2011 European Multidisciplinary Cancer Congress
`
`23-27 September, 2011
`Stockholm, Sweden
`
`SUMMARY
`
`2011 marked the advent of the European Multidisciplinary Cancer Congress (EMCC), created from a
`merger of the 16th European CanCer Organisation (ECCO), 36th European Society for Medical
`Oncology (ESMO), and 30th European Society for Therapeutic Radiology and Oncology (ESTRO)
`Congresses. The(cid:160)2011 EMCC capitalized upon the success of the first joint ECCO-ESMO Congress
`two years ago and the strong collaboration among European cancer organizations, including
`contributions from European Society of Surgical Oncology (ESSO), European Association for Cancer
`Research (EACR), European Oncology Nursing Society (EONS) and European Society for Pediatric
`Oncology (SIOPE). The EMCC emerged as a truly pan-European cancer community effort.
`
`Held in Stockholm, Sweden, 23 - 27 September 2011, EMCC drew 12,768 delegates, 1683 exhibitors
`and 423 guests. Congress coverage was provided by 380 media representatives who reported on the
`presentations of 694 invited speakers, in all totaling 15,931 participants.(cid:160) Delegates came from 116
`countries around the world, making this a truly global event.(cid:160) The USA was represented by 1144
`delegates with 1065 representatives from the UK, followed closely by approximately 1000 attendees
`from both Germany and France. Over 1000 delegates travelled from as far as China and Japan with
`Australia also represented, all joining this unique platform to exchange ideas intended to shape
`oncology care and practice. Twitter provided a new dimension, with 3,192 "tweets" posted during the
`congress using the hashtag #emcc2011.
`
`
`
`INTRODUCTION
`
`The multidisciplinary focus of the Congress expressed in the tagline -"Integrating basic and
`translational science, surgery, radiotherapy, medical oncology and care"- was reflected in the
`scientific program developed by Co-Scientific Chairs Jean Charles Soria (ESMO) and Anne-Lise
`Børresen-Dale (ECCO), Vice Chairs Jean Bourhis and Peter Naredi, and Education Chairs Dirk
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`Schrijvers (ECCO) and Rolf Stahel (ESMO), together with the help and expertise of the Scientific
`Committee. The program consisted of 33 individual disciplines and offered 285 sessions, including
`four Presidential Sessions and 25 Proffered Paper Sessions, reporting state of the art developments
`in research, treatment and patient care. The Congress is grateful to the 694 cancer specialists who
`shared their ideas and latest data in over 2000 abstracts and 34 Late Breaking Abstracts, many
`containing practice-changing information, and all with thought provoking and inspiring analyses.
`
`
`
`Fig.1. Chairpersons at the Opening session of 2011 EMCC
`
`Participants in the landmark EMCC were welcomed by Michael Baumann (ECCO President,
`Congress Chair) and David Kerr (ESMO President, ECCO Board Member) with the promise of a
`productive conference which would set the stage for successive congress collaborations.
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`Fig.2. Attendees visiting the ESMO dedicated booth
`
`Besides active participation in creation of the complex educational and scientific Congress program
`tracks, ESMO enhanced its visibility at the Congress with a dedicated booth, Members Launch,
`Award ceremony, and educational session with new guidelines presentation.
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`Fig.3. A detail from the ESMO Guidelines Interactive Session
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`This report will attempt a small overview of the expert scientific presentations made during the
`congress by medical oncologists, radiotherapists, surgical oncologists, basic scientists, oncology
`nurses, palliative care professionals and other clinicians involved in cancer diagnosis and treatment.
