This article reports on recent advances on metastatic breast cancer. Detection, prognostic factors, predictors of response to therapy and therapy, with particular regard to targeted therapies, were examined.

Calcitonin gene-related peptide (CGRP) is a 37-amino acid neuropeptide produced by tissue-specific alternative splicing of the primary transcript of the calcitonin/CGRP gene. CGRP is widely distributed in the central and peripheral neuronal systems and exhibits numerous biological activities in mammals. We examined in the present study whether or not endogenous CGRP released from neuronal systems facilitates neovascularization indispensable to wound healing. In CGRP knockout mice (CGRP−/−), wound-induced angiogenesis and wound closure were significantly suppressed compared with those in wild-type mice. The suppressed healing in CGRP−/− was accompanied by reduction in expressions of vascular endothelial growth factor (VEGF) in the wound granulation tissues. A CGRP antagonist, CGRP8-37 when infused with mini-osmotic pumps subcutaneously blocked the wound healing processes and reduced the expressions of CD31 and VEGF expression in the wound granulation tissues. Wound healing process was significantly delayed in neuropeptide-depleted mice pretreated with capsaicin, compared with vehicle-treated mice. These results indicate that CGRP derived from neuronal systems may facilitate wound healing and angiogenesis. Targeting of CGRP may be promising in controlling angiogenesis related to pathophysiological conditions.

3723 Background: Unlike long-term survival of colorectal cancer the time distribution of recurrences is not well known and no clear role of serum tumour markers to detect them has been defined. Methods: 173 operated colorectal cancer patients, prolongly followed-up with serial instrumental examinations and serum CEA,TPA,CA19.9,CA72.4 tumour markers, were retrospectively evaluated; 78 (46%) had relapsed, while the 95 others, all followed up longer than 48 months, did not. At the time of primary surgery 28 (36%) of the 78 relapsed patients, were metastatic (M1) and in the 50 (64%) remaining the mod. Duke’s stage was: B1 (2) (2.5%), B2 (21) (27%) and C2 (27) (35%). As to the 95 disease-free patients, 3 (3%) were metastatic, and in the 92 remaining the mod. Duke’s stage was: A (14), B1 (18), B2 (34), C1 (6) C2 (20); their mean follow up was 87 + 12 (74–99 range), 127 + 50 (48–210 range), 120 + 47 (49–222 range), 126 + 50 (48–236 range), 118 + 79 (51–237 range) and 124 + 57 months (52–200 range) respectively. Sensitivity of combined serum CEA, TPA, CA19.9 and CA72.4 was evaluated in 64 (82%) relapsed patients. Results: In 49 (98%) of the 50 post-operatively recurred patients, recurrence occurred within 46 months and the median time was: 38 (30–46 range), 16 (3–39 range) and 15 (2–41 range) months for B1, B2 and C2 stages respectively. In the last 1 (2%) patient, with C2 stage, recurrence occurred 105 months after primary surgery. So recurrences were 20 (40%), 18 (36%), 8 (16%) 3 (6%) and 1 (2%) during the first, second, third, fourth year after primary surgery and thereafter respectively. Sensitivity of CEA-TPA, CEA-TPA-CA19.9 and CEA-TPA-CA19.9-CA72.4 panels was 86%, 87.5% and 93% respectively and the mean lead time of the 3 panels from tumour marker increase to the first pathological instrumental sign ranged from 3.6 to 3.9 months (0–18 range). Conclusions: These data suggest: a) 4 years after primary surgery is a principal end-point for colorectal cancer recurrences; b) serum CEA-TPA-CA19.9-CA72.4 and alternately serum CEA-TPA are sensitive tumour marker panels to post-operatively early detect colorectal cancer recurrences. No significant financial relationships to disclose.

