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Background Society of Surgical Oncology and American Society for Radiation Oncology guidelines define clear margins in breast-conserving therapy (BCT) as 'no ink on tumour', in contrast to the attainment of margins of at least 1 mm widely practised in the UK. The primary aim of this study was to explore clinical, surgical and tumour-related factors associated with local recurrence after BCT, with a secondary aim of assessing the impact of margin re-excision on the risk of local recurrence. Methods Patient demographics, surgical details, tumour characteristics and local recurrence were recorded for consecutive women with BCT undergoing surgery between January 1997 and January 2007. Margins were defined as clear (greater than 1 mm), close (less than 1 mm but no ink on tumour), reaches (ink on tumour) and clear after re-excision. Results A total of 1045 women of median age 54 (range 18-86) years were studied. Median follow-up was 89 (range 4-196) months. Local recurrence occurred in 52 patients (5·0 per cent). Ink on tumour was associated with local recurrence (hazard ratio (HR) 4·86, 95 per cent c.i. 1·49 to 15·79; P = 0·009). Risk of local recurrence was the same for close and clear margins (HR 1·03, 0·40 to 2·62; P = 0·954). In women with involved margins, re-excision was still associated with an increased local recurrence risk (HR 2·50, 1·32 to 4·72; P = 0·005). Oestrogen receptor negativity increased risk (HR 2·28, 1·28 to 4·06; P = 0·005). Conclusion Adequately excised margins, even when under 1 mm, provide equivalent outcomes to wider margins in BCT. Achieving complete excision at primary surgery achieves the lowest rates of local recurrence.

The 15th St. Gallen International Breast Cancer Conference 2017 in Vienna, Austria reviewed substantial new evidence on loco-regional and systemic therapies for early breast cancer. Treatments were assessed in light of their intensity, duration and side-effects, seeking where appropriate to escalate or de-escalate therapies based on likely benefits as predicted by tumor stage and tumor biology. The Panel favored several interventions that may reduce surgical morbidity, including acceptance of 2 mm margins for DCIS, the resection of residual cancer (but not baseline extent of cancer) in women undergoing neoadjuvant therapy, acceptance of sentinel node biopsy following neoadjuvant treatment of many patients, and the preference for neoadjuvant therapy in HER2 positive and triple-negative, stage II and III breast cancer. The Panel favored escalating radiation therapy with regional nodal irradiation in high-risk patients, while encouraging omission of boost in low-risk patients. The Panel endorsed gene expression signatures that permit avoidance of chemotherapy in many patients with ER positive breast cancer. For women with higher risk tumors, the Panel escalated recommendations for adjuvant endocrine treatment to include ovarian suppression in premenopausal women, and extended therapy for postmenopausal women. However, low-risk patients can avoid these treatments. Finally, the Panel recommended bisphosphonate use in postmenopausal women to prevent breast cancer recurrence. The Panel recognized that recommendations are not intended for all patients, but rather to address the clinical needs of the majority of common presentations. Individualization of adjuvant therapy means adjusting to the tumor characteristics, patient comorbidities and preferences, and managing constraints of treatment cost and access that may affect care in both the developed and developing world.

Background Trastuzumab is currently the standard of care in combination with chemotherapy for patients with early and advanced HER2 positive breast cancer. Some patients with advanced disease have long remissions, but published data on the efficacy and safety of long-term trastuzumab are limited. Patients and Methods We have retrospectively assessed efficacy and safety of trastuzumab on all patients with HER2 positive advanced breast cancer, who received first-line trastuzumab-containing therapy between 2001 and 2009 at a single institution, The Royal Marsden Hospital. Patients who received adjuvant trastuzumab were excluded. The primary endpoints of the study were time to disease progression and response duration. Secondary endpoints included overall response rate, overall survival and cardiac toxicity related to maintenance trastuzumab beyond 12 months. An exploratory analysis of factors predicting long disease remission on trastuzumab beyond 12 months was also performed. Results 192 patients with HER2 positive locally advanced/metastatic breast cancer treated with trastuzumab containing therapy as first line treatment were identified. The median age at start of treatment was 52 years. The main site of metastatic disease was visceral in 136 (71%) of patients, and 16 patients (8.5%) with central nervous system (CNS) involvement. 152 (79%) patients received trastuzumab in combination with chemotherapy. 18 patients (9%) received trastuzumab with endocrine therapy only. 22 (11%) patients received trastuzumab alone. The median time to progression was 45. weeks (95% CI: 38 – 52 weeks). The overall response rate (ORR) was 63%, including 14 patients (7%) with CR and 107 patients (56%) with PR. Overall disease control (CR+ PR+ SD for at least 6 months) was achieved in 169 (88%) patients. Patients who received trastuzumab with chemotherapy had superior response rate (71%) to trastuzumab alone or in combination with endocrine therapy (37% and 58% respectively). 125 patients (65%) were on trastuzumab for more than 1 year, 88 (46%) for more than 2 years, 63 (33%) for more than 3 years and 25 (13%) for 5 years or more. The median overall survival was 125 weeks, and 28% still alive at 5 years. At the time of the analysis with a median follow-up 6yrs, 46 patients (24%) were still alive. 23 of these (50%) had stopped trastuzumab after discussion. 38 patients (20%) had CNS relapse on trastuzumab, of which 19 (10%) relapsed in the brain alone. Maintenance trastuzumab therapy was well tolerated. 29 (15%) patients had any grade LV dysfunction during trastuzumab treatment, of which 11 (6%) stopped trastuzumab. No deaths or other serious side effects related to trastuzumab were observed. Conclusion Trastuzumab frequently achieves long term control of metastatic breast cancer with more than 25% of patients alive after 5 years. The optimal duration of therapy remains uncertain. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-12-15.