`
`
`
`BASIC SCIENCE
`
`Small-molecule inhibition of Ras oncoprotein
`
`Fang et al. reported on a novel approach to target Ras, the major driver of oncogenesis in many
`tumor types. The group identified and characterized several small-molecules that bind a site next to
`the SOS interface of the Ras protein, preventing the nucleotide exchange that activates Ras
`oncoprotein. They screened fragments by Nuclear Magnetic Resonance (NMR) and characterized the
`candidates by NMR and X-ray crystallography. The subsequent effect upon Ras activation and
`signaling was described by biochemical and cellular assays.(cid:160) They tested a subset of the Ras-binding
`molecules and demonstrated that it blocks assembly of the Ras SOS complex by steric hindrance,
`thus inhibiting nucleotide exchange and preventing Ras activation and signaling. The biological
`activity of these compounds is being tested further in Ras mutant tumors that are dependent upon
`nucleotide exchange. (Fang, Abstract LBA 15)
`
`Practice point and future research opportunities
`
` A
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` functionally significant binding pocket plus a compound that competitively inhibits nucleotide
`exchange and Ras activation have been described, providing new intervention targets for Ras driven
`oncogenesis
`
`Novel mutations in SF3B1 implicate abnormalities of mRNA splicing, a pathway not previously
`known as a target in the pathogenesis of myelodysplastic syndromesChemotherapy during
`pregnancy: Large study on cognitive and cardiac outcome in children with prenatal exposure
`to chemotherapy
`
`Mutations in SF3B1, a gene coding for a key protein in mRNA processing, have been identified and
`shown to associate with the presence of ring sideroblasts, a morphological feature indicative of
`myelodysplastic syndromes (MDS). Papaemmanuil et al. searched for somatically acquired point
`mutations across all protein-coding exons in the genomes of nine MDS patients by massively parallel
`sequencing and then identified these recurrent mutations in the SF3B1 gene in 619 patients. They
`further characterized the prevalence of these mutations by re-sequencing samples of 2087 patients
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`with MDS, primary cancers and cancer cell lines; SF381 was found to be mutated in 28.1% of MDS
`patients, 19.3 % of patients with acute myeloid leukaemia and 5.3% of patients with myeloproliferative
`neoplasms. Similar genetic mutations were also seen in 1% to 5% of other tumor types examined,
`including breast cancer, multiple myeloma and renal cancer. Mutated SF381 associated with the
`presence of ring sideroblasts in the bone marrow (P<0.001), which are abnormal red blood cell
`precursor cells that have a ring of iron-laden mitochondria around the nucleus. Of 123 MDS patients,
`34 had the SF3B1 mutation; by multivariate analysis, mutated SF3B1 independently associated with
`improved overall survival (P=0.028) and a lower risk of leukemic progression (P=0.048).(cid:160) Mutations in
`SF381 are detectable in blood samples and offer a simple and quick method for MDS diagnosis,
`which usually is made by invasive bone marrow biopsy that detects ring siderobsts.(cid:160) Mutations in this
`gene may be predictive for patient outcome and useful in identifying patients with a good prognosis
`who may benefit from less aggressive treatment.(cid:160) This presentation coincided with the simultaneous
`publication of a paper about the research in the New England Journal of Medicine. (Papaemmanuil,
`Abstract LBA 11)
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`Practice point and future research opportunities
`
`The close association between novel somatic acquired mutations in SF3B1 and ring sideroblasts
`makes this the first gene to be strongly associated with a specific morphological feature in
`myelodysplastic syndromes. This molecular lesion has relevant clinical significance, as it is
`independently associated with a favorable clinical outcome. Besides confirming relevance of this
`pathway in myelodysplastic syndromes and probably some other epithelial tumors, this discovery may
`simplify diagnosis and aid in identifying patients who will benefit from optimized treatment.
`
`DNA vaccination against ALK in NSCLC
`
`Voena et al. built upon their previous results demonstrating Anaplastic Lymphoma Kinase (ALK) to be
`an effective oncoantigen for ALK positive lymphoma vaccination to test whether it could also
`represent a feasible target for vaccination in ALK positive non-small cell lung cancer (NSCLC). They
`generated transgenic mice ectopically expressing human TFG- or EML4-ALK gene products, that
`developed multifocal adenocarcinomas similar to human tumors approximately one month after birth.
`The mice were then vaccinated with 50 ug of either plasmid DNA or mock plasmid DNA. The immune
`response was determined after 30 days showing a strong ALK specific CTL response was elicited in
`vaccinated mice that overcame immune tolerance to the ALK protein. Vaccinated mice showed a
`reduced number of neoplastic foci and a smaller tumor mass compared to controls by NMR
`measurement. Vaccinated mice showed a significantly increased number of T lymphocytes infiltrating
`both the tumors and the spared lung. It was also observed that specific CTL activity against ALK and
`the ability to limit the tumor expansion decreased proportionally to the age of the mice. (Voena,
`Abstract 1007)
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`Practice point and future research opportunities
`
`This ALK+ transgenic mouse model allowed demonstration of the role of ALK in lung tumor
`pathogenesis and offered an opportunity to test the immune response to innovative treatment
`strategies. ALK-DNA vaccination elicited a specific cytotoxic response and delayed tumour
`progression, suggesting that DNA vaccination combined with standard chemotherapy or specific ALK
`inhibitor treatment may be an alternative in ALK positive NSCLC for preventing tumor relapse or
`metastasis.
