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The American Association for Cancer Research Annual Meeting

OBTN, June 2008, Volume 2, Issue 6

The American Association for Cancer Research (AACR), Philadelphia,is considered the world�s oldest and largest oncology-related scientific organization. Currently celebrating its centennial, the AACR recently held its 100th annual meeting at the San Diego Convention Center from April 12�16, 2008. The following sectionsprovide a general overview of breaking news and session highlights from the conference.

American Association for Cancer Research Translating the Latest Discoveries Into Cancer Prevention and Cures

The American Association for Cancer Research (AACR), Philadelphia, is considered the world’s oldest and largest oncology-related scientific organization. Currently celebrating its centennial, the AACR recently held its 100th annual meeting at the San Diego Convention Center from April 12—16, 2008. According to its organizers, the meeting focused on five key areas: (1) basic science, (2) translational medicine, (3) clinical research, (4) survivorship, and (5) prevention.

In a welcome letter to participants, William N. Hait, MD, PhD, President, AACR, and Eileen P. White, PhD, Chairperson, 2008 Program Committee, AACR, described the meeting as a “comprehensive scientific program that features the foremost breakthroughs in laboratory, translational, and clinical cancer research.” A full schedule of more than 250 educational sessions, plenary sessions, and scientific symposia were led by a roster of speakers that Drs. Hait and White characterized as “top scientists discussing innovative research approaches, novel technologies, life-saving therapies in the pipeline, clinical trials, and new approaches to cancer prevention.”

Various poster sessions featuring more than 6,000 abstracts of breaking clinical research, opinion-leader roundtable discussions, networking events, and a major exhibition of vendor exhibits (including pharmaceutical manufacturers, medical device concerns, biotechnology companies, health care publishers, patient advocacy organizations, and managed care companies) rounded out the slate of activities that AACR participants engaged in.

More than 15,000 participants representing more than 60 countries from around the globe attended the meeting. These included practicing oncologists, oncology fellows, scientists, researchers, academicians, key opinion leaders and other cancer care professionals (i.e., nurses, physician assistants, pharmacists, administrators) as well as patient group, physician group, employer group, and government agency representatives. The following sections provide a general overview of breaking news and session highlights from the conference.

Meeting Highlights and Breaking News

According to an AACR spokesperson, significant research news in the realms of both liver and ovarian cancer was unveiled during the meeting.

%u25BALiver Cancer Sunitinib Monotherapy in Advanced Hepatocellular Carcinoma Yields Evidence of Antitumor Activity

According to the results of a multidisciplinary phase II trial, sunitinib (Sutent) may slow the growth and the spread of liver cancer. A team of researchers from the Boston-based Massachusetts General Hospital Cancer Center asserted that treatment with sunitinib slows tumor growth and reduces the risk of metastasis in patients with hepatocellular carcinoma, a particularly aggressive form of liver cancer.

In the study, researchers enrolled 34 patients with advanced liver cancer who were dosed with 37.5 mg sunitinib daily over the course of a standard six-week regimen (4 wk on therapy, followed by 2 wk off therapy). After 12 weeks, one patient had a partial response (PR) and 17 patients had stable disease (SD). The median progression-free survival (PFS) was four months and the median overall survival (OS) was 10 months.

“Results are still preliminary, but there is clear evidence of an antitumor activity in these patients,” stated lead investigator Andrew X. Zhu, MD, PhD, Massachusetts General Hospital Cancer Center. Dr. Zhu and colleagues also measured changes in tumor vascular permeability using MRI, because the abnormally increased leakage of plasma from blood vessels in tumors is causally related to pathways blocked by sunitinib. They found that mean tumor permeability decreased after treatment with sunitinib by 40%, compared with measures taken at the start of the study.

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Circulating progenitor cells (CPCs), a potential measure of the risk of whether or not cancer will spread, were also reduced with sunitinib treatment. The number of CPCs was significantly decreased by sunitinib at days 15, 29, and 57, compared with baseline ( < 0.01). Dr. Zhu noted that an increase in CPCs during treatment appears to be associated with significantly increased mortality.

Researchers reported that the treatment was associated with a high degree of tolerability. Blood disorders such as neutropenia (12% of patients), lymphopenia (15%), thrombocytopenia (12%), and hyperbilirubinemia (6%) occurred at low rates. Fatigue was observed in 9% of patients and hand—foot syndrome in 6% of patients.

“Patients with this type of liver cancer have a very poor prognosis and the only currently available therapy is sorafenib (Nexavar). This study shows that we may be able to effectively use sunitinib with manageable side effects. Giving these patients more options would have a significant impact,” explained Dr. Zhu.

Hepatocellular carcinoma is a cancer that relies heavily on blood vessels for growth. According to Dr. Zhu, sunitinib controls the growth of blood vessels and could therefore potentially play an important role in treatment.