Aim: To identify molecular mechanisms and predictors of response to aromatase inhibitors (AIs) in primary ER+ breast cancer. Background: Although AIs are highly effective suppressants of estrogen synthesis in postmenopausal women, up to 50% of patients derive little or no clinical benefit from AI treatment. The proliferation marker Ki67 provides a valuable pharmacodynamic marker for response in the presurgical setting and 2 week measurements of this marker have been shown to predict recurrence-free survival1. However, understanding of the precise molecular effects of AIs and causes of resistance is limited. We present, to our knowledge, the largest study of the transcriptional effects of AI treatment in the neoadjuvant setting. Methods: Baseline and 2wk post-treatment core-cut tumor biopsies were obtained from 112 postmenopausal women with stage I to IIIB ER+ early breast cancer who received single agent neoadjuvant anastrozole2. RNA extracted from biopsies was analysed on Illumina 48K microarrays. Genes which changed expression upon anastrozole treatment were identified using paired class comparison of the 81 matched baseline and 2wk pairs from which gene expression data was available. Correlates of response were determined using multiple testing corrected Spearman correlation analysis. Pathway analysis was performed on the ranked list of correlated genes. IHC for Ki67, ER and PgR was performed centrally on FFPE sections from duplicate core biopsies. Results: At a false discovery rate (FDR) of 0.01, 1154 genes were differentially expressed (792 down-regulated and 362 up-regulated). Proliferation-associated genes and classical estrogen-dependent genes such as TOP2A, CCNB2, TFF1, and PDZK1 were strongly downregulated (FDR 1. Dowsett et al., JNCI, 2007, 99, 167-70. 2. Smith et al., JCO, 2007, 3816-22. Supported by the Mary-Jean Mitchell Green Foundation and Breakthrough Breast Cancer. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr S2-5.

Background: The epirubicin with cisplatin and infusional 5-fluorouracil (5-FU) (ECisF) regimen was found to be highly active in the treatment of metastatic breast cancer and as neoadjuvant therapy. The UK TRAFIC (trial of adjuvant 5-FU infusional chemotherapy) trial (CRUK/95/007) compared this schedule with 5-FU, epirubicin and cyclophosphamide (FEC60) as adjuvant therapy in patients with early breast cancer. Methods: In this multicentre, open-label, phase III randomised controlled trial, 349 women were randomly assigned to receive i.v. ECisF [epirubicin 60 mg/m(2), day 1, cisplatin 60 mg/m(2), day 1 and 5-FU 200 mg/m(2) by daily 24-h infusion (n = 172)] or FEC [5-FU 600 mg/m(2), day 1, epirubicin 60 mg/m(2), day 1 and cyclophosphamide 600 mg/m(2), day 1 (n = 177)]. Both treatments were delivered every 3 weeks for six cycles. The primary end point was relapse-free interval (RFI). TRAFIC is registered as an International Standard Randomised Controlled Trial (ISRCTN 83324925). Results: All randomised patients were included in the intent-to-treat population. With a median follow-up of 112 months, there was no significant difference in RFI between the treatment groups [hazard ratio 0.84 (95% confidence interval 0.60-1.19); P = 0.33]. Toxic effects were more frequent in patients allocated to ECisF. Conclusions: While limited by size, TRAFIC has long follow-up. No evidence of a clinically worthwhile benefit for the infusional treatment compared with standard treatment was observed which would justify further investigation or widespread use.

The objectives of this study were to determine the toxicity of intratumoural/intrapleural SRL172 in addition to intradermal SRL172 and standard chemotherapy (mitomycin-C, vinblastine and cisplatin) in patients with malignant mesothelioma. Patients received chemotherapy (mitomycin-C: 8 mg m−2, vinblastine: 6 mg m−2, cisplatin 50 mg m−2) on a 3-weekly basis for up to six courses. IP SRL172 injections were given 3-weekly prior to chemotherapy and escalated in groups of three patients from 1 μg to 1 mg bacilli in 10-fold increments. Patients were also given ID SRL172 at a dose of 1 mg bacilli 4-weekly. Patients were assessed for toxicity after each course of chemotherapy and for response by CT imaging. Immuno-haematological parameters were analyzed pre-treatment and 1 month after completion of treatment. There was no dose limiting toxicity with IP SRL172 although there was greater toxicity at the highest dose (n=13). There were six out of 16 partial responses (37.5%). Haemato-immunological parameters, measured in seven patients pre and post-therapy, revealed that response rate correlated with a decrease in platelet count and there was an increase in activation of natural killer cells and a decrease in the percentage of IL-4 producing T cells in all tested patients post-treatment. SRL172 can be given safely into tumour deposits and the pleural cavity in patients with malignant mesothelioma and we have established the dose for phase II testing. British Journal of Cancer (2002) 86, 336–341. DOI: 10.1038/sj/bjc/6600063 www.bjcancer.com © 2002 The Cancer Research Campaign