The chemotherapeutic approach to hormone-refractory metastatic prostate cancer (MHRPC) for a long time included only estramustine. Then, attempts have been made with other various agents as cyclophosphamide, vinblastine, etoposide, taxanes and carboplatinum. Although the new drugs and combinations have increased the response rate of MHRPC, they have had no impact on the natural history of MHRPC, which is about 1 year as median time of survival. After an occasional observation of prolonged response in a patient with MHRPC treated with a very well tolerated oral low-dose of cyclophosphamide, from February 1996 to October 2002, seven more patients with MHRPC and progressive disease were consecutively recruited. Response to treatment was evaluated by conventional radiological procedures and/or serial serum PSA measurements. The decline of PSA value was considered to assess the response consistent with the response guidelines from the prostate specific antigen-working group. All eight studied patients continuously received oral low dose cyclophosphamide until progression or the occurrence of significant toxicity. So far three patients (37.5%) progressed (PD), two (25%) showed PR and the three remaining SD. Response rate was 25%, and clinical benefit occurred in 62.5% of the studied patients. In the five patients with clinical benefit on cyclophosphamide median duration of clinical benefit, PR and SD were 9, 24+ and 8 months, respectively. In these five patients median overall survival times from cyclophosphamide and from the first regimen of chemotherapy were 17 and 32+ months respectively, while in the three patients with PD they were 4 and 13 months. The same interval times in patients with ≥50% decline of serum PSA were 29 and 50.5 months, while in those with <50% decline of the same marker, they were 13 and 32 months, respectively. Grade 2 or 3 neutropenia were observed in all the studied patients. In four (50%) of them pulmonary and urinary infections that were easily cured by the common antibiotics occurred. These data suggest that the metronomic use of cyclophosphamide, given alone, has similar or higher activity with lower toxicity than when administered with other active drugs. So it can be an useful option before or after the use of other single or combined potentially active chemotherapeutic agents.

Article Tools Breast Cancer Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/jco.2004.22.90140.753 Journal of Clinical Oncology - published online before print July 15, 2004 PMID: 28014168 Intensive post-operative follow-up of breast cancer patients with tumour markers: Accuracy of serum MCA-CA15.3 and CEA-TPA-CA15.3 tumour marker panels for early detection of relapse A. NicolinixA. NicoliniSearch for articles by this author , G. TartarellixG. TartarelliSearch for articles by this author , P. FerrarixP. FerrariSearch for articles by this author , A. CarpixA. CarpiSearch for articles by this author , M. ContexM. ConteSearch for articles by this author , C. SpinellixC. SpinelliSearch for articles by this author , L. AnselmixL. AnselmiSearch for articles by this author , R. SpisnixR. SpisniSearch for articles by this author , P. MiccolixP. MiccoliSearch for articles by this author Show More University of Pisa, Department of Internal Medicine, Pisa, Italy; University of Pisa, Department of Reproduction, Pisa, Italy; University of Pisa, Department of Surgery, Pisa, Italy https://doi.org/10.1200/jco.2004.22.90140.753 Abstract Abstract 753 Background: In breast cancer serum CEA-TPA-CA15.3 tumour marker panel is a cheap tool with high accuracy for the "early" detection of relapse (A Nicolini, Br J Cancer 1997); serum MCA and CA15.3 are also reported among the most useful serum tumour markers. However the most suitable cut-off of MCA has not yet been defined. The aims were to compare the MCA-CA15.3 with the CEA-TPA-CA15.3 tumour marker panel and to assess the effect of two different MCA cut-off values on this comparison. Methods: From May 2000 to February 2003, 264 breast cancer patients every 6 or 4 months, according to whether they were at low or high risk of relapse, were monitored with serial serum MCA, CEA, CA15.3, and TPA levels besides history and routine lab examinations. Cut-off value was 4.3 ng/mL (CEA), 32 U/mL (Ca15.3), 95 U/L (TPA), 11 and 16 U/mL (MCA). Tumour marker increase was dynamically evaluated according to a previously described method (A Nicolini, Br J Cancer 2000) Bone scintigraphy, liver echography and chest x-ray were carried out at the beginning of the study then at about 18 month interval. When a relapse was suspected by tumour markers, they were performed immediately. Results: So far 18 (7%) of the 264 patients relapsed. Accuracy of MCA-CA15.3 and CEA-TPA-CA15.3 was 46% and 69% respectively for MCA cut-off 11 U/mL and it was 77% and 71% for MCA cut-off 16 U/mL. For MCA cut-off 16 U/mL sensitivity, specificity and lead time were 58%, 78.5%, 7.4 months (mean; 0–22 range) for MCA-CA15.3 and 74%, 71%, 4.1 months (mean; 0–16 range) for CEA-TPA-CA15.3. Conclusions: 16 U/mL is MCA cut-off value more suitable than 11 U/mL. With MCA cut-off value of 16 U/mL, CEA-TPA-CA15.3 has similar accuracy but much higher sensitivity than MCA-CA15.3. No significant financial relationships to disclose. American Society of Clinical Oncology

