Stephen R. D. Johnston

Phase I Trial of Intraperitoneal Injection of the E1B-55-kd-Gene–Deleted Adenovirus ONYX-015 (dl1520) Given on Days 1 Through 5 Every 3 Weeks in Patients With Recurrent/Refractory Epithelial Ovarian Cancer

PURPOSE Resistance to chemotherapy in ovarian cancer is frequently associated with mutations in the p53 gene. The adenovirus dl1520 (ONYX-015) with the E1B 55-kd gene deleted, allowing selective replication in and lysis of p53-deficient tumor cells, has shown preclinical efficacy against p53-deficient nude mouse-human ovarian carcinomatosis xenografts. PATIENTS AND METHODS We undertook a phase I trial of intraperitoneal dl1520 in patients with recurrent ovarian cancer. Sixteen women with recurrent/refractory ovarian cancer received 35 cycles (median, two cycles) of dl1520 delivered on days 1 through 5 in four dose cohorts: 1 x 10(9) plaque forming units (pfu), 1 x 10(10) pfu, 3 x 10(10) pfu, and 1 x 10(11) pfu. RESULTS The most common significant toxicities related to virus administration were flu-like symptoms, emesis, and abdominal pain. One patient receiving 1 x 10(10) pfu developed common toxicity criteria grade 3 abdominal pain and diarrhea, which was dose-limiting. The maximum-tolerated dose was not reached at 10(11) pfu, and at this dose level patients did not experience significant toxicity. There was no clear-cut evidence of clinical or radiologic response in any patient. Blood samples were taken for adenovirus DNA and neutralizing antibodies. Polymerase chain reaction data indicating presence of virus up to 10 days after the final (day 5) infusion of dl1520 are suggestive of continuing viral replication. CONCLUSION This article therefore describes the first clinical experience with the intraperitoneal delivery of any replication-competent/-selective virus in cancer patients.

Aromatase inhibitors for breast cancer: lessons from the laboratory

Endocrine therapy with tamoxifen has been the mainstay of treatment for hormone-sensitive breast cancer for more than 20 years. An alternative strategy of oestrogen deprivation in postmenopausal women with aromatase inhibitors is set to replace tamoxifen based on better efficacy and a delay in the emergence of endocrine resistance. There are fundamental differences in how tamoxifen and aromatase inhibitors alter oestrogen-receptor signalling. Understanding the response and resistance to these different therapies is central to further improving therapeutic options for women with breast cancer.

High complete remission rates with primary neoadjuvant infusional chemotherapy for large 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.

Contribution of the MHC region to the familial risk of coeliac disease

Susceptibility to coeliac disease is genetically determined by possession of specific HLA-DQ alleles, acting in concert with one or more non-HLA linked genes. The pattern of risk seen in sibs and twins in coeliac disease is most parsimonious with a multiplicative model for the interaction between the two classes of genes. Based on a sib recurrence risk for coeliac disease of 10% and a population prevalence of 0.0033, the sib relative risk is 30. To evaluate the contribution of the MHC region to the familial risk of coeliac disease, we have examined haplotype sharing probabilities across this region in 55 coeliac disease families. Based on these probabilities the sib relative risk of coeliac disease associated with the MHC region is 3.7. Combining these results with published data on allele sharing at HLA, the estimated sib relative risk associated with the MHC region is 3.3. Therefore, the MHC genes contribute no more than 40% of the sib familial risk of coeliac disease and the non-HLA linked gene (or genes) are likely to be the stronger determinant of coeliac disease susceptibility.

Phase II Study of the Efficacy and Tolerability of Two Dosing Regimens of the Farnesyl Transferase Inhibitor, R115777, in Advanced Breast Cancer

PURPOSE R115777 is an orally active farnesyl transferase inhibitor that specifically blocks farnesylation of proteins involved in growth-factor-dependent cell-signal-transduction pathways. We conducted a phase II study in 76 patients with advanced breast cancer. PATIENTS AND METHODS Two cohorts of patients were recruited sequentially. The first cohort (n = 41) received a continuous dosing [CD] regimen of R115777 400 or 300 mg bid. The second cohort (n = 35) received 300 mg bid in a cyclical regimen of 21 days of treatment followed by 7 days of rest (intermittent dosing [ID]). RESULTS In the CD cohort, four patients (10%) had a partial response (PR) and six patients (15%) had stable disease at > or = 24 weeks (SD). In the ID cohort, five patients (14%) had a PR and three patients (9%) had prolonged SD. The first six patients in the CD cohort treated at 400 mg bid all developed grade 3 to 4 neutropenia, so the subsequent 35 patients were treated at 300 mg bid. The incidence of hematologic toxicity was significantly lower in the ID than in the CD (300-mg bid) cohort: grade 3 to 4 neutropenia (14% v 43%; P =.016) and grade 3 to 4 thrombocytopenia (3% v 26%; P =.013). One patient in the ID cohort developed grade 2 to 3 neurotoxicity compared with 15 patients in the CD cohort (3% v 37%; P =.0004). CONCLUSION The farnesyl transferase inhibitor R115777 has demonstrated clinical activity in patients with metastatic breast cancer, and the ID regimen has a significantly improved therapeutic index compared with the CD regimen.

