the IMN treatment group received adjuvant systemic therapy compared to 37% of the no treatment group ( p = 0.001). Radiation was directed to the breast only in 97% of the axillary node–negative women who had IMN treatment and 99% of the no IMN treatment group. For axillary node–positive women, 98% of the IMN-treated group had radiation to the breast and supraclavicular nodes ± a posterior axillary field compared to 77% of the no IMN treatment group ( p = 0.001). There were no significant differences between the two groups for median age, menopausal status, histology, final surgical margin, estrogen and progesterone receptor status, or the number of positive nodes. Results: There were no significant differences in the 5- and 10-year cumulative incidence of an IBTR, regional node recurrence, initial or total distant metastases for the two groups. Similarly 5- and 10-year actuarial overall and cause-specific survival were not significantly different. However, subset analysis revealed a statistically significant increase in initial (29% vs. 15% at 10 yr, p = 0.002) and total (30% vs. 17% at 10 yr, p = 0.01) distant metastases and a significant decrease in cause-specific survival (76% vs. 89% at 10 yr, p = 0.02) for postmenopausal women who received IMN treatment. These findings could not be attributed to differences in the use of systemic therapy or the number of positive nodes. Axillary node–positive patients did not experience a significant decrease in initial (36% vs. 22% at 10 yr, p = 0.21) or total distant metastases (37% vs. 28% at 10 yr, p = 0.62) or a significant improvement in cause-specific survival (72% vs. 76% at 10 yr, p = 0.76) with IMN treatment regardless of whether the tumor was lateral or medial/central in location. IMN treatment was not associated with an increase in non–breast cancer deaths during this period of observation. Conclusions: This retrospective series was unable to identify a significant benefit for IMN irradiation in terms of distant metastases or cause-specific survival for the entire patient population, and in particular, for patients with positive axillary nodes and medially located lesions. The results of the proposed or ongoing prospective randomized trials will further address this controversial issue.

Local Recurrence (LR) after Breast Conserving Therapy (BCT); risk factors predicting for subsequent distant metastasis

Local Recurrence (LR) after Breast Conserving Therapy (BCT); risk factors predicting for subsequent distant metastasis

Pattern of invasion and margin assessment in patients with oral tongue cancer.

Involvement of resection margins and the pattern of tumor invasion are reported to be important predictors of local recurrence and survival in surgically treated patients. In this study we have retrospectively assessed the significance of these two prognostic factors in a relatively homogeneous patient population. Patients and Methods This study was confined to 150 previously untreated patients who had surgery for squamous carcinoma of the oral tongue between 1987 and 1993. There were 82 men and 68 women who ranged in age from 25 to 89 years (median 60 years). Glossectomy was peroral in 129, whereas 8 and 13, respectively, had a cheek flap or mandibulotomy approach. Some form of lymphadenectomy was performed in 109 (73%), and 51 patients (34%) received postoperative radiotherapy. Histologic slides from each primary tumor were reviewed to verify the margin status. In addition, the pattern of invasion was evaluated and graded from 1 to 4, varying from a consistently well-defined, "pushing" border (Grade 1) to diffuse infiltration and cellular dissociation (Grade 4). Intraoperative frozen section assessment of margins was accurate, whether positive or negative, in 118 of 133 patients (89%). Positive or close margins (within one high-power field) and an endophytic growth pattern were associated with a significant increase in local recurrence (p <0.003 and <0.04, respectively). With higher grades of infiltration (Grade 3 or 4; 82 patients), the tumors tended to be larger and the patients younger. Although the likelihood of nodal involvement and subsequent distant metastasis was significantly greater in those with Grade 3 or grade 4 patterns (p <0.0003 and <0. 01, respectively), there was no impact on local recurrence. Cumulative survival was similar whether or not the surgical margins were involved, but was significantly reduced when the pattern of tumor invasion was of higher grade (p <0.01). Frozen section provided reasonably accurate information about margins in our patients, whether taken from the patient or the surgical specimen. Positive margins increased the likelihood of local recurrence, but did not impact on survival because subsequent surgery and/or irradiation controlled tumor recurrence in some patients. Grade 3 or 4 patterns at the tumor/host interface were associated with an increased incidence of nodal and distant metastasis, as well as a significant decrease in survival.