Sunitinib is a small molecule tyrosine kinase inhibitor that targets multiple receptors, including vascular endothelial growth factor receptor 2 (VEGFR2), the receptor tyrosine kinase (c-Kit), and FMS-like tyrosine kinase 3 (FLT3). Researchers believe that these receptors may be present in cancer cells as well as in endothelial and immune cells.

%u25BAOvarian Cancer Mifepristone Found to Prevent Regrowth of Ovarian Cancer Cells in Between Courses of Cisplatin Treatment

One of the big news stories in ovarian cancer research came from an AACR poster session where researchers demonstrated that mifepristone (Mifeprex or RU-486) prevents regrowth of ovarian cancer cells that survive standard chemotherapy. Senior study author Carlos M. Telleria, PhD, Sanford School of Medicine, University of South Dakota, Sioux Falls, South Dakota, and colleagues investigated whether mifepristone would prevent ovarian cancer regrowth if administered with cisplatin (Platinol). Ovarian cancer cells in culture were treated with cisplatin at 20 μM for one hour every 12 days for 36 days. Researchers assessed the number and viability of cancer cells, and how likely they were to reproduce, every four days.

Cisplatin killed the majority of cancer cells, but those that remained were able to reproduce. However, when mifepristone was added at a dose of 5, 10, or 20 μM, the cells—and their ability to reproduce—decreased. The larger the dose of mifepristone, the stronger the effect; at the 20 μM dose, the cultures contained no cancerous cells to test by day 12 of the study.

“Utilizing a cell culture system, our work provides evidence that giving mifepristone between courses of cisplatin has the potential to improve treatment success,” reported Dr. Telleria, “The regrowth of cancer cells between chemotherapy cycles is a major treatment challenge. One strategy to prevent regrowth is the use of drugs like mifepristone, which has been shown in separate studies to prevent cancer cells from multiplying.”

%u25BAAdvances in Gastrointestinal Cancer

A variety of new strategies and diverse approaches for the treatment of a range of types of gastrointestinal cancers were discussed at several AACR educational and poster sessions. Some of the highlights of the presented research are summarized in the following section.

Positive Effect of Anti-VEGF Therapy Observed In a Study of Neoadjuvant Bevacizumab with Chemoradiation Therapy in Rectal Cancer

A group of Harvard Medical School researchers presented results from a multidisciplinary dual phase I/II study examining the addition of bevacizumab (Avastin) to standard chemotherapy and radiation in patients with rectal cancer. Findings indicated that the combination regimen fully prevented tumor spread and “normalized” tumor blood vessels enough to enable effective therapy.

In the study, researchers enrolled 24 patients with late-stage rectal cancer. All patients completed four cycles of therapy including bevacizumab, additional standard chemotherapy, radiation, and surgery. Bevacizumab is currently approved for colorectal cancer, and works by destroying the blood vessels that tumors need to grow.

At four years, local control, or the absence of cancer spread beyond the original tumor site, was observed in 100% of patients and disease-free survival in 88%. Of the 24 patients treated, five had no residual cancer. Of the 19 patients with residual disease, 12 displayed severe disease. Downstaging of the tumor was observed in 12 out of 22 observable tumors.

Commenting on the findings, lead investigator Rakesh Jain, PhD, Harvard Medical School, Boston, stated, “I know of no other therapy in this patient population where we can even get close to 100% tumor control. Although this needs to be confirmed in a randomized trial against a placebo group, these are very impressive numbers.”

Dr. Jain added that the investigation posed a fairly unique set of challenges, explaining, “this mechanism of action was a conundrum for scientists because in order for radiation and chemotherapy to work, you need blood vessels. However, the current study adds evidence to a concept called normalization whereby restoring order to blood vessels inside a tumor opens up a window of opportunity for treatment.”

Blood vessel normalization allows the vessels that remain to perform more efficiently. “With a drug like bevacizumab, some of the tumor vasculature is pruned away immediately, but the vessels that remain become less abnormal. These normalized vessels make the surviving cancer cells more vulnerable to the treatments that can now be delivered more efficiently. Cancer therapies in this environment should be maximally effective. We had shown in previous mouse studies that normalizing blood vessels would decrease tumor activity, but the question with mouse studies is whether it will work in humans. This is the first study to confirm the idea of the effect of normalization in patients,” stated Dr. Jain.

Bortezomib Is Shown to Induce p27kip1 Associated Cell Cycle Arrest and Apoptosis Through Down-Regulation of SKP2 Ubiquitin Ligase Pathway in Colorectal Carcinoma

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Shahab Uddin and colleagues, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia, investigated the role of S-Phase Kinase Protein 2 (SKP2) (frequently overexpressed in a variety of cancers) and its ubiquitin-proteasome pathway in colorectal carcinoma using a panel of cell lines, clinical samples, and NUDE mouse model. Using immunohistochemical analysis on a large tissue microarray of 448 samples, an inverse association of SKP2 expression with p27Kip1 protein levels was seen. The subset of patients with colorectal cancer who had high levels of SKP2 and low levels of p27Kip1 showed a decreased rate of OS ( = 0.0057).