Serum p53 antibodies have been shown to be a poor prognostic marker in resected non-small-cell lung cancer (NSCLC), but studies in small-cell lung cancer (SCLC) have been contradictory. We have studied the incidence of p53 antibodies in a large SCLC cohort treated at one oncology centre and correlated the results with survival. 231 patients (63% male, median age 65), diagnosed and treated for SCLC between 1987 and 1994 at The Royal Marsden Hospital NHS Trust, had sera stored pretreatment. All samples were tested for p53 antibodies (p53-Ab) using a standardized ELISA technique with a selection of strongly ELISA positive, weakly ELISA positive and negative samples being confirmed with immunoprecipitation. 54 patients were positive for p53-Ab (23%). The presence of a high titre of p53-Ab (titre ratio >5) appears to be associated with a survival advantage with a relative risk of death of 1.71 (95% CI: 1.14–2.58) in those without the antibody (P = 0.02). This study, the largest homogenous group so far looking at p53-Ab in SCLC, suggests that p53 antibody detection may have a role in predicting outcome in this type of cancer. © 2000 Cancer Research Campaign http://www.bjcancer.com

Mycobacterial preparations have been used with limited success against cancer apart from superficial bladder cancer. Recently, a therapeutic vaccine derived from Mycobacterium vaccae has been given to patients with prostate cancer and melanoma indicating a possible beneficial effect on disease activity in such patients. We have recently initiated a series of randomized studies to test the feasibility and toxicity of combining a preparation of heat-killed Mycobacterium vaccae (designated SRL172) with a multidrug chemotherapy regimen to treat patients with inoperable non-small cell lung cancer (NSCLC) and mesothelioma. 28 evaluable patients with previously untreated symptomatic NSCLC and mesothelioma were randomized to receive either 3 weekly intravenous combination chemotherapy alone, or chemotherapy given with monthly intra-dermal injections of SRL172. Safety and tolerability were scored by common toxicity criteria and efficacy was evaluated by survival of patients and by tumour response assessed by CT scanning. The toxicity of chemotherapy was similar in the two groups. SRL172 caused mild inflammation at the injection site. In the group of patients randomized to receive chemotherapy combined with SRL172, there was a trend towards improved response rate (54% vs. 33%) with more patients in the combined arm receiving radical surgery and radiotherapy, improved median survival (9.7 months vs. 7.5 months) and improved 1 year survival (42% vs. 18%). SRL172 appeared to improve sleep (P = 0.08) and improved appetite (P = 0.01). There was no detectable change in serum cytokine levels for gamma-interferon and TNF-α before and after treatment. In patients with NSCLC and mesothelioma, there may be a beneficial interaction when chemotherapy is administered in combination with SRL172. Confirmation of this effect and further investigation is underway in a randomized phase III trial and in laboratory models. © 2000 Cancer Research Campaign

Numerous recent studies have indicated the central role of apoptosis as a determinant of the growth abnormalities occurring with malignancy and of the effectiveness of a wide range of therapeutic manoeuvres in cancer treatment. However, there has been a relative paucity of studies measuring apoptosis in human solid tumours, because of the low incidence of apoptotic cells, the difficulty of identifying cells undergoing apoptosis, and the ethical and practical restrictions on obtaining repeat biopsies from patients during therapy. Fine-needle aspirates (FNAs) may be obtained from breast carcinomas as a minimally invasive technique allowing repeat sampling. We describe an approach in which the in situ end labelling (TUNEL) assay is applied to cells in FNAs prior to their analysis by flow cytometry, which allows many thousands of cells to be analysed automatically by objective criteria. Cells that were discriminated as apoptotic on flow cytometric analysis were sorted onto microscope slides and found to show nuclear morphology typical of apoptotic cells. A statistically significant relationship was found between the flow cytometric analysis and the conventional application of TUNEL on histological sections (P 5 0.03). Repeat analyses of FNAs from 12 carcinomas showed a median 2.05% apoptotic cells and an overall coefficient of variation of 34.9%. Of the total variability in 12 tumours, 80% was attributed to variation between tumours, 12% between batches, and 8% was random. Thus, this technique should be able to detect the major differences in the percentage of apoptotic cells that occur between different tumours (range 0.3‐11.3% by flow cytometry) and between different phases of treatment, and should provide a useful tool for further research on this process in solid tumours. Cytometry 32:291‐300

This study was undertaken to determine if recombinant interferon-gamma (rIFN-gamma) given every other day as maintenance therapy could prolong the survival of patients with small cell lung cancer (SCLC) who achieved a complete or nearly-complete response to induction therapy. A secondary endpoint was to assess the toxicity of alternate day doses of this treatment. One hundred and seventy seven patients in complete or nearly-complete response following chemotherapy with or without thoracic radiotherapy were studied. Patients were randomised to receive either rIFN-gamma 4 million units (0.2 mg) subcutaneously every other day for 4 months or observation. One hundred and twenty of the 127 registered patients were eligible; 59 patients received IFN and 61 patients without maintenance therapy were followed. Alternate day IFN was reasonably well tolerated by the majority of patients, but in 12% substantial non-haematological toxicity (including flu-like syndrome) occurred. One of 3 patients with pneumonitis died after having received 3.6 mg IFN. The median survival time from the date of randomisation was 8.9 months for the IFN arm and 9.9 months for the observation arm. rIFN-gamma at the dose and schedule used in this study failed to prolong response duration and survival in SCLC patients in complete or nearly-complete response. The toxicity seen with every other day doses of IFN was less than that reported with daily dosing. The hypothesis that this agent may increase the deleterious effects of radiation on normal lung tissue was supported by the development of pneumonitis in 3 cases of whom 1 had a fatal outcome. The results do not warrant further studies with rIFN-gamma on maintaining response in SCLC.