Ipsilateral Breast Tumor Recurrence Following Breast-Conserving Surgery for Early-Stage Invasive Cancer

Ipsilateral breast tumor recurrence (IBTR) following conservative surgery and radiation for early stage invasive cancer occurs in approximately 15% of all patients at 10 years and is diminished with surgical excisions which achieve negative margins. Treatment strategies of breast-conserving surgery with or without radiation that result in IBTR rates of 30-40% will impact negatively on survival and the magnitude of this effect will be influenced by the predominant pattern of local failure as well as initial and subsequent distant metastases. Optimal local control in early-stage invasive breast cancer is important to minimize the risk of a salvage mastectomy and maximize the potential for long-term survival.

Local and distant recurrence after conservative management of “very low-risk” breast cancer are dependent events: a 10-year follow-up

Purpose: To determine the risk factors associated with recurrence after breast-conserving treatments, and the relationship between occurrence of a local recurrence and subsequent distant metastases. Methods and Materials: Among the 3697 patients with primary breast cancer treated at Institut Paoli-Calmettes Cancer Center, Marseille, between 1980 and 1995, we retrospectively analyzed 756 patients who had been treated with conservative surgery with uninvolved margins of excision, were node-negative, and had received uniform radiotherapy and no chemotherapy. One third of the patients received hormonal therapy via tamoxifen or surgical castration. The endpoints considered were local failures and distant metastases. All tumors were reviewed by our pathologists. The median follow-up for the 700 survivors was 62 months. Results: In the multivariate analysis, histological multifocality ( p = 0.0076), peritumoral vessel invasion ( p = 0.0215), and young age ( p = 0.0245) were associated with an increased risk of local recurrences, whereas tumor size ( p = 0.0013), young age ( p = 0.003), and histological multifocality ( p = 0.0414) were associated with an increased risk of distant metastases. Local recurrences and distant metastases had similar yearly-event probabilities. Median time to distant metastases was shorter after a local recurrence. Early timing of local recurrences did not mark a higher risk of distant metastases. Hazard of relapsing from distant metastases was 4.4 times higher after a local recurrence. Conclusion: our results support the hypothesis that, in this subset of patients, local recurrences favor further dissemination of cancer cells. We are unable to clearly identify a group who would benefit from more aggressive local therapy.

Association of local recurrence with subsequent survival in extremity soft tissue sarcoma.

The aim of this study was to analyze local recurrence in a large cohort of prospectively followed patients with primary extremity soft tissue sarcoma. In particular, we analyzed the correlation of local recurrence with subsequent metastasis and disease-specific survival. Patients who underwent treatment for primary extremity soft tissue sarcoma from July 1982 through July 1995 at Memorial Sloan-Kettering Cancer Center were the subject of this study. Local recurrence, distant metastasis, and disease-specific survival were used as end points of the study. The influence of local recurrence on subsequent distant metastasis and disease-specific survival were examined using the Cox proportional hazards model. We treated 911 patients, of whom 297 (33%) developed recurrent disease. Local recurrence occurred in 116 patients (13%), metastasis in 167 (18%), and synchronous local recurrence and metastasis in 13 (2%). Of 116 patients who developed local recurrence, 38 subsequently developed metastasis and 34 died of disease. Metastasis after local recurrence was predicted in patients with initial high-grade (P = .005; risk = 3.5) or deep (P = .02; risk = 2.9) tumors. Tumor mortality after local recurrence was predicted in patients with initial high-grade (P = .007; risk = 3.7) or large (> 5 cm; P = .01; risk = 3.2) primary tumors. These findings suggest that there is a strong association of local recurrence with the development of subsequent metastasis and tumor mortality, and that local recurrence is a poor prognostic factor. It would seem prudent to consider patients who develop local recurrence and have high-grade tumors as being at high risk for systemic disease and therefore eligible for investigational adjuvant systemic therapy.

Prognostic factors of locoregionally recurrent nasopharyngeal carcinoma--a retrospective review of 182 cases.