`
`Prognostic factors in patients with metastatic renal cell carcinoma treated with sunitinib
`
`Motzer et al. conducted a retrospective analysis of pooled data from six clinical trials testing single
`agent sunitinib treatment in 1059 patients with metastatic renal cell carcinoma (mRCC) to determine
`prognostic factors for progression free-survival (PFS), overall survival (OS) and long term survival,
`defined as survival of thirty or more months. Baseline variables were analyzed for prognostic
`significance using a Cox proportional hazards model, in univariate and then multivariate analyses
`using a stepwise algorithm. The same independent predictors were identified for PFS and OS, with
`the presence/absence of bone metastases, baseline hemoglobin and corrected calcium being the
`most significant (all P<0.0001), which also associated with Memorial Sloan-Kettering Cancer Center
`(MSKCC) (P<0.0001) prognostic criteria (Motzer, 2002). Favorable risk factors by MSKCC criteria
`were seen in the baseline data of 70% of patients with long term survival compared with 31% of non-
`long-term survivors. In the non-long-term survivor group, 42% had intermediate and 5% had poor risk
`features compared with 28% and 0%, respectively, of long-term survivors. Additional predictors of
`ethnic origin and the presence of bone metastasis were identified; sunitinib benefit favored Caucasian
`patients who demonstrated increased OS of 10.5 versus 6.6 months in Asian patients (P=0.0002).
`Patients with bone metastasis had OS of 16.1 compared to 27.8 months in patients without bone
`metastasis (P=0.0001). Long term survival with continued sunitinib use was observed in 215 (20%)
`patients. A separate analysis of their baseline characteristics identified the same predictive indicators
`of ethnicity, normalized calcium, no prior cytokine use and the absence of bone metastasis.(cid:160) Even
`within long term survivors, patients with bone metastasis fared less favorably than those without,
`demonstrating long term survival of 42.7 compared to 54.5, respectively (P=0.0061). (Motzer,
`Abstract 1006)
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`Practice point and future research opportunities
`
`Previously reported MSKCC clinical risk factors were validated and shown to be predictive of shorter
`progression-free survival; favorable MSKCC risk status is associated with higher likelihood of
`achieving long term survival after treatment with sunitinib. The same predictors were independently
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`identified for overall and progression free-survival, supporting the utility of progression free-survival as
`a surrogate endpoint. Further exploration of tumor-specific biology is needed.
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`BREAST CANCER
`
`Everolimus overcomes resistance to hormonal therapy in postmenopausal women with
`advanced breast cancer
`
`Baselga reported findings from the BOLERO-2 phase III trial that evaluated whether the addition of
`the mTOR (mammalian Target Of Rapamycin) inhibitor everolimus to exemestane could improve
`response to aromatase inhibitors. The trial was conducted in 24 countries and enrolled 724
`postmenopausal women with estrogen receptor (ER)-positive, HER2-negative disease who were
`refractory to letrozole or anastrozole. Following randomization, 485 patients received everolimus plus
`exemestane and 239 received sole exemestane. BOLERO-2 was halted prematurely after a
`preplanned analysis demonstrated median 6.9 months PFS for combination treatment, compared to
`2.8 months with exemestane alone (P<0.0001) by local investigator assessment. Progression-free
`survival by central assessment also significantly favored combination treatment, with these patients
`experiencing a median PFS of 10.6 versus 4.1 months for the exemestane group (P<0.0001); both
`analyses met the pre-specified criteria for significance. Response rates were 9.5% and 0.4% with
`combination and exemestane, respectively (P<0.0001). The improvement was consistent across all
`subgroups including the number of prior therapies, presence of visceral disease, bone metastases,
`and prior use of chemotherapy. Overall survival data were not yet mature. Numerically, more grade 3
`to 4 side effects occurred with combination treatment than in the exemestane group; commonly
`reported adverse events were consistent with those reported for everolimus (stomatitis, anemia,
`dyspnea, hyperglycemia, fatigue and pneumonitis).(cid:160) (Baselga, Abstract LBA 9)
`
`Practice point and future research opportunities
`
`Although hormonal therapy is a mainstay of treatment for estrogen receptor-positive breast cancer,
`nearly all patients who develop metastatic disease become resistant to hormonal therapy. The
`rationale for combination therapy with everolimus plus exemestane in this trial rests on the crosstalk
`between estrogen receptor and mTOR signalling. Everolimus is the first agent to enhance the clinical
`benefit of hormonal therapy in patients refractory to aromatase inhibitors. Combination therapy
`significantly improved response rate and more than doubled the time to disease progression over
`exemestane alone in patients highly resistant to hormonal therapy. The improvement was consistent
`across all subgroups, including number of prior therapies, presence of visceral metastases, bone
`metastases, and prior use of chemotherapy. Overall survival data will be presented upon maturity and
`an analysis of the effect of everolimus on bone metabolism is underway. This treatment represents a
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`paradigm shift in the treatment of breast cancer, and a world-wide application is being filed for
`licensing of everolimus for the treatment of estrogen receptor-positive advanced breast cancer.