The effect of idoxifene, a novel anti-oestrogen with less agonist activity than tamoxifen, was compared with that of tamoxifen on the growth of hormone-dependent MCF-7 breast cancer xenografts. Forty tumours were established with oestradiol support in ovariectomized athymic mice, allowed to grow to a median volume of 420 mm3 and then continued with oestradiol, no support, tamoxifen or idoxifene delivered by 1.5-cm silastic capsule. Tumour regression occurred with both anti-oestrogens, although maximum regression was observed following oestradiol withdrawal alone. While prolonged anti-oestrogen therapy was associated with static growth, tumour volumes were significantly lower with idoxifene (P=0.01). After 6 months, 0/10 idoxifene-treated tumours developed acquired resistance compared with 3/10 tumours treated with tamoxifen. In separate experiments, 94 animals were treated initially with oestradiol, tamoxifen, idoxifene or placebo following implantation with 1-mm3 pieces of either wild-type (WT) or tamoxifen-resistant (TR) MCF-7 tumour. After 4 months, only 1/11 WT tumours became established with idoxifene compared with 4/11 with tamoxifen, 8/12 with oestradiol and 0/12 with placebo. Likewise, fewer TR tumours were supported by idoxifene (3/12) than by tamoxifen (8/12) or oestrogen (11/12). These data indicate that, compared with tamoxifen, idoxifene shows reduced growth support of MCF-7 xenografts and may share only partial cross-resistance. Furthermore, the development of acquired anti-oestrogen resistance may be reduced during long-term idoxifene therapy. The drug's reduced agonist activity may, in part, explain these observations and indicate a preferable biochemical profile for breast cancer treatment.

The use of primary chemotherapy represents a novel approach being used with increasing frequency in the management of early breast cancer. Many studies now testify to the usefulness of this modality in increasing the frequency of breast conservation. The acceptance of high-risk breast cancer as a systemic, and therefore predominantly medical rather than a surgical, disease suggests, however, that its role is likely to be far more reaching. While some trials have so far suggested the possibility of a survival benefit for this approach, definitive conclusions are not yet possible and await the final mature results from several large randomized studies. Even if such studies do not show a large extra benefit for primary chemotherapy over existing adjuvant treatment, the use of the primary tumour as an in vivo model of individual chemosensitivity and the identification of molecular markers as early predictors of response, suggest that this approach will become an integral part of the modern multidisciplinary management of early breast cancer.

PURPOSE To investigate the efficacy of continuous infusion fluorouracil (5FU) with every-3-week epirubicin and cisplatin (ECF) as primary chemotherapy instead of immediate mastectomy for patients with large, potentially operable, breast cancer. PATIENTS AND METHODS Fifty patients with large operable breast cancer, median tumor diameter 6 cm (range, 3 to 12), were treated with 5FU 200 mg/m2/d via a Hickman line using an ambulatory pump for 6 months with epirubicin 50 mg/m2 intravenously (IV) and cisplatin 60 mg/m2 IV every 3 weeks for eight courses. Subsequent surgery and/or radiotherapy was determined by clinical response. RESULTS Forty-nine patients achieved an overall response (98%; 95% confidence interval [CI], 94% to 100%), including 33 complete clinical remissions (CRs) (66%; 95% CI, 53% to 79%). Only three patients (6%) still required mastectomy. Tumor cellularity was markedly reduced on repeat needle biopsy following 3 weeks of treatment in 81% of patients versus only 36% in similar patients after conventional chemotherapy (P < .002). Severe (World Health Organization [WHO] grade 3 to 4) toxicity was rare, with nausea/vomiting being the most common, occurring in 20% of patients. CONCLUSION Primary infusional ECF appears to be more active on clinical and histopathologic grounds than conventional chemotherapy for large operable breast cancer and is well tolerated. This approach now merits randomized comparison to determine if high CR rates may translate into improved survival.