In 102 N- and 44 N+ disease-free breast cancer patients, lymphocytic populations and skin reaction of delayed hypersensitivity (SRDH) were monitored up to 266 months after mastectomy to find out whether they were similar or different from control values. In two selected groups of 34 N- and 11 N+ breast cancer patients, the whole 10 year follow-up was divided into three subintervals, each of them lasting 40 months and the time course of lymphocytic populations was evaluated. In the 102 N- patients, mean CD4+, CD8+, CD3+ values were lower (P < 0.01, P < 0.001, P < 0.01, respectively) while CD4+/CD8+ ratio was higher (P < 0.05) than in controls. Fifteen N- breast cancer patients (16%) were anergic compared to 30(32%) of controls (P < 0.05). In the 34 selected N- breast cancer patients soon after mastectomy the mean value of CD4+, CD8+, CD3+ T subpopulations was lower (P < 0.01, P < 0.001, P < 0.01, respectively) than in controls. Successively their mean value increased so that in the last subinterval they were not or were only slightly lower (P n.s., P < 0.05, P < 0.05, respectively) than in controls. In the 44 N+ patients, mean CD4+, CD8+, CD3+ values were lower (P < 0.001, v < 0.05, P < 0.01, respectively) and CD19+ lymphocytes higher (P < 0.001) than in controls. Five N+ breast cancer patients (13%) were anergic compared to 32% of controls (P < 0.05). In the 11 selected N+ breast cancer patients soon after mastectomy, the mean value of CD4+, CD8+ T subpopulations and CD16+56+ cells was significantly lower (P < 0.001, P < 0.001, P < 0.01, respectively) than in controls. Successively their mean value constantly increased so that in the last subinterval, no or slight (P n.s., P < 0.05, P n.s., respectively) significant difference compared to controls occurred. The mean CD4+/CD8+ ratio value of N- patients was significantly higher than in controls. However in the last subinterval, the significance was lower than in the first one (P < 0.05 and P < 0.01, respectively). In the N+ patients, the mean value of CD4+/CD8+ ratio was constant, although not significantly, lower than in controls; however it progressively increased from the first to the last subinterval. Therefore the significance of the difference of the mean CD4+/CD8+ ratio between N- and N+ patients strongly decreased from the first to the last subinterval (P < 0.001 and P < 0.05, respectively). These data indicate that in breast cancer patients, following mastectomy, a significant activation of memory and CD4+ T cells and long-term decrease of the circulating immunocompetent CD4+, CD8+ and CD16+56+ cells occurs. The prolonged disease-free interval observed in the 34 N- and 11 N+ breast cancer patients can be correlated with the restoration of the normal state of cell-mediated immunity.

The aim of this retrospective study was to assess the value of a serum tumour marker panel in selecting from among the patients with equivocal chest X-ray (CXR) or liver echography (LE) those with thoracic or liver metastases respectively. Between January 1984 and December 1999, 467 (341 non-relapsed and 126 metastatic) breast cancer patients were followed-up postoperatively. Among the 126 metastatic patients 36 showed thoracic (19 patients) or liver (17 patients) metastases, alone or in conjunction with other organs as the first evidence of distant spread. We focused on this series of 377 patients including 341 non-relapsed plus 36 with liver or thoracic metastases. The patients were followed-up after mastectomy with serial determinations of a panel of CEA-TPA-CA15.3 tumour markers, bone scintigraphy, CXR and LE. Up to December 1999, equivocal CXR occurred in 23 (6.1%) patients of whom 11 (47.8%) developed thoracic metastases; 14 (3.7%) patients showed an equivocal LE of whom 5 developed liver metastases. In the 37 patients with equivocal CXR or equivocal LE prolonged clinical and imaging follow-up over 41 ± 36 months (mean ± SD, range 3–163) was used to ascertain the presence or absence of thoracic or liver metastases. In the 23 patients with equivocal CXR the negative and positive predictive values of the tumour marker panel to predict thoracic metastases were 92% and 100% respectively. In the 14 patients with equivocal LE the negative and positive predictive values of the tumour marker panel for prediction of liver metastases were 90% and 100% respectively. This study shows that in breast cancer patients the CEA-TPA-CA15.3 tumour marker panel has a high value for selecting those patients at high risk of developing clinically evident pulmonary or liver metastases from amongst those subjects with equivocal CXR or equivocal LE. © 2000 Cancer Research Campaign http://www.bjcancer.com