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`Reversal of tamoxifen resistance by addition of mTOR inhibitor sirolimus
`
`Findings from Bhattacharyya et al. suggested that tamoxifen resistance may be overcome by co-
`treatment with sirolimus, an mTOR (mammalian Target Of Rapamycin) inhibitor with activity against
`AKT kinase. AKT kinase is a key molecule in oncogenesis that antagonizes tamoxifen binding to the
`estrogen receptor and is expressed at high levels in tamoxifen resistance. This two-part study
`enrolled 400 patients with metastatic breast cancer who were estrogen receptor/progesterone
`receptor (ER/PgR) positive. Part 1 of the study enrolled 200 patients who could not afford aromatase
`inhibitors and were randomized to receive tamoxifen or tamoxifen plus sirolimus. Part 2 included 200
`patients who had failed treatment with an aromatase inhibitor (cid:160)and/or tamoxifen and were randomized
`to receive sirolimus/tamoxifen combination. Patients in part 1 demonstrated a response rate of 36%
`with tamoxifen only and 68% with tamoxifen plus sirolimus. Time to progression was 9 and 16 months
`with sole tamoxifen and combination, respectively.(cid:160) In part 2, the response rates were 4% and 40%,
`with time to progression of 3 and 11 months in patients receiving tamoxifen alone and tamoxifen plus
`sirolimus, respectively.(cid:160) (Bhattacharyya, Abstract LBA 16)
`
`Practice point and future research opportunities
`
`Combination treatment with tamoxifen and sirolimus could offer an alternative to treatment with
`aromatase inhibitors in patients with ER/PgR positive metastatic breast cancer and also restore
`response in patients with hormone receptor positive tumors and acquired tamoxifen resistance.
`
`Synchronous chemoradiation can reduce local recurrence in early stage breast cancer
`
`Fernando reported long term follow-up results at median 8.8 years of the SECRAB trial, which found
`a 35% risk reduction of local recurrence following treatment of early breast cancer in women who
`received synchronous, wherein radiation was delivered during or in-between chemotherapy cycles,
`rather than sequential chemoradiation. The study enrolled 2296 women who had completely excised
`early breast cancer that required adjuvant chemotherapy and radiotherapy and were fit for treatment.
`No difference between arms was seen in PFS or OS; PFS was 79% with synchronous therapy and
`78% with sequential therapy and OS was 83% versus 82%, synchronous and sequential,
`respectively. However, the five-year incidence of local recurrence was 2.8% with synchronous
`therapy and 5.1% among women who received sequential administration of adjuvant chemotherapy
`followed by radiotherapy (P=0.19).(cid:160) Subgroup analysis of patients with local recurrence revealed a
`statistically significant advantage in favor of synchronous therapy (P=0.03) which was seen across all
`treatment and biological subgroups, including tumor grade and size, lymph node status, vascular
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`invasion and excision margin. Primary analysis showed no difference in the recurrence rate between
`the two groups, 5.4% with synchronous therapy versus 7.4% with sequential therapy (P=0.19);
`however, upon further analysis it was found that 80% of regional recurrences were outside the
`radiation field. Synchronous chemoradiation had minimal adverse side-effects but did show an
`increased risk for moderate or severe radiation-associated skin toxicity; 24% of synchronous patients
`compared to 15% of patients in the sequential arm experienced skin reactions, and severe reactions
`were seen in 4% of patients. However, 96% of cases resolved within four to six weeks post therapy.