Background: There is great interest in the mutational landscape of metastatic breast cancer (BC) for personalised medicine. Knowledge about how this landscape differs in recurrent lesions from primary BC as a result of metastatic selection or the impact of treatment will extend our knowledge of mechanisms of endocrine resistance and determine the manner in which diagnostics and treatment are integrated. A small number of limited series have reported an increased presence of ESR1 mutations in metastatic lesions after endocrine treatments including aromatase inhibitors (AIs) which are the most common agents for ER+ postmenopausal BC. Aim: To determine the change in mutational profile of 16 genes affected by driver mutations in patients with metastatic BC at the time of progression after an AI. Methods: We conducted targeted sequencing with a custom AmpliSeq panel in 48 matched pairs of FFPE archival blocks of pre-treatment diagnostic and recurrent lesions. 24 of these were metastatic, 24 local recurrences. The genes were AKT1, BRAF, CDH1, ERBB2, ESR1, GATA3, KIT, KRAS, MAP2K4, MAP3K1, PIC3CA, PIK3R1, PTEN, RUNX, SF3B1 and TP53. Only mutations with high depth (>250x) were retained. Germline mutations were identified by 1000 Genomes Project data. C:G>T:A transitions with low frequency ( Results: Median coverage was 782-fold. Good quality data was available on 42 pairs. At least one mutation was found in 34 pairs. Three cases had lost IHC expression of ER in the recurrence. A total of 115 mutations in coding regions or splice sites were identified, the largest number in PIK3CA (in 20 samples), CHD1 (18), MAP3K1 (12), TP53 (12) and PTEN (9). In 47 instances the mutation was private to one or other sample. There was no difference in the number of mutations between the presentation and recurrent lesions. Six ESR1 mutations were found, all private to 5 recurrent lesions (all IHC ER+). Four of these mutations have been previously reported (2x E380Q, 2x D538G), one was novel (D484G) and also in the ligand-binding domain. One had an additional previously reported mutation (H524L). Four of these lesions were metastatic but one in a local recurrence suggesting that the metastatic process is more likely, but not essential in selecting the emergence of ESR1 mutations. HER2 mutations were identified in 3 patients; in two cases private in the presentation tumour while in the other case the mutation in the recurrent lesion (L755S) differed from that in the primary. L755S has been reported to be sensitive to neratinib in experimental systems. CDH1 (e-cadherin) mutations were numerically higher than reported in other series. The mutations were across the gene and private in 4 pretreatment and 2 recurrent lesions (6 had identical mutations). They were not associated with lobular phenotype. Conclusions: These data confirm that recurrences after AI but not primary ER+ tumours often contain ESR1 mutations that could influence clinical decision making. The high number of CDH1 mutations at diagnosis may be at least in part because of the selection of recurrent ER+ cases. The data stress the individuality of mutational profiles in recurrent BC and the need for individual interpretation of the data. Citation Format: Gellert P, Ribas R, Pancholi S, Lopez-Knowles E, Yeo B, Garcia-Murillas I, Pearson A, Smith I, Turner N, Dowsett M, Martin L-A. Occurrence of natural ESR1 mutations during acquisition of endocrine resistance in breast cancers and widely used ER+ cell lines. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S6-02.

We have performed a phase I study of the effect of a single dose of CGS 20267, an oral nonsteroidal aromatase inhibitor, in 12 healthy volunteer postmenopausal women. Each subject received 2 single doses of CGS 20267 (0.1, 0.5, or 2.5 mg) or placebo separated by a washout period of at least 6 weeks. There was statistically significant suppression of serum estrone and estradiol at all three doses of CGS 20267 tested. Serum estrone and estradiol concentrations were maximally suppressed by 76% and 79% from baseline levels, respectively. Urinary excretion of estrone and estradiol was also suppressed, although this did not reach statistical significance. Serum concentrations of aldosterone, cortisol, 17 alpha-hydroxyprogesterone, androstenedione, testosterone, FSH, LH, and TSH were unaffected by CGS 20267. The drug was well tolerated, with no significant side-effects. This study has shown CGS 20267 to be a potent and specific aromatase inhibitor, and further studies are now needed to assess its clinical efficacy.

Over-expression of c-erbB2 in human breast cancer correlates with a poor prognosis and increased tumour aggressiveness. Recent in-vitro evidence has suggested that expression of c-erbB2 may be hormonally regulated, and in particular that oestrogen-withdrawal or tamoxifen administration to ER+ve breast cancer cells may inhibit cell proliferation but actually increase c-erbB2 expression. We have studied the effect of short-term tamoxifen in-vivo on the immunohistochemical expression of c-erbB2 in human primary breast carcinomas. Typical membrane staining for c-erbB2 which correlates with oncogene amplification occurred in 13% (537) of tamoxifen-treated tumours and 11% (438) of untreated control tumours, and showed a significant association with ER-ve tumours in the control group (p = 0.03). In addition granular cytoplasmic staining for c-erbB2 was demonstrated in 57% (2137) of the tamoxifen-treated tumours, but was only observed in 3% (138) of the untreated control tumours (p

Bone metastases secondary to breast cancer are an important clinical problem responsible for much of the morbidity seen with this disease. From animal studies and observations using scanning electron microscopy osteoclast activation appears to be the first step in the development of bone metastases. Conditioned media produced from short-term culture of breast cancer explants are capable of stimulating osteolysis. Some of this osteolytic activity is due to prostaglandins while the rest is due to a poorly characterised mixture of peptides. In recent years many peptides have been shown to be produced by tumour cells while others may be produced by the surrounding stromal cells. Recent evidence has suggested that parathyroid hormone-related peptide (PTHrP) may have a role in the pathogenesis of bone metastases as PTHrP positive tumours appear more likely to develop bone metastases. Another osteolytic growth factor, transforming growth factor α has also been shown to be produced by breast cancers. Stromal cells are capable of producing many cytokines including interleukin 1, tumour necrosis factor and lymphotoxin, all of which are capable of stimulating osteolysis. A combination of these peptides possibly acting synergistically is likely to be responsible for breast cancer associated osteolysis.