Dr. Uddin found that treatment of colorectal carcinoma cell lines with bortezomib (Velcade) or expression of siRNA of SKP2 causes downregulation of SKP2 and accumulation of p27Kip1. Furthermore, treatment of colorectal carcinoma cells with bortezomib causes apoptosis by involving mitochondrial pathway and activation of caspases. In addition, treatment of colorectal carcinoma cells with bortezomib downregulated the expression of XIAP, cIAP1 and survivin. Finally, treatment of colorectal carcinoma cell line xenografts with bortezomib resulted in growth inhibition of tumors in NUDE mice by down-regulation of SKP2 and accumulation of p27Kip1.

“Altogether,” said lead investigator Dr. Uddin, “our results suggest that SKP2 and ubiquitinproteasome pathway may be a potential target for therapeutic intervention for treatment of colorectal carcinoma.”

Individualized Tumor Response Testing Found to be Effective Predictor of Response to Paclitaxel and Cisplatin in Patients With Advanced Gastric Cancer

In a recent prospective dual phase II/III study, Jee Hyn Kim and colleagues, Seoul National University Bundang Hospital, Seongnam, Republic of Korea, investigated the correlation between adenosine triphosphate—based chemotherapy response assays (ATP-CRA) and clinical outcomes in patients with advanced gastric cancer receiving a combination chemotherapy regimen of paclitaxel (Taxol) and cisplatin.

in vitro

Patients with chemo-naïve, histologically confirmed, locally advanced, or metastatic gastric cancer were enrolled for the study. After chemosensitivity testing, patients were treated with a combination chemotherapy regimen of paclitaxel (175mg/m2) and cisplatin (75mg/m2) for a maximum of six cycles. Response was assessed every two cycles utilizing World Health Organization criteria.

in vitro

In vitro

in vivo

in vitro

Researchers performed a generating receiver operator characteristic (ROC) curve analysis using patient responses and ATP-CRA results such as chemosensitivity index, AUC, and deviation from reference database. and correlation was evaluated focusing on the diagnostic accuracy, specificity, sensitivity, positive, and negative predictive value of ATP-CRA. Data relative to the progression-free survival and OS, according to chemosensitivity, were also analyzed.

A total of 48 patients were enrolled in the study. Twelve patients were excluded from the analysis; four because of receiving an inaccurate dose of chemotherapeutic agents, six because of follow-up loss before response assessment, and two because of test failure. Patient characteristics were as follows: median age 57 (ranging from 31—70 yr of age), 39 males/nine females, 17 locally advanced tumors/31 metastatic tumors, and the majority of specimens were primary tumors (46 of 48). Median number of chemotherapy cycles were four (with a range of 1–6), and 27 patients received second-line chemotherapy upon progression.

Median PFS was 4.0 months and median OS was 11.0 months for all enrolled patients. Among 36 evaluable patients, the response rate (RR) was 41.7% (PR 15, SD 12, progressive disease [PD] 9).

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The chemosensitivity index method, which used the sum of percentage of cell death at given concentrations, had highest accuracy of 77.1% with specificity of 95.5% and sensitivity of 46%. Positive and negative predictive values were 85.7% and 75%, respectively. According to the chemosensitivity index method, 40% of patients were defined as sensitive (S) and 60% as resistant (R). The S group had longer PFS than the R group (6.0 mo vs. 2.0 mo [ = 0.01]). The S group had longer median OS compared with the R group (12.0 mo vs. 11.0 mo), but the difference did not reach statistical significance ( = 0.63).

Researchers concluded that ATP-CRA could predict clinical response to paclitaxel and cisplatin chemotherapy with accuracy of 77.1% in patients with advanced gastric cancer. They also determined it was feasible with only a small amount of available tissue (i.e., such as the amount of tissue that would be harvested by endoscopic biopsy). Furthermore, the high specificity value (95.5%) of ATP-CRA could help spare the patients toxicity and cost of chemotherapy in in vitro—resistant patients.

Cetuximab Provides a Significant Boost to the Antitumor Effects of Irinotecan and Oxaliplatin Combination Therapy in Human Colorectal Cancer Xenograft Models

Marie Prewett, MD, and colleagues, ImClone Systems Incorporated, New York City, investigated whether cetuximab (Erbitux) increases the therapeutic response to a combination regimen of irinotecan (Camptosar) and oxaliplatin (Eloxatin) (IROX) in colorectal cancer models.