`Quality of life data showed no difference between the two arms, however synchronous treatment was
`shorter, allowing women to resume normal family and work routines sooner, making it a popular
`therapy among participants. (Fernando, Best Abstract 2)
`
`
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`Fig.4. Synchronous chemotherapy and radiotherapy resulted in reduced risk for developing a local
`recurrence (courtesy of Dr Indrajit Fernando)
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`Practice point and future research possibilities
`
`This trial raises the important issue of how radiotherapy and chemotherapy after surgery should be
`sequenced or integrated to obtain the best outcome in the treatment of early breast cancer. The
`largest study to investigate synchronous chemo-radiation produced firm evidence that the risk of loco-
`regional recurrences could be reduced by applying radiotherapy simultaneously with chemotherapy.
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`Longer follow-up is necessary to assess potential late side-effects and the benefits versus the risk of
`this approach.
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`Patients' baseline characteristics after a successful MINDACT trial accrual
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`The MINDACT (Microarray in Node Negative and 1 to 3 Positive Lymph Node Disease May Avoid
`ChemoTherapy) trial seeks to bring personalized medicine forward by comparing the clinical utility of
`genomic profiling with standard clinicopathological criteria for risk assessment and adjuvant
`chemotherapy use in breast cancer therapy. Piccart et al. successfully completed patient accrual in
`104 sites in nine European countries for the largest randomized prospective trial ever designed to
`determine risk factors based on genomic profile, which will allow optimal selection of breast cancer
`candidates for adjuvant chemotherapy.(cid:160) As of the presentation date, 11300 patients had registered,
`genomic testing was done in 7491 and 6527 (58%) patients suitable for enrollment. The patients
`baseline characteristics were presented: 33% of the trial population is less than 50 years of age, 80%
`are node negative, 71% have lymph node status verified by sentinel node biopsy, 63% had breast
`conservation surgery, 72% have tumors approximately 2 cm, 88% are hormone receptor positive
`(estrogen or progesterone receptor or both), 11% are HER2 positive, and 9% of patients have triple
`negative breast cancer. The study accrual was completed one month after the presentation of
`baseline characteristics. (Piccart, Abstract LBA10)
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`Practice point and future research possibilities
`
`MINDACT is the largest European randomized prospective trial evaluating the clinical value of a gene
`expression profile for risk assessment and adjuvant chemotherapy prescription in breast cancer
`patients. Accrual has been successfully completed and the trial's complex logistics, including real-
`time collection of frozen tumor tissue, were proven feasible in a multinational, multicentric setting.
`Data from this large, well planned trial should provide additional information in determining optimal
`therapies for several subsets of breast cancer patients and identify patients who will benefit from
`personalized treatment strategies.
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`CANCER IN OLDER PATIENTS
`
`Standard thoracic radiotherapy with or without concurrent daily low-dose carboplatin in
`elderly patients with locally advanced NSCLC
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`
`
`Atagi et al. presented results on behalf of the Japan Clinical Oncology Group (JCOG) from the first
`trial to demonstrate significant clinical benefit in patients over 70 years with unresectable stage III
`NSCLC from treatment consisting of thoracic radiotherapy plus daily low-dose carboplatin compared
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`to radiotherapy alone. Following the second-planned interim analysis, the trial was halted upon
`recommendation from the JCOG Data and Safety Monitoring Committee due to the difference in OS
`which strongly favored the combination treatment arm. Overall survival was 22.4 months in the
`combination arm and 16.9 in the radiotherapy arm (P=0.0179). Median PFS was 8.9 and 6.8 months
`with combination therapy and radiotherapy, respectively (P=0.0044). The objective response rates
`were 51.5% and 44.9% in 99 patients treated with radiotherapy plus low-dose of daily carboplatin and
`in 98 patients treated with radiotherapy, respectively. Stable disease was achieved in 34 (34.3%)
`patients who received combination treatment compared to 37 (37.8%) patients treated with
`radiotherapy only. Disease progression also favored combination treatment, with 8 (8.1%) and 13
`(13.3%) patients receiving combination therapy and radiotherapy progressing to disease,
`respectively. Major grade 3/4 toxicities associated with combination treatment and radiotherapy were
`febrile neutropenia (2.1% versus 0%), and infection (14.9% versus 4.1 %), respectively. Adverse
`events resulting in death were reported in 3 patients in the combination group and in 4 patients
`treated with radiotherapy. (Atagi, Abstract 4001)
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`Practice point and future research possibilities
`
`This is a first trial which demonstrated that concurrent daily low-dose carboplatin and thoracic
`radiotherapy provides clinically significant benefit in elderly patients with locally advanced NSCLC,
`and this combined modality could be considered as a standard treatment in this population.