Locoregional relapse is the major cause of failure of nasopharyngeal carcinoma (NPC) after radical radiation therapy. The prognosis of such patients is dismal, and the factors related to the outcome are not well identified. Between January 1983 and December 1989, 1,168 new patients with biopsy-proven NPC were seen at this hospital. Eight hundred and eighty-three of these patients were treated uniformly with radical external irradiation and intracavitary treatment with or without chemotherapy. The clinical courses, retreatment outcomes, and prognostic factors for locoregional relapse and subsequent distant metastasis were analyzed. During the follow-up period of 3-10 years or until death, 182 patients (20.6%) developed locoregional relapses without distant metastasis initially. T stage and age were significant prognostic factors for locoregional recurrence. In contrast, histopathologic subtype, N stage, sex, and systemic chemotherapy were not. There were 36 patients (19.8%) who developed subsequent distant metastasis with or without retreatment. The median time from locoregional relapses to distant metastasis was 6 months in this study, and bone was the most frequent and the earliest site of distant metastasis. The N stage at diagnosis, the initial disease-free interval, the presence of neck nodal disease at relapse, and age were the significant factors for predicting the subsequent distant metastasis in locoregionally recurrent NPC patients. We recommend that additional systemic chemotherapy should be considered for retreatment of locoregional relapsed NPC, not only for enhancement of local control but also for eradicating microscopic metastasis as anticipated.

Cisplatin-fluorouracil exclusive chemotherapy for T1-T3N0 glottic squamous cell carcinoma complete clinical responders: five-year results.

To evaluate cisplatin-fluorouracil exclusive chemotherapy (EC) for T1-T3N0 glottic squamous cell carcinoma complete clinical responders (CCR) after cisplatin-fluorouracil induction chemotherapy (IC). A retrospective analysis was performed of 58 patients with T1-T3N0 glottic squamous cell carcinoma CCR after IC consecutively managed at our department between 1985 and 1992. Twenty-one CCR were managed with EC. Thirty-seven CCR were managed with IC and a conventional laryngeal-preservation modality. Analyses of survival, local control, nodal recurrence, distant metastasis, and metachronous second primary tumor were performed using the Kaplan-Meier actuarial life-table method. In CCR managed with EC, the independent factors of age, tumor classification, exact tumor location, true vocal cord motion, arytenoid cartilage motion, total dosage of drugs delivered, and number of courses received were tested for potential correlation with survival, local recurrence, nodal recurence, and distant metastasis. The 5-year survival, local control, nodal recurrence, distant metastasis, and metachronous second primary tumor rates in CCR managed with EC were 95.2%, 70.7%, 0%, 0%, and 14.3%, respectively. The 5-year rates of survival, local control, nodal recurrence, distant metastasis, and metachronous second primary tumor in CCR managed with IC and a conventional laryngeal-preservation modality were 86.1%, 97%, 2.7%, 6%, and 14.5%, respectively. Local recurrence was statistically more likely in CCR managed with EC (P = .002). Local recurrence in CCR managed with EC was always salvaged with partial laryngectomy or radiation therapy, which resulted in an overall 100% local control and laryngeal-preservation rate within this group. In CCR managed with EC, none of the variables analyzed was statistically related to survival, local recurrence, nodal recurrence, or distant metastasis. The present retrospective studies demonstrated that within T1-T3N0 glottic squamous cell carcinoma CCR, there is clearly a significant subset of patients with chemocurable tumors who achieved both perfect preservation of structure-supporting voice and long-term survival after EC. Careful monthly follow-up evaluation allowed for timely successful salvage of local recurrence after EC without the need for total laryngectomy. Such management did not appear to increase the risk for subsequent nodal failure, subsequent distant metastasis, or reduced survival.

Clinicopathological study of colorectal mucinous carcinoma in Taiwan: A multivariate analysis