Cancer

Researchers first established a maximum tolerated dose (MTD) for IROX in athymic mice bearing established HT-29 tumors by using pairwise combinations of irinotecan at 200-, 150-, and 100 mg/kg with oxaliplatin at 18-, 12-, or 6 mg/kg, intraperitoneally, q21d. The q21d dosing was based on published standards for patient safety and convenience drawn from a recent phase II clinical trial (Hoff PM, Wolff RA, Xiong H, et al: Phase II trial of combined irinotecan and oxaliplatin given every 3 weeks to patients with metastatic colorectal cancer. 2006;106:2241-2246). The MTD of IROX in mice was determined to be irinotecan at 200 mg/kg and oxaliplatin at 6 mg/kg where the T/C% was 31% and the overall weight loss was less than 4%.

Findings indicated that treatment with cetuximab, when added to an IROX treatment regimen, significantly inhibited the growth of xenograft tumors compared with IROX. In DLD-1 tumors, the T/C% for combination therapy was 29% versus 59% or 61% for cetuximab or for IROX, respectively. In the HT-29 tumor model, the T/C% for combination therapy was 15% compared with 50% for cetuximab monotherapy or 40% for IROX.

Researchers concluded that the data generated by this study support adding cetuximab therapy to IROX for achieving increased antitumor effects in colorectal cancer in patients who are 5-FU/LV intolerant or resistant.

Many of the sessions and posters at AACR presented the latest research data on advances in breast cancer diagnosis and treatment. A common thread uniting much of the presented research regarding breast cancer, according to many of the expert clinicians who spoke on the subject, is a focus on the formulation of targeted therapies based on the differences between and the distinctive characteristics of the numerous breast cancer subtypes. Oncologists were encouraged to avoid one-size-fits- all approaches to treatment in favor of developing a therapeutic tool chest designed to attack, in a tailored manner, the set of specific genetic and molecular characteristics presented by each different manifestation of the heterogeneous disease.

%u25BABreaking News

Thalidomide, Lenalidomide, and Pomalidomide Shown to Reduce Metastatic Capability of Cancer Cells Both in Vivo and in Vitro

in vivo

in vitro

Finally, a poster focusing on general cancer research received a notable amount of participant attention and on-site media coverage. As part of a continuing research effort aimed at targeting cancer metastasis for therapeutic intervention, a team of University of London scientists have investigated the effects of thalidomide (Thalomid), lenalidomide (Revlimid), and pomalidomide (CC-4047) on the metastatic capacity of a murine colorectal cell line and . The effects of these agents on the metastatic capacity of CT26 cells were established using a number of models. Results indicated that all three drugs significantly inhibited the metastatic capability of CT26 cells. Anchorage-independent growth was significantly reduced, as was migratory capacity and invasive competence

(Figure 1).

in vivo

In addition, an metastasis model was used whereby CT26 cells were administered intravenously into the tail vein of BALB/c mice (N = 15) at 10 weeks of age, and allowed to develop spontaneous metastases within the lungs. Mice challenged intraperitoneally (IP) with pomalidomide (50 mg/kg) presented with a significantly lower number of metastatic pulmonary nodules relative to control mice injected with dimethyl sulfoxide (DMSO) (50.8 % ± 6.6% vs. 100.0% ± 10.1 % at day 14; P < 0.001). Similarly, inspection of the gross anatomy of the lung revealed reduced surface changes indicative of tumor location/formation, such as tissue puckering and scarring.

According to lead investigator Waj M. Liu, St George’s University of London, in London, England, “these results provide evidence that thalidomide, lenalidomide, and pomalidomide can impair the metastatic capacity of tumors.”

Figure 1. Effect of Thalidomide, Pomalidomide, and Lenalidomide on Metatastic Capability of CT26 Cells

Model

Untreated Control

10 uM Thalidomide

10 uM Pomalidomide (CC-4047)

10 uM Lenalidomide (CC-5013)

Anchorage-Independent Growth

(# live colonies)

83

10

7

2

Invasive Competence

(% cells)

51.1 ± 5.8

28.7 ± 4.8*

31.0 ± 2.0*

39.5 ± 2.2†

Migratory Capacity

(% cells)

50.7 ± 8.3

23.1 ± 3.9‡

22.4 ± 2.0‡

36.0 ± 4.9‡

The means and standard deviations of at least three separate experiments. *P < 0.05; †P = 0.0.6; ‡P < 0.01.

Adapted from: Liu WM, Henry JY, Meyer B, et al: Thalidomide, lenalidomide, and pomalidomide reduce the metastatic capability of cancer cells in vivo and in vitro. Presented at the American Association for Cancer Research 100th Annual Meeting, Philadelphia, April 13, 2008. Abstract no. 1173.

%u25BAAdvances in Breast Cancer

Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) (ER, PR, and HER2 negative), for example, was one key breast cancer subset in which significant progress was disclosed. Within a larger forum focusing on the condition entitled, ‘Triple-Negative Breast Cancer (New Concepts in Organ Site Research Session),’ Lisa A. Carey, MD, University of North Carolina, Chapel Hill, North Carolina, discussed “Clinical and Therapeutic Implications of Triple-Negative Breast Cancer.”