New Strategies in Estrogen Receptor–Positive Breast Cancer

Endocrine therapy has led to a significant improvement in outcomes for women with estrogen receptor–positive (ER+) breast cancer. Current questions in the adjuvant setting include the optimal duration of endocrine therapy, and the accurate molecular prediction of endocrine responsiveness using gene array–based assays compared with ER expression itself. In advanced disease, novel selective estrogen receptor antagonists (SERM) have failed to make an impact, although the pure ER antagonist fulvestrant may have a role, albeit optimal dose and sequence remain unclear. Overcoming de novo or acquired endocrine resistance remains critical to enhancing further the benefit of existing endocrine therapies. Recent progress has been made in understanding the molecular biology associated with acquired endocrine resistance, including adaptive “cross-talk” between ER and peptide growth factor receptor pathways such as epidermal growth factor receptor (EGFR)/human epidermal growth factor receptor 2 (HER2). Future strategies that are being evaluated include combining endocrine therapy with inhibitors of growth factor receptors or downstream signaling pathways, to treat or prevent critical resistance pathways that become operative in ER+ tumors. Preclinical experiments have provided great promise for this approach, although clinical data remain mixed. Enriching trial recruitment by molecular profiling of different ER+ subtypes will become increasingly important to maximize additional benefit that new agents may bring to current endocrine therapies for breast cancer. Clin Cancer Res; 16(7); 1979–87. ©2010 AACR.

Plasma ESR1 Mutations and the Treatment of Estrogen Receptor–Positive Advanced Breast Cancer

PURPOSE ESR1 mutations are selected by prior aromatase inhibitor (AI) therapy in advanced breast cancer. We assessed the impact of ESR1 mutations on sensitivity to standard therapies in two phase III randomized trials that represent the development of the current standard therapy for estrogen receptor-positive advanced breast cancer. MATERIALS AND METHODS In a prospective-retrospective analysis, we assessed ESR1 mutations in available archived baseline plasma from the SoFEA (Study of Faslodex Versus Exemestane With or Without Arimidex) trial, which compared exemestane with fulvestrant-containing regimens in patients with prior sensitivity to nonsteroidal AI and in baseline plasma from the PALOMA3 (Palbociclib Combined With Fulvestrant in Hormone Receptor-Positive HER2-Negative Metastatic Breast Cancer After Endocrine Failure) trial, which compared fulvestrant plus placebo with fulvestrant plus palbociclib in patients with progression after receiving prior endocrine therapy. ESR1 mutations were analyzed by multiplex digital polymerase chain reaction. RESULTS In SoFEA, ESR1 mutations were found in 39.1% of patients (63 of 161), of whom 49.1% (27 of 55) were polyclonal, with rates of mutation detection unaffected by delays in processing of archival plasma. Patients with ESR1 mutations had improved progression-free survival (PFS) after taking fulvestrant (n = 45) compared with exemestane (n = 18; hazard ratio [HR], 0.52; 95% CI, 0.30 to 0.92; P = .02), whereas patients with wild-type ESR1 had similar PFS after receiving either treatment (HR, 1.07; 95% CI, 0.68 to 1.67; P = .77). In PALOMA3, ESR1 mutations were found in the plasma of 25.3% of patients (91 of 360), of whom 28.6% (26 of 91) were polyclonal, with mutations associated with acquired resistance to prior AI. Fulvestrant plus palbociclib improved PFS compared with fulvestrant plus placebo in both ESR1 mutant (HR, 0.43; 95% CI, 0.25 to 0.74; P = .002) and ESR1 wild-type patients (HR, 0.49; 95% CI, 0.35 to 0.70; P < .001). CONCLUSION ESR1 mutation analysis in plasma after progression after prior AI therapy may help direct choice of further endocrine-based therapy. Additional confirmatory studies are required.