The clinicopathological significance of colorectal mucinous carcinoma is controversial, although some authors feel mucinous carcinoma has a worse prognosis than that of non-mucinous carcinoma. To clarify the significance of this type of carcinoma in Taiwan, a retrospective review of patients with colorectal carcinoma treated at Chang Gung Memorial Hospital between 1984 and 1988 was undertaken. During this period, 53 mucinous carcinomas and 401 non-mucinous carcinomas fulfilling the inclusion criteria were analysed. Mucinous carcinomas were more common in patients 39 years of age or under (P < 0.005). Most mucinous carcinomas were located in the rectum/rectosigmoid, followed by the right colon; however, the right colon had a higher relative incidence (38 vs 8%, respectively; P < 0.005). Mucinous carcinomas presented at a significantly more advanced stage (23 vs 8%, respectively, stage D disease; P < 0.005) and had a markedly lower curative resection rate (68 vs 84%, respectively; P < 0.05). Following curative resection, mucinous carcinomas tended to have an increased incidence of subsequent distant metastasis (27.8 vs 18.8%, respectively; P < 0.005). The overall survival rate of patients with mucinous carcinoma was worse than that of non-mucinous carcinoma (P < 0.005). Multivariate analysis showed that clinically important predictive factors were stage of disease on diagnosis and subsequent distant metastasis. The mucinous histological type itself was not an independent prognostic factor in colorectal cancer.

Prognostic value of Cathepsin D expression in breast cancer: Immunohistochemical assessment and correlation with radiometric assay

The prognostic significance of Cathepsin D and optimal methodologies to measure Cathepsin D in breast cancers are controversial. Quantitative (immunoradiometric) and semiquantitative (immunohistochemical) assays for Cathepsin D expression were compared using 25 breast carcinomas. Immunohistochemical Cathepsin D results were derived using 3 different anti-Cathepsin D antibodies and significant associations between immunohistochemical and radiometric Cathepsin D data were observed for each reagent. Immunohistochemical analysis of Cathepsin D expression was performed on nearly 500 fixed-embedded archival breast cancers with long-term patient follow-up using 2 anti-Cathepsin D antibodies (CDR2-11/23, IC11). The immunohistochemical reagents recognized generally overlapping subsets of Cathepsin D positive tumors (correlation co-efficient 0.54; p = 0.00016). Correlations between Cathepsin D data and clinical, histologic or biologic features differed for each antibody. For the node-negative patient subset, Cathepsin D immunopositivity correlated with erbB-2 and stress-response protein 27 overexpression but not survival. Cathepsin D positivity was associated with subsequent distant metastasis and estrogen receptor positivity in node positive patients. Univariate analysis of all patients suggested that Cathepsin D immunopositivity may be predictive of a reduced metastasis-free but not overall survival. Multivariate analysis, however, failed to confirm an independent prognostic value for Cathepsin D in breast cancer patients. These data do not confirm an independent prognostic significance for Cathepsin D using immunohistochemical methods on breast cancers.

Nuclear polymorphism — a prognostic parameter to evaluate local recurrence of female breast cancer

Between 1980 and 1986 676 patients underwent surgery for primary breast cancer. Of these, 35 patients developed locoregional recurrence. Retrospective analysis of the spontaneous postoperative development revealed 2 groups: group A had subsequent distant metastases, group B was tumor-free after surgical treatment of local recurrence. Analysis of the commonly employed characterization criteria of primary tumors (tumor size, lymph node involvement, estrogen receptors, histologic grading of primary tumors, and excised locoregional recurrence) showed no statistically significant difference between the two groups. However, a more detailed differentiation of the subcriteria for the histologic grading according to Bloom and Richardson revealed a prevalence of anaplastic nuclei in the primary tumors of group A (9/11). Even in this small patient population the parameter of nuclear polymorphism revealed a highly significant statistical difference between the two groups.

Multivariate analysis of recurrence after anterior resection for colorectal carcinoma

We performed a multivariate analysis of survival data from 278 patients who underwent potentially curative anterior resection with hand-sewn anastomosis for nonobstructing colorectal carcinoma to evaluate the interaction of the resection margin with distance from the anal verge and their contributions to local and distant recurrence. Cumulative 5-year disease-free survival was 66 percent for the 258 patients with complete follow-up. Forty-nine patients (19 percent) had local recurrence and 42 (16 percent) developed initial distant metastases. Local recurrence rates increased with increasing age and with more advanced Dukes' stage. It developed in twice as many patients with colostomies as without colostomies. Distant metastases developed significantly more often in patients with nodal involvement and in patients with resection margins exceeding 3.5 cm. Forty-four percent of patients with lesions within 14 cm of the anal verge resected with margins of at least 3.5 cm developed distant recurrence. This study suggests that aggressive pelvic dissection to achieve resection margins greater than 3.5 cm may contribute to tumor dissemination and subsequent distant metastases.