Dr. Carey presented a brief review of the current state of TNBC treatment. She characterized TNBC as an “aggressive” form of breast cancer with a “poor prognostic signature” that is “usually characterized by frequent and early relapse.”

“The treatment options that we know about are limited to chemotherapy right now. Chemotherapy works and that’s all we know,” stated Dr. Carey. After reviewing outcomes associated with standard chemotherapy regimens (i.e., anthracycline and/or taxane)— the current standard of care—Dr. Carey provided data on a variety of novel and experimental treatment pathways.

“There are a lot of hypothetical approaches (to TNBC) that are actively being tested,” reported Dr. Carey. One innovative approach Dr. Carey tried involved a novel approach to improve upon existing chemotherapy, using genetic information to develop regimens that more narrowly and accurately target specific types of breast cancer. Working from the hypothesis that one “can use the (breast cancer) subtype to choose the type of chemotherapy that you use,” Dr. Carey pointed out, for example, that “if the patient has BRCA loss or malfunction (as occurs in the TNBC subtype), that would confer relative sensitivity to platinum and relative resistance to spindle poisons.”

Although Dr. Carey was quick to concede “we don’t have a lot of clinical data to back this up,” she did cite some compelling evidence to support her thesis, including a study in which 28 stage II and III patients with TNBC received four “relatively modest” dosage cycles of neoadjuvant cisplatin therapy and demonstrated a pathological complete response (pCR) rate of 22%. Although Dr. Carey commented that the study was a small one, she hastened to add that “as a clinician I can tell you that is not (a) bad (result) for a single agent.” (Garber JE, Richardson A, Harris LN, et al: Neo-adjuvant cisplatin [CDDP] in ‘triple negative’ breast cancer [BC], Abstract #3074, 29th Annual San Antonio Breast Cancer Symposium, December 2006).

Cancer Chemother Pharmacol

Another study, which examined the outcomes of 30 patients with locally advanced stage II and III TNBC who received a combination neoadjuvant treatment regimen of cisplatin, epirubicin (Ellence), and 5 FU (5-fluorouracil), followed by subsequent paclitaxel treatment, demonstrated a 43% pCR rate, which Dr. Carey characterized as “quite good.” (Torrisi R, Balduzzi A, Ghisini R, et al: Tailored preoperative treatment of locally advanced triple negative [hormone receptor negative and HER2 negative] breast cancer with epirubicin, cisplatin, and infusional fluorouracil followed by weekly paclitaxel. December 7, 2007 [Epub ahead of print]).

Moving on to other agents with potential to treat TNBC, Dr. Carey noted that researchers are currently expressing “a great deal of interest in targeting against angiogenic pathways,” reporting that there are “a number of drugs and agents out there” that may provide an effective means of pursuing such a strategy. “There are lots of ways to skin this particular cat,” quipped Dr. Carey.

One promising therapeutic avenue encompasses anti-VEGF antibodies such as bevacizumab. While speaking to the possibilities of this agent, Dr. Carey discussed ECOG 2100, a randomized phase III trial of bevacizumab added to paclitaxel in stage IV breast cancer. The trial randomized 722 patients with HER negative stage III and IV breast cancer into two separate cohorts. One cohort was treated with weekly paclitaxel in combination with bevacizumab and the other cohort received weekly paclitaxel monotherapy.

Commenting on the results, Dr. Carey stated, “ECOG 2100, of course, is the pivotal trial that established that, in a stage four, HER2 negative setting, bevacizumab added to weekly paclitaxel markedly augments the time-to-disease progression from six months to about 12 months, which is a spectacular improvement.” Furthermore, she noted, the TNBC subset “benefitted at least as much as everyone else.” (Miller KD: Update on phase III ECOG E2100 trial: Paclitaxel/bevacizumab in metastatic breast cancer, presented at the 28th Annual San Antonio Breast Cancer Symposium, December 2005).

J Clin Oncol

Dr. Carey also touted the promise of small molecule VEGFR inhibitors such as sunitinib. “In a recently published phase II trial, sunitinib demonstrated a 15% RR in a pretreated triple-negative subset,” reported Dr. Carey, adding that “it appears that this drug (sunitinib) has as much efficacy in the triple negative (patient population) as for any other subtype.” (Burstein HJ, Elias AD, Rugo HS, et al: Phase II study of sunitinib malate, an oral multitargeted tyrosine kinase inhibitor, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. 2008;26:1810-1816.) Upcoming trials, currently in the planning and enrollment phases, are likely to provide more information on the efficacy of agents such as bevacizumab and sunitinib.