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`Clinical outcomes after stereotactic radiotherapy in stage I NSCLC patients 80 years and older
`
`With the aim of shifting the primary focus of treatment to curative from simply avoiding toxicity in
`patients 80 years and older, Testolin et al. conducted this study to determine the tolerance and
`outcomes following stereotactic body radiation therapy (SBRT) in this age group. They used a real-
`time tumor tracking technique to determine the local tumor control rate, and treatment related toxicity
`after SBRT in 25 octogenarian patients with stage I NSCLC that was considered inoperable. All
`patients were treated using a CyberKinife System with Synchrony® Respiratory Tracking System
`device and followed-up for a median of 15 months. At that time, five patients demonstrated local
`recurrence; one local recurrence was in a patient who received a biologically effective dose (BED)
`and 4 recurrences were seen in patients receiving a lower dose. The overall actuarial local
`progression free probability (LPFP) at 2 years was 63.6%; LPFP for patients receiving BED 100Gy10
`was 42.8% and 90.9% in patients who were treated with BED >100Gy10. Overall and cancer specific
`survival at 2 years were 66.5% and 75%, respectively. Octogenarian patients tolerated the treatment
`well, with only 7 (28%) patients reporting fatigue, 2 (8%) patients had local chest wall pain, 1 (4%)
`patient suffered rib fracture, and symptoms of increased dyspnoea were reported by 2 (8%) patients.
`Asymptomatic radiation induced lung fibrosis was detected in 9 (36%) patients but no clinically
`symptomatic pneumonitis was observed. Six patients died during the 40 month follow-up, 4 from
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`disease progression, which occurred at 21, 23, 24 and 37 months after SBRT and 2 patients from
`intercurrent disease between 6 and 13 months. (Testolin, Abstract 4002)
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`Practice point and future research opportunities
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`Stereotactic body radiation therapy appears to be safe and minimally invasive modality for treatment
`of patients 80 years and older with medically inoperable stage I NSCLC. Even those with
`comorbidities, tolerated treatmentwell and biological effective dose >100Gy achieved high local
`control with minimal toxicity. Longer follow-up is needed to establish the probability of local failure and
`overall toxicity profile.
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`Age specific competing mortality in breast cancer patients
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`Women diagnosed with breast cancer later, as opposed to earlier in life, may experience poorer
`outcome due to different treatment based upon perceptions that the elderly are not fit enough for
`aggressive therapies. Markopoulos et al. analyzed data from the TEAM trial wherein 9766 women
`with hormone receptor positive tumors were randomized to receive either daily exemestane for 5
`years or daily tamoxifen for 2.5 to 3 years, followed by daily exemestane for an additional 2 to 2.5
`years. Upon analysis at 5 years, no difference in outcome between either arm was seen, as reported
`in Lancet. Given the equivalent results, patients could then be stratified by age at diagnosis into
`groups of younger than 65 years, ages 65 to 74 and 75 years and older. At a follow-up of median 5.1
`years, 50% had node negative disease, 68% had received radiotherapy and 36% had received
`chemotherapy. Data analysis using a Cox Proportional Hazard Model(cid:160)showed(cid:160) the risk of dying from
`both breast cancer and non breast cancer-related causes increased with age (P<0.001). However,
`when data were further analyzed by statistical methods accounting for the risk of competing causes of
`death, findings emerged that showed the risk of dying from breast cancer was greater for patients
`diagnosed at older age. When hazard ratios (HR) were(cid:160) adjusted for country, histological grade,
`tumor size, nodal status, estrogen receptor, progesterone receptor, type of surgery, radiotherapy and
`chemotherapy, the risks of dying overall were HR 1.0 (reference), 1.22 and 1.50 while the risks of
`breast cancer mortality were HR 1.0 (reference), 2.46(cid:160) and 6.57 in the three increasing age groups,
`respectively (P<0.001). It was also observed that radiotherapy and chemotherapy were administered
`less frequently with increasing patient age and that deaths from breast cancer were higher in older
`compared to younger patients who had similar tumor characteristics. Taken together, the data
`suggested that older breast cancer patients were being under-treated. (Markopoulus, Abstract 5015)
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`Practice point and future research opportunities
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`Although the risk of mortality from breast cancer and other causes both rose with increasing age,
`deaths from breast cancer increased more sharply in older patients, even in groups of women with
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`similar tumor characteristics but different ages, suggesting the possibility of suboptimal treatment.(cid:160)
`Elderly patients are often considered unfit for state-of-the-art cancer care, but health status rather
`than age per se should be the basis when deciding to provide standard cancer treatments. It is
`needed to improve the breast cancer prognostic classification in the elderly, developing specific tools
`or implementing those developed for younger patients, in order not to deprive those who might derive
`a real benefit from additional treatment including chemotherapy.