While the presence of oestrogen receptors (ERs) in human breast cancer may determine the biological response to tamoxifen, the extent to which ER status governs tumour tamoxifen accumulation is unclear. We investigated the intra-tumoural disposition of tamoxifen (TAM) and its major metabolite N-desmethyltamoxifen (DMT) in 36 human breast carcinomas following short-term therapy. Steady-state serum concentrations appeared to be reached following 2 weeks therapy, after which no significant difference in the intratumoural concentrations of TAM between ER − ve and ER + ve tumours was observed (717.9 ± 166.4 ng/gm, and 518.6 ± 109.4 ng/gm, respectively). In patients treated for less than 2 weeks, there was significantly less intra-tumoural TAM in ER − ve compared with ER + ve tumours (120.9 ± 49.9 ng/gm and 450.1 ± 75.3 ng/gm, respectively; p < 0.04). The rate of tumour TAM accumulation correlated with duration of therapy only for ER − ve tumours (r = 0.72, p < 0.02), whereas for ER + ve tumours the absolute ER value appeared to be weakly associated with TAM accumulation (r = 0.41; p < 0.05). The intra-tumoural ratio of TAM to DMT reflected the serum concentrations in ER − ve tumours, but in ER + ve tumours relatively more TAM to DMT was observed. A similar intracellular distribution of both TAM and DMT was observed, although following 2 weeks therapy relatively less of each compound was found in the cytosol of ER − ve compared with ER + ve tumours (18% vs 34%). These results demonstrate that ER status may influence the rate of accumulation and intra-cellular distribution of tamoxifen and its metabolites, but not the final concentrations which are achieved. Following steady-state, both ER + ve and ER − ve tumours, not all of which would be expected to respond to the drug, achieve intra-tumoural concentrations 5–7 fold greater than serum. Unlike recent reports on acquired resistance, therefore,de novo resistance to tamoxifen is unlikely to represent an inability of the tumour to achieve adequate intra-tumoural concentrations of the drug or its metabolites.

Analogues of the neurotransmitter substance P (SP) can interact with neuropeptide receptors, and are reported to inhibit growth of small cell lung cancer cell lines (SCLC CLs). We found [D-Arg1, D-Phe5, D-Trp7,9, Leu11] substance P (D-Phe5SP) significantly inhibited DNA synthesis by 10/10 human tumour CLs; six SCLC, one N-SCLC (squamous), two ovarian and one squamous cervical carcinoma, with inhibition to 50% control levels (IC50) of 20-50 microM. There was dose dependent inhibition of colony forming efficiency (CFE) in 3/3 SCLC and 1/1 N-SCLC CL, IC50s of 0.5-6.5 microM in 5% serum. Exposure of SCLC CL HC12 to 100 microM D-Phe5SP for 1-4 h caused a progressive fall in viable cell number; surviving cells, grown in the absence of peptide, showed a decreased growth rate. During 1 week's exposure of two SCLC CLs to 20 microM D-Ph5SP, growth was slower than control cultures, while 50-100 microM completely inhibited growth. These inhibitory effects were partially reversed by increasing serum concentration from 5 to 20%, but not by SP, vasopressin, bombesin or insulin-like growth factor 1. There was some inhibition of CFE by 3/3 normal human bone marrows, IC50s of 30-80 microM, compared with 8 microM for HC12 in 20% FCS. Therefore D-Phe5SP appears to have more potent antiproliferative effects in tumour cells than normal cells, suggesting a role for this analogue in tumour treatment.

72. 6. Harbeck N, Jakesz, R. St. Gallen 2007: Breast Cancer Treatment Consensus Report. Breast Care 2007;2:130–4. 7. Sledge GW, O’Neill A, Thor A, et al. Adjuvant trastuzumab: long-term results of E2198. Breast Cancer Res Treat 2006;100:S106. 8. Norris B, Chia S, Cheang M, et al. Poor 10yr breast cancer specific survival (BCSS) and relapse free survival (RFS) for HER-2 positive T1pN0 tumors. San Antonio Breast Cancer Conference 2006; Poster 2031. 9. Joensuu H, Isola J, Lundin M, et al. Amplification of erbB2 and erbB2 expression are superior to estrogen receptor status as risk factors for distant recurrence in pT1N0M0 breast cancer: a nationwide population-based study. Clin Cancer Res

Neoadjuvant therapy provides a unique and powerful opportunity to derive biopsy material before, during and subsequent to the treatment of otherwise untreated breast cancers and, by measuring the expression of biomarkers in these, to study the biology of the disease in vivo. We have conducted such studies involving endocrine therapy or chemotherapy and have focused on the concept that measurement of change in expression of critical biomarkers shortly after starting therapy may be more closely associated with clinical outcome than before therapy.