Another area of investigative interest is the emerging PARP-1 inhibitor drug class. Explaining the rationale behind the hopes, Dr. Carey focused on the role of BRCA1 in the repair of DNA damage. When BRCA1 is lost or its pathways are lost…they become more dependent on PARP1. “So the theory goes,” related Dr. Carey, “that if you have both BRCA1 dysfunction and you inhibit PARP, agents that work by DNA damage have augmented efficacy. There are preclinical data supporting this assumption. There are (currently ongoing) PARP-1 inhibitor trials in both BRCA1-mutated tumors and triple-negative tumors, so, hopefully, we’ll have clinical data shortly.”

Dasatinib (Sprycel), a multitargeted inhibitor currently approved for the treatment of leukemia, has aroused interest as a possible TNBC therapy. “Dasatinib has a cell-line derived predictive model. When this model is applied to expression arrays from human breast cancers, the responders overlapped significantly with tumors that were triple negative, (raising) some expectation that dasatinib may have a role to play.” Dr. Carey disclosed that a phase II trial of dasatinib in TNBC was recently completed from an accrual standpoint and results are expected to be reported soon.

Dr. Carey observed that endothelial growth factor receptor (EGFR) is emerging as a possible molecular target. “In tissue microarray studies, more than half of triple-negative cell lines are dependent on EGFR for growth and proliferation,” stated Dr. Carey, and “building on these findings are studies such as the TBCRC001 trial.” The translational breast cancer research consortium 001 trial is a randomized phase II trial of patients with stage four TNBC who were treated either with cetuximab alone, followed by carboplatin (Paraplatin) upon disease progression, or were treated with the combination regimen from the outset of the study.

Arm one of the study, presented by Dr. Carey herself at the 2007 San Antonio Breast Cancer Symposium, was closed because of the lack of efficacy demonstrated in the monotherapy cohort. All subjects were transferred into the combination arm where a RR of 18% and a clinical benefit (CB) of 27% were observed.

Arm two is slated to be unveiled at the American Society of Clinical Oncology’s (ASCO’s) 2008 meeting. Commenting on TCBRC001, Dr. Carey observed that “a subset of patients allowed themselves to be biopsied. After receiving the combination therapy, EGFR was no longer expressed and the response cluster (typical of basal-cell TNBC) was largely inactivated. These are the things we need to figure out how to do up front, as we are selecting our tissues. This is the direction we need to go in more in our selective trials.”

Breast Cancer Res

A second trial that, according to Dr. Carey, “sheds a little more light on this particular idea,” was also examined (O’Shaughnessy J, Weckstein DJ, Vukelja SJ, et al: Preliminary results of a randomized phase II study of weekly irinotecan/carboplatin with or without cetuximab in patients with metastatic breast cancer. Treat 2007;106(suppl 1):S32. Abstract no. 308 at the San Antonio Breast Cancer Symposium 2007). The randomized phase II trial, conducted by US Oncology, compared two groups of patients who each received a combination regimen of irinotecan and carboplatin. One group was given cetuximab upon disease progression, while the other group received cetuximab up front, from the very beginning.

“In all subjects,” reported Dr. Carey, “there was only a modest improvement with the addition of the anti-EGFR monoclonal antibody to chemotherapy. However, within the triple negative subset, it was a more substantial one, giving us some idea that, at least in some patients, this may be a useful strategy” (Figure 2).

Figure 2. Response Rate by Subtype and Combination Regimen US Oncology Phase II Trial Presented by O’Shaughnessy J and Colleagues at the 2007 San Antonio Breast Cancer Symposium

Response Rate %

Irinotecan and Carboplatin

Irinotecan and Carboplatin Plus Cetuximab

All Subjects

21/69 (31%)

26/69 (38%)

Triple Negative

10/33 (30%)

19/39 (49%)

Estrogen Receptor Positive

10/35 (29%)

7/28 (25%)

Adapted from: O’Shaughnessy J, Weckstein DJ, Vukelja SJ, et al: Preliminary results of a randomized phase II study of weekly irinotecan/carboplatin with or without cetuximab in patients with metastatic breast cancer. Breast Cancer Res Treat

2007;106(suppl 1):S32.

“We need to revisit risk and prevention modeling,” concluded Dr. Carey, “we need to go back to the drawing board and rethink our modeling. Conventional chemotherapy works but unfortunately, we don’t want to rely on it and we don’t know of targeted treatments yet. We also need to know better why some respond well and others do not (to given therapeutic regimens). That will depend on tissue-based analysis to go along with clinical trials. Obtaining a better understanding of response and resistance is crucial and requires tissue-based correlative studies. The identification of targeted therapies to add to avoid chemotherapy is definitely the future. That’s the direction were going in.”