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`
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`CENTRAL NERVOUS SYSTEM
`
`Everolimus in subependymal giant cell astrocytomas associated with tuberous sclerosis
`complex
`
`Everolimus was tested(cid:160) by Bebin et al. for treating the genetic disorder Tuberous Sclerosis Complex
`(TSC), which is characterized by constitutive activation of the mammalian Target Of Rapamycin
`(mTOR), and results in the growth of benign tumors in several organs including the brain, where the
`presence of subependymal giant cell astrocytomas (SEGA) can cause hydrocephalus and require
`surgery. This double-blind, placebo controlled phase III trial enrolled 117 patients definitively
`diagnosed with TSC who had SEGA of 1 cm or larger, and documented serial SEGA growth. Patients
`were randomized 2 to 1 to receive oral everolimus or placebo until SEGA progression or
`unacceptable toxicity; randomization was stratified by concomitant use of antiepileptic drugs.
`Response was monitored by brain magnetic resonance imaging (MRI), kidney MRI or CT-scan, and
`24-hour video electroencephalogram (EEG) at baseline and other timepoints. Patients in the placebo
`group were offered everolimus upon SEGA progression. Everolimus was given to 78 patients for a
`median of 41.93 weeks (range, 24.0-78.9) and 39 patients received placebo for median 36.14 weeks
`(range 13.9-79.7 weeks). The primary trial endpoint of(cid:160) SEGA response rate of 50% or greater
`reduction was achieved by 35% of patients receiving everolimus compared to 0% of placebo patients
`(P<0.0001). Seizure reduction, as recorded by video EEG, was similar in both groups. No everolimus
`treated patients progressed, while 15% of placebo treated patients experienced progression.
`Response rates were higher with everolimus: 41.7 % of everolimus compared to 10.5% of placebo
`treated patients had a skin lesion response and 53.3% compared to 0% response rates were seen for
`angiomyolipomas in the everolimus and placebo treated patients, respectively. No new safety signals
`were raised for everolimus treatment, and no patients discontinued due to adverse events. (Bebin,
`Abstract LBA 4)
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`Practice point and future research opportunities
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`Tuberous sclerosis complex is a devastating disease affecting multiple organ systems with limited
`treatment options available. This phase III trial is the first placebo-controlled (cid:160)study to demonstrate
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`that everolimus is an effective and safe pharmacotherapeutic option to reduce subependymal giant
`cell astrocytomas volume and improve other clinical manifestations of tuberous sclerosis complex,
`including renal angiomyolipomas and skin lesions.
`
`Clinical and molecular profile exploratory subset analysis of study comparing standard
`adjuvant temozolomide with a dose-dense schedule for glioblastoma
`
`Although the RTOG 0525 phase III trial reported earlier this year did not show an advantage for dose
`dense temozolomide over standard temozolomide treatment of patients with glioblastoma, upon
`extensive post hoc subset analyses, Mehta et al. reported two subsets that demonstrated benefit;
`subset analyses were performed on data from patients who had received either dose dense or
`standard temozolomide and had an appropriate sized tissue sample for prospective analysis of the
`MGMT (O6-methylguanine-DNA methyltransferase) gene. Data from all randomized patients and
`over eleven subgroups were reviewed. No significant difference was seen for median OS or PFS in
`all randomized patients or in th