Fulvestrant plus anastrozole or placebo versus exemestane alone after progression on non-steroidal aromatase inhibitors in postmenopausal patients with hormone-receptor-positive locally advanced or metastatic breast cancer (SoFEA): a composite, multicentre, phase 3 randomised trial

BACKGROUND The optimum endocrine treatment for postmenopausal women with advanced hormone-receptor-positive breast cancer that has progressed on non-steroidal aromatase inhibitors (NSAIs) is unclear. The aim of the SoFEA trial was to assess a maximum double endocrine targeting approach with the steroidal anti-oestrogen fulvestrant in combination with continued oestrogen deprivation. METHODS In a composite, multicentre, phase 3 randomised controlled trial done in the UK and South Korea, postmenopausal women with hormone-receptor-positive breast cancer (oestrogen receptor [ER] positive, progesterone receptor [PR] positive, or both) were eligible if they had relapsed or progressed with locally advanced or metastatic disease on an NSAI (given as adjuvant for at least 12 months or as first-line treatment for at least 6 months). Additionally, patients had to have adequate organ function and a WHO performance status of 0-2. Participants were randomly assigned (1:1:1) to receive fulvestrant (500 mg intramuscular injection on day 1, followed by 250 mg doses on days 15 and 29, and then every 28 days) plus daily oral anastrozole (1 mg); fulvestrant plus anastrozole-matched placebo; or daily oral exemestane (25 mg). Randomisation was done with computer-generated permuted blocks, and stratification was by centre and previous use of an NSAI as adjuvant treatment or for locally advanced or metastatic disease. Participants and investigators were aware of assignment to fulvestrant or exemestane, but not of assignment to anastrozole or placebo. The primary endpoint was progression-free survival (PFS). Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, numbers NCT00253422 (UK) and NCT00944918 (South Korea). FINDINGS Between March 26, 2004, and Aug 6, 2010, 723 patients underwent randomisation: 243 were assigned to receive fulvestrant plus anastrozole, 231 to fulvestrant plus placebo, and 249 to exemestane. Median PFS was 4·4 months (95% CI 3·4-5·4) in patients assigned to fulvestrant plus anastrozole, 4·8 months (3·6-5·5) in those assigned to fulvestrant plus placebo, and 3·4 months (3·0-4·6) in those assigned to exemestane. No difference was recorded between the patients assigned to fulvestrant plus anastrozole and fulvestrant plus placebo (hazard ratio 1·00, 95% CI 0·83-1·21; log-rank p=0·98), or between those assigned to fulvestrant plus placebo and exemestane (0·95, 0·79-1·14; log-rank p=0·56). 87 serious adverse events were reported: 36 in patients assigned to fulvestrant plus anastrozole, 22 in those assigned to fulvestrant plus placebo, and 29 in those assigned to exemestane. Grade 3-4 adverse events were rare; the most frequent were arthralgia (three in the group assigned to fulvestrant plus anastrozole; seven in that assigned to fulvestrant plus placebo; eight in that assigned to exemestane), lethargy (three; 11; 11), and nausea or vomiting (five; two; eight). INTERPRETATION After loss of response to NSAIs in postmenopausal women with hormone-receptor-positive advanced breast cancer, maximum double endocrine treatment with 250 mg fulvestrant combined with oestrogen deprivation is no better than either fulvestrant alone or exemestane.

Farnesyl transferase inhibitors: a novel targeted therapy for cancer

Activating oncogenic mutations of the RAS gene are common in cancer, occurring in 30% of solid tumours in adults. Inhibitors of the enzyme farnesyl protein transferase prevent a key step in the post-translational processing of the RAS protein, and were developed initially as a therapeutic strategy to inhibit cell signalling in RAS-transformed cells. As more has been learnt about the biological effects of farnesyl transferase inhibitors on cancer cells, it has become increasingly clear that tumours without oncogenic RAS mutations may also be targets for farnesyl transferase inhibitor therapy. Encouraging results from phase I and II clinical trials have emerged, creating both enthusiasm and new challenges for the optimum clinical development of this important new class of anticancer drug.

INDUCTION OF APOPTOSIS BY TAMOXIFEN AND ICI 182780 IN PRIMARY BREAST CANCER

Hormonal breast cancer therapies have traditionally been considered cytostatic, but recent pre‐clinical data suggest that anti‐oestrogens can induce apoptosis. The aim of this study was to assess whether tamoxifen (TAM) and ICI 182780 (ICI) could induce apoptosis in human breast cancer, and whether this was related to oestrogen receptor status. We measured apoptosis in primary breast cancer patients before and after pre‐surgical treatment with 20 mg/day TAM (study 1) or 6 or 18 mg/day ICI (study 2). In each study there was a randomised non‐treatment (NT) control group. TAM significantly increased apoptotic index (AI) in ER+ but not in ER− tumours. There was a significant increase in AI following treatment with ICI. Insufficient pairs of samples were available to determine whether this change was confined to ER+ tumours, but in a cross‐sectional analysis AI was significantly higher in excision biopsies for ICI‐treated than NT patients for ER+ but not ER− tumours. Our results provide clinical evidence that apoptosis may be induced in ER+ primary breast cancer by both non‐steroidal and steroidal anti‐oestrogens. Int. J. Cancer 72:608–613, 1997.