Targeted Treatment Strategies Further Affirmed

Dennis J. Slamon, MD, PhD, David Geffen School of Medicine at the University of California, Los Angeles, affirmed the wisdom of subtypefocused treatment strategies in two separate presentations: (1) “Clinical Trials for Personalized Medicine: A Dream or a Dream Come True?” (a component of a larger clinical trials design methods workshop entitled, “A Journey from Classical to Innovative Approaches”), and (2) a breast cancer “Meet-the- Expert” session. During the former presentation, Dr. Slamon reminded his audience that “human breast cancer is highly heterogeneous…breast cancer isn’t just one disease, it’s a series of diseases… although they (various breast cancer subtypes) share in common an organ of origin, they are molecularly diverse diseases.” He optimistically stated that “the hope (is that) with the advent of being able to molecularly characterize (individual breast cancer malignancies) we can decipher new molecular genetic information for these complex and variable tumors and establish new classifications with real and meaningful therapeutic impacts.”

According to Dr. Slamon, the evolution of knowledge concerning HER2-type (both negative and positive) breast cancer provides one of the best narratives concerning the development of targeted therapies. Indeed, opined Dr. Slamon, the presence of estrogen reception in some breast cancer subtypes and the absence of estrogen reception in others provided the “initial idea of targeted therapy.”

Dr. Slamon explained that “HER2 alteration, which occurs in 25% of all breast cancers, identifies a more aggressive form of the disease.” HER2 oncogene expression amplification leads to HER oncoprotein overexpression which, in turn, leads to shortened survival.

Many credit seminal data published by Dr. Slamon himself back in 1987 with establishing a clear association between breast cancer subtypes and disease outcomes. Dr. Slamon’s findings demonstrated that median survival rates from the time of first diagnosis for HER2 normal breast cancer were more than double the median survival rates shown by patients whose breast cancer was characterized by HER2 overexpression (6 to 7 yr vs. 3 yr).

Dr. Slamon and colleagues also provided key data in support of the FDA approval of trastuzumab (Herceptin) for the first-line treatment of metastatic breast cancer, including one study in particular, cited by Dr. Slamon herein owing to what he asserted was its continued relevance (Slamon et al Science 1989). The ‘648’ trial, a randomized, multicenter study of 450 patients compared trastuzumab plus chemotherapy to chemotherapy alone. The trastuzumab cohort, when compared with their chemotherapy-only counterparts demonstrated an improved response rate to 53%, a 58% improvement in duration of response, and a roughly two-thirds improvement in time-to-progression (TTP) of disease (7.6 mo in the trastuzumab plus chemotherapy cohort vs. 4.6 mo in the chemotherapyonly group).

In results that were “a surprise even to us (researchers),” recalled Dr. Slamon, “we saw improved survival that was sustained even after 12 months (78% vs. 67%). This improvement would have been much greater but all subjects were given the option to switch over to trastuzumab monotherapy or a combination regimen of chemotherapy and trastuzumab. Roughly twothirds elected to do that and just over one-third of those patients responded.”

Additionally, Dr. Slamon’s research found that trastuzumab’s safety was “exquisitely good,” with the notable exception of cardiac dysfunction. The cardiac dysfunction, however, may be a result of the agents that were used in combination with trastuzumab. “There are regimens that don’t contain anthracycline, and when you use those, the heart issues do not occur,” asserted Dr. Slamon.

N Engl J Med

Other research cited by Dr. Slamon demonstrated that trastuzumab’s disease-free survival (DFS) benefit extended across a wide spectrum of breast cancer subtypes. A meta-analysis confirmed that the agent’s benefits “go across all substrata, regardless of subgroup, age, or region.” (Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al: Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. 2005;353:1659-1672.)

Breast Cancer Res Treat

A second meta-analysis presented by Dr. Slamon “showed essentially the same thing. (Slamon D, Eiermann W, Robert N, et al: BCIRG 006: 2nd interim analysis phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab with docetaxel, carboplatin and trastuzumab in Her2neu positive early breast cancer patients. 2006;100[suppl 1]. Abstract 52.) A median follow-up of 36 months (showed that there was) already a 25% rate of recurrence (in the non-trastuzumab population). That percentage was halved by the inclusion of trastuzumab.”

The reason Dr. Slamon digressed into older data is because there are lessons to be learned which are applicable to current breast cancer research and treatment efforts. These lessons include, according to Dr. Slamon, “the importance of target identification and validation. Had we taken trastuzumab and used it in all breast cancer patients…had we used a one-size-fits-all approach, the results would have been negative. (Clinicians must) identify the right patient population and administer their targeted therapeutic there. That’s the challenge some of more recent drugs are facing…bevacizumab being an example. It is clear that bevacizumab has a response in some patients. The problem occurs when we are not able to identify the specific patient population.”