We have detected somatostatin receptors (SSR) by autoradiography in 3/4 established small cell lung cancer (SCLC) cell lines but not in two non-SCLC cell lines. The growth of 1/3 SSR positive SCLC cell lines was significantly inhibited by the long-acting somatostatin analogue octreotide (SMS 201-995, Sandostatin) 10(-9) M. We treated 20 SCLC patients with octreotide 250 micrograms three times daily for 1 week prechemotherapy (six patients) or at relapse after chemotherapy (14). Octreotide was well tolerated, and serum insulin-like growth factor-I levels were suppressed to 62 +/- 7% of pre-treatment levels. However there was no evidence of anti-tumour activity measured by tumour bulk or serum levels of neuron-specific enolase. In one patient metastatic skin nodules were shown to be SSR positive before and at the end of 2 weeks octreotide. Despite this the patient had progressive disease, and tumour cells obtained by fine needle aspirate before and after treatment showed no growth inhibition when cultured with octreotide immediately or following establishment as a cell line. In summary we saw little correlation between SSR expression and growth inhibition by octreotide, either in vitro or clinically. Images Figure 4

Carboplatin has been incorporated into a new low toxicity combination chemotherapy regimen with methotrexate and vinblastine (CVM) against small cell lung cancer (SCLC). We have compared CVM (carboplatin 300 mg/m 2 , vinblastine 6 mg/m 2 , methotrexate 30 mg/m 2 , all intravenously every 4 weeks) with ACE (doxorubicin 40 mg/m 2 , cyclophosphamide 600 mg/m 2 , etoposide 100 mg/m 2 all intravenously day 1–3, every 3 weeks) in a randomised trial. 3654 evaluable patients treated with CVM achieved an objective response (67%) (95% confidence limits [CL] 54–79%) compared with 4450 treated with ACE (88%) (95% CL 80–97%, P = 0.06). For patients with limited disease treated with CVM, 1417 (83%) (95% CL 64–100%) had an objective response compared with 1415 (93%) (95% CL 81–100%) treated with ACE (not significant). Overall median survival was 8 months for CVM and 7 months for ACE. Haematological toxicity was significantly lower for CVM than ACE and consequently dose reduction/delay and infection were less with CVM. Subjective toxicity was low and alopecia was significantly less for CVM than ACE. CVM is an active, well tolerated new chemotherapy regimen for SCLC.

Mitozantrone (Novantrone) has recently been incorporated into a new combination chemotherapy regimen with mitomycin-C and methotrexate (MMM) against advanced breast cancer. We have compared MMM (mitozantrone 8 mg m-2 i.v. q 3 weekly, methotrexate 35 mg m-2 i.v. q 3 weekly, mitomycin-C 8 mg m-2 i.v. q 6 weekly) with CMF (cyclophosphamide 100 mg orally, days 1-14, methotrexate 35 mg m-2 i.v., days 1 and 8, 5-FU 1,000 mg i.v., days 1 and 8, q 4 weekly), each regimen with folinic acid rescue, in a randomised trial, 29/57 evaluable patients treatment with MMM achieved an objective response (51%) compared with 33/55 treated with CMF (60%). Overall median survival was 16 months for MMM and 12 months for CMF. Subjective toxicity was low for both regimens and the only significant difference was in incidence of diarrhoea (50% for CMF vs 21% for MMM). Haematological toxicity was similar, leading to treatment delays and/or dose reductions in 35% patients with CMF vs 43% with MMM. Thrombocytopenia was significantly increased in MMM (34% vs 14%). No clinical cardiotoxicity was seen, but a significant reduction in left ventricular ejection fraction occurred in four patients on CMF vs 2 on MMM. MMM is an active, well tolerated new chemotherapy regimen for advanced/metastatic breast carcinoma with an efficacy and toxicity spectrum very similar to CMF.

Aim: The Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (ALTTO) Trial is a randomised phase III adjuvant breast cancer trial comparing 3 oral lapatinib (L)-containing regimens with trastuzumab (T), each given for 1 year. DFS results of L + T and T—> L compared to T, presented at ASCO 2014, showed a non-significant DFS benefit. Results of L vs T and key secondary analyses are presented for the first time. Methods: 8381 patients (pts) were randomised to receive either T (N = 2097), L (N = 2100), T —> L (N = 2091), or L + T (N = 2093) from 2007-2011. Primary comparison of L vs T evaluated non-inferiority at a margin of 1.11 and the futility boundary for this arm was crossed resulting in premature arm closure (Aug 2011). Pts in the L arm who were free of disease recurrence at that time were offered T as adjuvant treatment. Key secondary analyses including DFS by hormone receptor status and CNS endpoints are now presented. Results: In 4197 pts and at a median follow-up of 4.5 years, 366 (17%) DFS events in the L and 301 (14%) DFS events in the T arms were observed. 1090 (52%) pts in the L arm received at least one T dose. In post-hoc analysis, there was evidence that these pts benefitted from receiving T [hazard ratio (HR) = 0.67; 95% CI 0.49-0.91 from a time-dependent Cox model of DFS]. The non-inferiority HR was 1.34 (95% CI 1.15-1.56) in the ITT population; 1.45 for hormone receptor negative, 1.23 for hormone receptor positive. CNS as first site of metastases occurred in 2% of cases in all arms. AEs of any grade were more common with L than T: diarrhoea (64% vs 20%), rash or erythema (54% vs 20%) and hepatobiliary (25% vs 16%). Any cardiac events were infrequent in both arms, but more common in T compared to L (4.5% vs 1.9%; p Conclusions: Overall, L added to T did not statistically improve DFS. L did not appear to decrease the rate of CNS as first site of metastases. T confers a better outcome compared to L in pts with HER2-positive EBC and remains the standard of care. There is evidence of T benefit even when initiated later in the course of follow-up. Disclosure: E. De Azambuja: Disclosed an advisory role with GSK; honoraria from Roche; research funding from GSK; and travel grants from GSK/Roche; G. Viale: disclosed an advisory role with Roche and Dako; and honoraria from GSK, Roche, and Dako; R. Crescenzo: disclosed compensated employment with GlaxoSmithKline; and stock ownership with Glaxo SmithKline; K. Pritchard: disclosed an advisory role with Roche; honoraria from Roche; research funding from Roche; and expert testimony on behalf of Roche; C. Jackisch: disclosed honoraria from Roche and GSK; F. Boyle: disclosed honoraria from GlaxoSmithKline; and research funding from GlaxoSmithKline; R.D. Gelber: disclosed research funding from GSK and Roche; M. Piccart: disclosed consultancy with PharmaMar; honoraria from Amgen, Astellas, AstraZeneca, Bayer, Eli Lilly, Invivis, MSD, Novartis, Pfizer, Roche-Genentech, Sanofi Aventis, Symphogen, Synthon, and Verastem; research grants from most companies. All other authors have declared no conflicts of interest.

