Breast cancer patients whose chemotherapy is initiated >60 days following surgery experience worse survival outcomes, according to a large, retrospective review of patient medical records conducted by Mariana Chavez-MacGregor, MD, and her colleagues at The University of Texas MD Anderson Cancer Center. The impact of treatment delay is greatest among patients with stage III or triple-negative breast cancer (TNBC) and those whose HER2-positive tumors have been treated with trastuzumab.

Most adjuvant breast cancer chemotherapy begins within a few weeks of surgery; however, previous research results differ on the impact that longer time to chemotherapy (TTC) might have on survival. Treatment delays also have been reported to occur more frequently among low-income groups, racial minorities, and Medicare patients.

To further investigate the impact of TTC, Chavez-MacGregor, an assistant professor in the department of Breast Medical Oncology, Division of Cancer Medicine, at MD Anderson, and colleagues analyzed the records of 6827 patients diagnosed with stage I to III invasive primary breast cancer who received treatment at the cancer center between 1997 and 2011. Most patients had stage I/II disease (84.3%) and 15.5% had stage III.

Patient medical records were divided into three groups based on the number of days between completion of surgery and start of chemotherapy: ≤30 days (n = 2716), 31 to 60 days (n = 2994), and ≥61 days (n = 1117). Overall survival (OS), relapse-free survival (RFS), and distant relapse-free survival (DRFS) were assessed for the study population as a whole and also according to breast cancer subtype, with a median follow- up of 59.3 months.

Investigators applied multivariable models and adjusted for confounders to estimate 5-year OS, RFS, and DRFS for all patients based on TTC and other patient characteristics. They determined that when compared with patients who had adjuvant chemotherapy ≤30 days after surgery, patients whose TTC was ≥61 days post-surgery had a 19% increased risk of death (HR = 1.19; 95% CI, 1.02-1.38).

Although TTC was not significantly linked to outcome in patients with stage I disease, the risk of distant relapse was estimated to increase by 18% in stage II patients whose chemotherapy started 31 to 60 days after surgery, and by 20% in the ≥61 days cohort. For patients with stage III disease who started chemotherapy ≥61 days after surgery, the risk of death was increased by 76%, the risk of relapse by 34%, and the risk of distant relapse by 36%, when compared with patients whose TTC was ≤30 days.

The impact of TTC on survival and relapse also varied according to breast cancer subtype. Patients with hormone receptor (HR)-positive tumors receiving chemotherapy ≥61 days after surgery had a 29% increased risk of death (HR = 1.29; 95% CI, 1.02-1.64).

HR-positive patients who received chemotherapy 31 to 60 days after surgery were estimated to have a 15% increased risk of relapse and an 18% increased risk of distant relapse, compared with patients whose TTC was ≤30 days, the researchers reported.

The magnitude of risk was more pronounced when the researchers looked at the records of patients with TNBC and those who were HER2-positive and treated with trastuzumab.

Patients with TNBC who received chemotherapy either 31 to 60 days or ