• O(6)-(4-bromothenyl)guanine improves the therapeutic index of temozolomide against A375M melanoma xenografts.

      Middleton, Mark R; Kelly, Jane; Thatcher, Nick; Donnelly, Dorothy J; McElhinney, R S; McMurry, T B; McCormick, J E; Margison, Geoffrey P; Cancer Research Campaign Department of Carcinogenesis, Paterson Institute for Cancer Research, Manchester, UK. mmiddleton@picr.man.ac.uk (2000-01-15)
      Tumour resistance to methylating agents is linked to expression of the DNA repair protein O(6)-alkylguanine-DNA alkyltransferase (ATase). There is considerable interest in improving the efficacy of O(6)-alkylating chemotherapy by prior depletion of ATase. We have tested the ability of a modified guanine base, O(6)-(4-bromothenyl)guanine (4BTG), to inactivate ATase and to enhance the anti-tumour effect of temozolomide in an animal model system. A375M human melanoma xenografts were established in the flanks of nude mice. ATase depletion after a single dose of 4BTG or O(6)-BG (20 mg/kg i.p.) was determined over a 24 hr period. Subsequently, we tested the effect of 4BTG (20 mg/kg i.p. daily) and/or temozolomide (80-175 mg/kg i.p. daily) over a 5-day schedule on tumour growth. 4BTG was an effective inactivator of ATase in tumour, producing complete depletion within 2 hr of dosing. Furthermore, it enhanced the tumour growth delay achieved with temozolomide, increasing the tumour quintupling time by 8.7 days (95% confidence interval 6.1-11.3 days, p < 0.0001). Whilst the delay in tumour growth was indistinguishable from that observed with O(6)-benzylguanine (O(6)-BG) and temozolomide, the 4BTG combination resulted in considerably less toxicity (0/9 vs. 2/9 deaths; 6.84% weight loss vs. 9.48%, p = 0.019). 4BTG is a potent inactivator of ATase and enhances the therapeutic ratio of temozolomide in this model system to a greater extent than O(6)-BG.
    • O6-(4-bromothenyl)guanine reverses temozolomide resistance in human breast tumour MCF-7 cells and xenografts.

      Clemons, Mark; Kelly, J; Watson, Amanda J; Howell, Anthony; McElhinney, R S; McMurry, T B H; Margison, Geoffrey P; Cancer Research UK Carcinogenesis Group, Paterson Institute for Cancer Research, Manchester M20 9BX, UK. (2005-11-14)
      Tumour resistance to chemotherapy involving methylating agents such as DTIC (dacarbazine) and temozolomide is linked to expression of the DNA repair protein O(6)-alkylguanine-DNA alkyltransferase (MGMT). There is considerable interest in improving the efficacy of such O(6)-alkylating chemotherapy by the prior inactivation of MGMT. We have examined the effect of the modified guanine base, O(6)-(4-bromothenyl)guanine (PaTrin-2, Patrin, Lomeguatrib) on MGMT activity and cell or xenograft tumour growth inhibition by temozolomide in the human breast carcinosarcoma cell line, MCF-7. PaTrin-2 effectively inactivated MGMT in MCF-7 cells (IC(50) approximately 6 nM) and in xenografts there was complete inactivation of MGMT within 2 h of dosing (20 mg kg(-1) i.p.) and only slight recovery by 24 h. MGMT inactivation in a range of murine host tissues varied between complete and approximately 60%, with extensive recovery by 24 h. PaTrin-2 (10 microM) substantially increased the growth inhibitory effects of temozolomide in MCF-7 cells (D(60)=10 microM with PaTrin-2 vs 400 microM without). In MCF-7 xenografts, neither temozolomide (100 mg kg(-1) day(-1) for 5 days) nor PaTrin-2 (20 mg kg(-1) day(-1) for 5 days) had any significant effect on tumour growth. In contrast, the PaTrin-2-temozolomide combination produced a substantial tumour growth delay: median tumour quintupling time was increase by 22 days (P<0.005) without any significant increase in toxicity as assessed from animal weight. A PaTrin-2-temozolomide combination may therefore be beneficial in the treatment of human breast cancers.
    • O6-alkylguanine-DNA alkyltransferase depletion and regeneration in human peripheral lymphocytes following dacarbazine and fotemustine.

      Lee, Siow Ming; Thatcher, Nick; Margison, Geoffrey P; Department of Medical Oncology, Paterson Institute for Cancer Research, Christie Hospital, Manchester, United Kingdom. (1991-01-15)
      O6-Alkylguanine-DNA alkyltransferase (ATase) levels were measured in peripheral blood lymphocytes of 13 patients with advanced malignant melanoma treated with sequential dacarbazine (DTIC) and fotemustine. Wide interindividual variation in the pretreatment levels and in depletion and regeneration of ATase activity was noted. Depletion of ATase was seen within the first h after DTIC administration with values ranging from 44 to 92% of pretreatment levels. In 10 patients, progressive depletion of ATase activity occurred with nadir activity occurring at about 4 to 6 h with values ranging from 0 to 67% of pretreatment activity; at 18 h after DTIC infusion. ATase activity varied from 6 to 81%. No significant difference was seen between the rates of ATase depletion or regeneration between the two groups of patients receiving either 500 or 800 mg/m2 of DTIC with the same dose of fotemustine (100 mg/m2). In one patient, maximum depletion occurred within 1 h and no ATase activity was detectable over the next 18 h. In another patient, maximum depletion occurred at 2 h after DTIC followed by recovery of ATase activity to 71% at 18 h. In 2 patients who returned for subsequent cycles of chemotherapy, an increase in pretreatment ATase activity was seen. Overall, the extent of depletion of ATase following DTIC/fotemustine was directly proportional to the initial ATase level.
    • O6-methylguanine formation, repair protein depletion and clinical outcome with a 4 hr schedule of temozolomide in the treatment of advanced melanoma: results of a phase II study.

      Middleton, Mark R; Lee, Siow Ming; Arance, Ana; Wood, Michelle; Thatcher, Nick; Margison, Geoffrey P; Cancer Research Campaign Department of Medical Oncology, Christie Hospital NHS Trust, Manchester, UK. mmiddleton@picr.man.ac.uk (2000-11-01)
      O6-Methylguanine-DNA methyltransferase (MGMT) is a major determinant of resistance to temozolomide. Its levels are depleted in lymphocytes after drug administration, but there is partial recovery by 24 hr, the usual time of subsequent dosing. Administering subsequent doses of temozolomide at the MGMT nadir could enhance its effectiveness, by increasing the amount of O6-methylguanine (O6-meG) in DNA. We evaluated the efficacy of such a schedule of temozolomide and determined the kinetics of MGMT depletion and O6-meG formation in DNA following treatment. Thirty patients with advanced malignant melanoma were treated with temozolomide 1,000 mg/m2 equally split into 5 doses over a 16 hr period every 28 days. O6-meG formation was determined in peripheral blood mononuclear cell (PBMC) DNA and, in a subset of patients, in tumor tissue during the first treatment cycle. MGMT levels fell rapidly with dosing, reaching a nadir in PBMCs of 18.0 +/- 2.26% of initial levels. O6-meG levels increased during the treatment period, peaking at 11.1 +/- 1.25 micromol/mol dG in PBMCs and at 4.25 +/- 0.79 micromol/mol dG in tumor biopsies. The main toxicities were grade IV thrombocytopenia in 12 patients (42.8%) and grade IV neutropenia in 11 patients (39.2%), associated with fever in 8 cases. There were 7 responses (1 complete), for an overall response rate of 23.3%; median overall survival was 6.1 months. The compressed schedule has activity against melanoma, with greater MGMT depletion and O6-meG formation than previously reported for O6-alkylating agent regimens. Myelosuppression precludes its wider application, but MGMT in PBMCs predicted the dose intensity of temozolomide that patients could sustain, suggesting a means by which individuals suitable for this approach might be identified.
    • O6-methylguanine-DNA methyltransferase in pretreatment tumour biopsies as a predictor of response to temozolomide in melanoma.

      Middleton, Mark R; Lunn, J M; Morris, Charles; Rustin, G; Wedge, S R; Brampton, M H; Lind, Michael J; Lee, Siow Ming; Newell, D R; Bleehen, N M; et al. (1998-11)
      Resistance of tumour cells to methylating and monochloroethylating agents in vitro and in vivo has been linked to levels of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT). In a clinical trial of temozolomide in advanced malignant melanoma, the relationship between pretreatment MGMT levels in biopsies of cutaneous tumours and involved lymph nodes and clinical response to the drug has been studied. Among 50 evaluable patients, there were three complete responses (CR), four partial responses (PR), six with stable disease (SD) and 37 with progressive disease (PD), with an overall response rate of 14%. In 33 patients in whom MGMT level and clinical response could be evaluated, the tumour MGMT levels (fmol mg(-1) protein) were: CR, 158 +/- 119; PR, 607 +/- 481; NC, 171 +/- 101; PD, 185 +/- 42.3. Thus, measurements of pretreatment levels of MGMT in melanoma did not predict for response to temozolomide.
    • OA05.07 Prognostic value of circulating tumor cells in limited-disease small cell lung cancer patients treated on the CONVERT Trial.

      Fernandez-Gutierrez, Fabiola; Foy, Victoria; Burns, Katy; Pierce, Jackie; Morris, Karen; Priest, Lynsey; Tugwood, Jonathan D; Ashcroft, Linda; Faivre-Finn, Corinne; Dive, Caroline; et al. (2017-01)
    • Obese patients with endometrial cancer: is the robotic approach a challenge or a new era of safer and more cost-effective management of such patients?

      Iavazzo, Christos; Iavazzo, P; Gkegkes, I; Gynaecological Oncology Department, Christie Hospital, Manchester (2016-03-10)
    • Obesity and cancer risk: the role of the insulin-IGF axis.

      Renehan, Andrew G; Frystyk, Jan; Flyvbjerg, Allan; Department of Surgery, Christie Hospital NHS Trust, Wilmslow Road, Manchester M20 4BX, UK. arenehan@picr.man.ac.uk (2006-10)
      Accumulating epidemiological evidence shows that being either overweight or obese, in other words having excess body weight (EBW), is associated with an increased risk of several, common, adult cancers. The molecular mechanisms that underlie these associations are not understood fully, but insulin resistance is likely to be important. The insulin-cancer hypothesis postulates that chronic hyperinsulinemia is associated with decreased concentrations of insulin-like growth factor binding protein1 (IGFBP-1) and IGFBP-2, leading to increased availability of IGF-I and concomitant changes in the cellular environment that favor tumor formation. However, the situation is likely to be more complex because hyperinsulinemia is also associated with alterations in related molecular systems (e.g. sex steroids and adipocytokines). As the prevalence of EBW increases to epidemic proportions, untangling the links between EBW and the insulin-IGF axis and its wider molecular interactions will become increasingly important in the development of preventive strategies.
    • Obesity and cancer treatment outcomes: interpreting the complex evidence

      Slawinski, CGV; Barriuso, J; Guo, H; Renehan, Andrew G; Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK. (2020)
      A wealth of epidemiological evidence, combined with plausible biological mechanisms, present a convincing argument for a causal relationship between excess adiposity, commonly approximated as body mass index (BMI, kg/m2), and incident cancer risk. Beyond this relationship, there are a number of challenges posed in the context of interpreting whether being overweight (BMI 25.0-29.9 kg/m2) or obese (BMI ? 30.0 kg/m2) adversely influences disease progression, cancer mortality and survival. Elevated BMI (? 25.0 kg/m2) may influence treatment selection of, for example, the approach to surgery; the choice of chemotherapy dosing; the inclusion of patients into randomised clinical trials. Furthermore, the technical challenges posed by an elevated BMI may adversely affect surgical outcomes, for example, morbidity (increasing the risk of surgical site infections), reduced lymph node harvest (and subsequent risk of under-staging and under-treatment) and increased risk of margin positivity. Suboptimal chemotherapy dosing, associated with capping chemotherapy in obese patients as an attempt to avoid excess toxicity, might be a driver of poor prognostic outcomes. By contrast, the efficacy of immune checkpoint inhibition may be enhanced in patients who are obese, although in turn, this observation might be due to reverse causality. So, a central research question is whether being overweight or obese adversely affects outcomes either directly through effects of cancer biology or whether adverse outcomes are mediated through indirect pathways. A further dimension to this complex relationship is the obesity paradox, a phenomenon where being overweight or obese is associated with improved survival where the reverse is expected. In this overview, we describe a framework for evaluating methodological problems such as selection bias, confounding and reverse causality, which may contribute to spurious interpretations. Future studies will need to focus on prospective studies with well-considered methodology in order to improve the interpretation of causality. Keywords: Cancer; chemotherapy; immunotherapy; obesity; radiotherapy; surgery.
    • Obesity and cancer treatment outcomes: interpreting the complex evidence

      Slawinski, C. G. V.; Barriuso, J.; Guo, H.; Renehan, Andrew G; Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK. (2020)
      A wealth of epidemiological evidence, combined with plausible biological mechanisms, present a convincing argument for a causal relationship between excess adiposity, commonly approximated as body mass index (BMI, kg/m2), and incident cancer risk. Beyond this relationship, there are a number of challenges posed in the context of interpreting whether being overweight (BMI 25.0-29.9 kg/m2) or obese (BMI ? 30.0 kg/m2) adversely influences disease progression, cancer mortality and survival. Elevated BMI (? 25.0 kg/m2) may influence treatment selection of, for example, the approach to surgery; the choice of chemotherapy dosing; the inclusion of patients into randomised clinical trials. Furthermore, the technical challenges posed by an elevated BMI may adversely affect surgical outcomes, for example, morbidity (increasing the risk of surgical site infections), reduced lymph node harvest (and subsequent risk of under-staging and under-treatment) and increased risk of margin positivity. Suboptimal chemotherapy dosing, associated with capping chemotherapy in obese patients as an attempt to avoid excess toxicity, might be a driver of poor prognostic outcomes. By contrast, the efficacy of immune checkpoint inhibition may be enhanced in patients who are obese, although in turn, this observation might be due to reverse causality. So, a central research question is whether being overweight or obese adversely affects outcomes either directly through effects of cancer biology or whether adverse outcomes are mediated through indirect pathways. A further dimension to this complex relationship is the obesity paradox, a phenomenon where being overweight or obese is associated with improved survival where the reverse is expected. In this overview, we describe a framework for evaluating methodological problems such as selection bias, confounding and reverse causality, which may contribute to spurious interpretations. Future studies will need to focus on prospective studies with well-considered methodology in order to improve the interpretation of causality. Keywords: Cancer; chemotherapy; immunotherapy; obesity; radiotherapy; surgery.
    • Obesity and covid-19: the unseen risks

      Syed, A. A.; Soran, H.; Adam, Safwaan; Salford Royal NHS Foundation Trust, Salford M6 8HD, (2020)
      None
    • Obesity and endometrial cancer: unanswered epidemiological questions.

      Renehan, Andrew G; MacKintosh, M; Crosbie, E; Department of Surgery, Institute of Cancer Sciences, University of Manchester, Manchester, UK (2016-01)
    • Obesity as an avoidable cause of cancer (attributable risks).

      Renehan, Andrew G; Soerjomataram, I; Division of Molecular and Clinical Cancer Sciences, Faculty of Biology, Medicine and Health, The Christie NHS Foundation Trust, Manchester Academic Health Science Centre, University of Manchester, Wilmslow Road, Manchester, Wilmslow Road, Manchester, M20 4BX, UK (2016)
      Excess body weight, commonly categorised as overweight (body mass index, BMI 25.0-29.9 kg/m(2)) and obesity (BMI ≥30 kg/m(2)) is an established risk factor for increased incidence of several adult cancers. As body weight is modifiable, there is a potential for cancer prevention. Calculation of attributable risk (here expressed at population attributable fraction, PAF) offers an estimate of the burden of excess cancers attributable to elevated BMI in populations, and thus an approximation of avoidable cases and the opportunity for prevention. Using counterfactual methods, the estimated PAF worldwide attributed to elevated BMI is 3.6 % or nearly half a million new cancer cases in adults (aged 30 years and older after a 10-year lag period). PAFs are higher in women compared with men (5.4 % vs. 1.9 %). Endometrial, post-menopausal breast, and colon cancers account for nearly two-thirds of cancers attributable to elevated BMI. Globally, excess body weight is the third commonest attributable risk factor for cancer (after smoking and infection); in western populations such as the UK, excess weight ranks as second commonest risk factor.
    • The 'obesity paradox' and survival after colorectal cancer: true or false?

      Renehan, Andrew G; Department of Surgery, Institute of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, The Christie NHS Foundation Trust, Wilmslow Road, Manchester, M20 4BX, UK, andrew.renehan@ics.manchester.ac.uk. (2014-08-02)
      Body mass index (BMI), as an approximation of general adiposity, is an established risk factor for incidence of several adult cancer types, including colorectal cancer (CRC). There is a common perception that these relationships extrapolate directly as adverse prognostic factors after diagnosis, but evidence for this is lacking. The paper from Sclesinger et al. in this issue of the journal adds a new dimension to this debate focusing on relationships of post-diagnosis BMI (as a marker of the steady-state weight among survivors) and survival, and provides evidence on a decreased mortality risk among overweight (post-diagnosis BMI 25.0-29.9 kg/m(2)) compared with normal weight (post-diagnosis BMI 18.5-24.9 kg/m(2)) CRC survivors-an example of an 'obesity paradox.' The observation of the 'obesity paradox' is well documented in the methodology literature, but perhaps, less familiar to the cancer readership. Three broad classes of explanation are posited: (1) the associations are true and plausible; (2) the associations are false and reflect methodological issues; or (3) the observations represent a specific form of selection bias, known as collider bias. The present author argues that the obesity paradox reflects the latter-a product of a statistical bias-and emphasizes that, while these findings are hypothesis generating, they will not alter clinical practice or recommendations.
    • Obesity: A critical risk factor in the COVID-19 pandemic

      Kwok, S.; Adam, Safwaan; Ho, J. H.; Iqbal, Z.; Turkington, P.; Razvi, S.; Le Roux, C. W.; Soran, H.; Syed, A. A.; Cardiovascular Trials Unit, Manchester University NHS Foundation Trust, Manchester, UK. (2020)
      Obesity is an emerging independent risk factor for susceptibility to and severity of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Previous viral pandemics have shown that obesity, particularly severe obesity (BMI > 40 kg/m2 ), is associated with increased risk of hospitalization, critical care admission and fatalities. In this narrative review, we examine emerging evidence of the influence of obesity on COVID-19, the challenges to clinical management from pulmonary, endocrine and immune dysfunctions in individuals with obesity and identify potential areas for further research. We recommend that people with severe obesity be deemed a vulnerable group for COVID-19; clinical trials of pharmacotherapeutics, immunotherapies and vaccination should prioritize inclusion of people with obesity.
    • Obinutuzumab (GA101) plus CHOP or FC in relapsed/refractory follicular lymphoma: results of the GAUDI study (BO21000).

      Radford, John A; Davies, A; Cartron, G; Morschhauser, F; Salles, G; Marcus, R; Wenger, M; Lei, G; Wassner-Fritsch, E; Vitolo, U; et al. (2013-07-10)
      The safety and activity of obinutuzumab (GA101) plus chemotherapy in relapsed/refractory follicular lymphoma was explored in 56 patients. Participants received GA101 plus cyclophosphamide, doxorubicin, vincristine, and prednisone (G-CHOP; every 3 weeks, 6-8 cycles) or GA101 plus fludarabine and cyclophosphamide (G-FC; every 4 weeks, 4-6 cycles). Patients were randomized to either GA101 1,600 mg on days 1 and 8 of cycle 1 followed by 800 mg on day 1 of subsequent cycles or 400 mg for all doses. Treatment responders were eligible for GA101 maintenance (3-monthly). Grade 1/2 infusion-related reactions (IRRs) were the most common treatment-related adverse event (AE) (all grades: G-CHOP, 68%; G-FC, 82%). Grade 3/4 IRRs were rare (7%) and restricted to first infusion. All patients received the planned GA101 dose. Neutropenia was the most common treatment-related hematologic AE for G-CHOP (43%) and G-FC (50%). At induction end, 96% (27/28; CR, 39% [11/28]) of patients receiving G-CHOP and 93% (26/28; CR, 50% [14/28]) receiving G-FC achieved responses. GA101 plus CHOP or FC had an acceptable safety profile, with no new or unexpected AEs, but G-FC was associated with more AEs than G-CHOP. GA101 plus chemotherapy resulted in 93% to 96% response rates, supporting phase 3 investigation. (Registered at www.clinicaltrials.gov: NCT00825149).
    • Obinutuzumab in hematologic malignancies: lessons learned to date.

      Illidge, Timothy M; Klein, C; Sehn, L; Davies, A; Salles, G; Cartron, G; Institute of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Manchester (2015-07-14)
      The routine use of anti-CD20 monoclonal antibodies (mAbs) has improved patient outcomes in CD20-positive non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Despite the clinical success achieved with rituximab, relapses are still common with further improvements in anti-CD20 mAb efficacy required. Many novel anti-CD20 antibodies are in development, but obinutuzumab is currently the only type II glycoengineered anti-CD20 mAb in clinical testing. Obinutuzumab has increased antibody-dependent cell-mediated cytotoxicity, reduced complement-dependent cytotoxicity and enhanced direct non-apoptotic cell death. In preclinical models, obinutuzumab induced superior tumor remission compared with rituximab at the equivalent dose levels, and was active in rituximab-refractory tumors. Obinutuzumab exhibits encouraging efficacy as monotherapy in NHL, and combined with chemotherapy in relapsed/refractory NHL and treatment-naïve symptomatic CLL. In a recent randomized, phase III trial in patients with untreated comorbid CLL, overall response rate was significantly greater (78% vs. 65%, P<0.0001) and median progression-free survival was significantly prolonged (26.7 vs. 15.2months, P<0.0001) for obinutuzumab plus chlorambucil vs. rituximab plus chlorambucil. Obinutuzumab is a type II anti-CD20 antibody that utilizes distinct mechanisms of action relative to type I antibodies like rituximab and has led to significant clinical improvement over rituximab in a phase III trial in CLL. Further trials are ongoing to determine whether such improvements in outcome will be seen in CD20-positive B-cell malignancies.
    • Objective comparison of stapled anopexy and open hemorrhoidectomy: a randomized, controlled trial.

      Wilson, Malcolm S; Pope, V; Doran, H E; Fearn, S J; Brough, W A; Department of Surgery, Christie Hospital, Wilmslow Road, Withington, Manchester M20 4BX, United Kingdom. (2002-11)
      PURPOSE: This trial compares stapled anopexy with open hemorrhoidectomy in patients with prolapsing (Grade 3) hemorrhoids. Particular attention was paid to changes in anorectal physiology, nature of tissue resected, quality-of-life assessments, and cost implications of the treatments studied. METHODS: An initial pilot study was followed by a randomized, controlled trial in a District General Hospital in the United Kingdom. All patients had Grade 3 hemorrhoids. Nineteen patients were studied in the pilot study, with 99 patients in the randomized, controlled trial. All patients in the pilot study and 59 in the randomized, controlled trial underwent stapled anopexy. Thirty patients in the randomized, controlled trial underwent open hemorrhoidectomy. Of the 59 patients in the stapled group, 32 were treated with the Ethicon PPH stapling device, and 27 received stapling with a reusable Autosuture stapling device. The following variables were measured: demographic details, quality of life (Medical Outcomes Study Short Form 36 and directed questions), anorectal manometry, and histology. RESULTS: There was no difference in the case mix within or between the groups. The stapled anopexy groups showed a significant reduction in operative time (P < 0.001) and blood loss (P < 0.001) compared with open hemorrhoidectomy. Open hemorrhoidectomy resulted in significantly greater usage of protective pads postoperatively (P < 0.001) and longer rehabilitation (P < 0.006). CONCLUSIONS: Stapled anopexy is an effective alternative treatment for prolapsing hemorrhoids that allows reduced operative time and shorter rehabilitation. It does not appear to affect continence or overall quality of life.
    • The objective measurement of remission and progression in metastatic breast cancer by use of serum tumour markers. European Group for Serum Tumour Markers in Breast Cancer.

      Robertson, John F R; Jaeger, W; Syzmendera, J J; Selby, C; Coleman, Robert E; Howell, Anthony; Winstanley, J; Jonssen, P E; Bombardieri, Emilio; Sainsbury, J R; et al. (1999-01)
      An established biochemical index for monitoring therapy in patients with metastatic breast cancer was tested prospectively in a multicentre study. The index uses two serum tumour markers--carcinoembryonic antigen (CEA) and carbohydrate antigen 15-3 (CA15-3) along with erythrocyte sedimentation rate (ESR). 67 patients treated by either endocrine or chemotherapy had CA15-3, CEA and ESR measured at diagnosis of metastases and sequentially during therapy. Two markers, CA15-3 and CEA, were measured on a further 16 patients giving a total of 83 patients who were assessable for CA15-3 and CEA. Of the patients with CA15-3, CEA and ESR measured at diagnosis of metastases 84% (56/67) had elevation of 1 or more markers. During therapy the number with elevated marker(s) rose to 96% (64/67). Changes in the markers were in line with and often pre-dated therapeutic outcome as assessed by the International Union Against Cancer (UICC) criteria both for remission and progression. Patients without elevation of markers on diagnosis subsequently showed a rise in the marker(s) at or before documented disease progression by UICC. The 3 women in whom markers were at no time significantly elevated remain in remission. The results using CA15-3 and CEA were similar but 12% less patients were assessable. CA15-3 and CEA (with and without ESR) provide an objective method to guide therapy in patients with metastatic breast cancer.