Summary Background: In many centres surgery is used as part of a combined modality approach to the treatment of inflammatory breast cancer (IBC). Nevertheless, its value is controversial given the high risk of metastatic relapse and poor overall prognosis. We have reviewed patients with true IBC prospectively treated at the Royal Marsden Hospital in chemotherapy trials to assess further the role of surgery as part of combined modality treatment. Patients and methods: Fifty-four patients who had responsive or stable disease to primary chemotherapy went on to have either radiotherapy alone (n = 35) or surgery plus radiotherapy (n = 19); the decision on surgery was based partly on clinician preference and partly on clinical response. Results: The 35 patients undergoing radiotherapy alone had a median progression-free survival (PFS) of 16 months and median overall survival (OS) of 35 months. Twenty-four patients (69%) have relapsed with a total of twelve (34%) relapsing locally. In comparison, the 19 patients receiving both surgery and radiotherapy had a PFS of 20 months, and a median OS of 35 months. Fifteen patients (79%) have relapsed, eight (42%) of these locally. None of these differences were statistically significant. Conclusions: These results do not suggest a clinical advantage for surgery in addition to chemotherapy and radiotherapy for patients with IBC. They support the need for a prospective randomised trial to address this question.

To grow and metastasize, solid tumours must develop their own blood supply by neo-angiogenesis. Thalidomide inhibits the processing of mRNA encoding peptide molecules including tumour necrosis factor-alpha (TNF-α) and the angiogenic factor vascular endothelial growth factor (VEGF). This study investigated the use of continuous low dose Thalidomide in patients with a variety of advanced malignancies. Sixty-six patients (37 women and 29 men; median age, 48 years; range 33–62 years) with advanced measurable cancer (19 ovarian, 18 renal, 17 melanoma, 12 breast cancer) received Thalidomide 100 mg orally every night until disease progression or unacceptable toxicity was encountered. Three of 18 patients with renal cancer showed partial responses and a further three patients experienced stabilization of their disease for up to 6 months. Although no objective responses were seen in the other tumour types, there were significant improvements in patients' sleeping (P< 0.05) and maintained appetite (P< 0.05). Serum and urine concentrations of basic fibroblast growth factor (bFGF), TNF-α and VEGF were measured during treatment and higher levels were associated with progressive disease. Thalidomide was well tolerated: Two patients developed WHO Grade 2 peripheral neuropathy and eight patients developed WHO grade 2 lethargy. No patients developed WHO grade 3 or 4 toxicity. Further studies evaluating the use of Thalidomide at higher doses as a single agent for advanced renal cancer and in combination with biochemotherapy regimens are warranted. © 2000 Cancer Research Campaign

The interaction between cell death and cell proliferation determines the growth dynamics of all tissues. Studies are described here which relate the changes in proliferation and apoptosis that occur in human breast cancer during medical therapeutic manoeuvres. Xenograft studies strongly support the involvement of increased apoptosis as well as decreased proliferation after oestrogen withdrawal, and limited studies in clinical samples confirm the involvement of both processes. Cytotoxic chemotherapy induces increases in apoptosis within 24 h of starting treatment. However, after 3 months therapy the residual cell population shows apoptotic and proliferation indices much below pretreatment levels. Further molecular studies of this "dormant" population are important to characterise the mechanism of their resistance to drug therapy. The early changes in proliferation and apoptosis may provide useful intermediate response indices.

Aminoglutethimide, the first aromatase inhibitor, was established in the 1970s as an active treatment for patients with advanced breast cancer, but its lack of specificity was associated with side effects. Since that time, a series of much more specific non-steroidal aromatase inhibitors has been developed which are up to 10 000 times as potent as aminoglutethimide in vivo with no evidence of inhibition of other steroid pathways at doses required to inhibit oestrogen. Two of these inhibitors, letrozole (Femara; Novartis) and anastrozole (Arimidex; Zeneca) are now well established in the treatment of advanced breast cancer and are under investigation as adjuvant therapy. These agents achieve 98-99% aromatase inhibition in patients, and reduce serum concentrations of oestrone and oestradiol beyond the limit of detection in many patients (Iveson et al. 1993). Until recently, it had been assumed that no clinical dose-response effect could exist beyond the achievement of maximum serum oestrogen suppression, but recent data have suggested this may not be the case. If a dose-response effect does indeed exist for modern aromatase inhibitors, then it has important implications for their future development.