Researchers must focus on the genes and pathways likely to be contributing to the disease. Correct answers, counseled Dr. Slamon, will come from more carefully phrased questions. For example, stated Dr. Slamon, “we have an inhibitor of the HER2 alteration (trastuzumab). If we introduce the inhibitor, do we reverse the change in the gene? That would tell us that the pathways are linked. If they’re linked, that may be something HER2 is engaging to cause the phenotype expression changes reversed by trastuzumab. In HER2-positive breast cancer, we see (by array analysis) a rich network of vessels that are feeding the tumors. We believe this is because of increased VEGF levels that the HER2 is inducing. So, now we understand at least part of the phenotype. HER 2 is taking the hormone receptor pathway out of the picture…it’s turning on the angiogenic pathway… it’s also turning on a motility pathway. So, it is engaging all these other pathways. However, the increased VEGF levels that HER2 is producing dropped significantly and dramatically with the introduction of trastuzumab.” Thus, the $64,000 question is: “Does trastuzumab decrease the levels of VEGF production (and consequent overexpression) in tumor cells?”

According to Dr. Slamon, preclinical data have shown that “levels of VEGF in cells, after adding trastuzumab, dropped precipitously. That really proved that the pathways were linked. We are not using an anti-VEGF molecule, we are using an anti-HER2 molecule, causing a dramatic drop in the VEGF production of these cells.”

Dr. Slamon explained, “the correlation between higher VEGF and HER2 levels in primary breast cancer, and their combined effects on survival, told us that perhaps it makes sense to combine these two therapeutics (trastuzumab and bevacizumab) to confirm functional relevance.” Dr. Slamon and colleagues then began to research the effect of trastuzumab combined with a VEGFantibody (bevacizumab) on tumor growth in vivo. Findings were encouraging. “The combination of bevacizumab and trastuzumab reduces the growth of breast cancer cells…resulting in dramatic suppression,” reported Dr. Slamon, asserting that “two targeted therapies will have a better effect than either alone.”

The objective of the next phase of research, according to Dr. Slamon, would be to find out if the encouraging preclinical data outlined above would translate into findings in clinical specimens. In Dr. Slamon and colleagues’ initial phase I study of bevacizumab and trastuzumab, researchers began to see patient responses within four weeks, no untoward toxicity was induced by the combination, and there was no change in the pharmacokinetics of either antibody when both were used in combination with one another. Among the nine evaluable patients who participated in the phase I trial, there were two CR’s, three PRs, 2 SDs (>11 mo), and two occurrences of progressive disease (PD).

Interim phase II data were presented at the end of last year at the 2007 San Antonio Breast Cancer Symposium. These data were drawn from the first 39 patients enrolled in the trial, 36 of whom have had at least one evaluable response. Among this group, there were three CRs, 16 PRs (many, with continued response, may lead to being classified as having CR over the duration of the study, speculated Dr. Slamon), 12 cases of SD (out to a minimum of 29 wk, thus meeting the definition of clinical benefit), and only five patients who experienced disease progression. The interim overall response rate (ORR) was 53% and the incidence of clinical benefit was 86%. As far as safety was concerned, only two patients demonstrated any toxicities (both of whom had prior anthracycline therapy that may have contributed to their adverse reactions) and, as was the case in the phase I trial, there was no change in the pharmacokinetics of either antibody when they were used in tandem. Overall, commented Dr. Slamon, the combination showed itself to be “very, very safe.”

The encouraging phase I/II results achieved by Dr. Slamon and colleagues have led to the so-called BETH (BEvacizumab with Trastuzumab in Her2 positive breast cancer) trial. “We will enroll roughly 4,000 women,” reported Dr. Slamon, in an effort to demonstrate the superior effectiveness of the two combined biological therapies, and provide an alternative to standard anthracycline- based chemotherapy regimens.

The trial will compare the outcomes of one group who will be given trastuzumab plus chemotherapy (TCH) with a second group that will receive trastuzumab, bevacizumab, and chemotherapy (TCHB). Dr. Slamon and colleagues initially designed a study that would test the safety and efficacy of the two biologic agents (bevacizumab and trastuzumab) in a cohort that received no chemotherapy at all. “We wanted a third arm, but the FDA said it is too early to be testing pure biologic regimens (on such a large subject population),” explained Dr. Slamon. Yielding to FDA resistance, Slamon and colleagues incorporated chemotherapy into both arms of the BETH trial and scrapped plans for an all-biologic therapy cohort. “It’s what we had to settle for,” conceded Dr. Slamon. The BETH trial, which will launch around the time that these words are published, will, according to Dr. Slamon, “provide a really good look at what’s happening in HER2 positive disease for the next generation.”

Dr. Slamon concluded by advising attendees to try to move away from standard chemotherapy regimens in favor of emerging options, many of which are likely to offer the clinical benefits of chemotherapy without the toxicity. “We now have two targeted therapies: trastuzumab, which is approved in an adjuvant setting, and lapatinib (Tykerb), which is approved in a metastatic setting, that appear to replace the gained efficacy of anthracycline-based chemotherapy while leaving the well known and well established toxicities behind,” summarized Dr. Slamon.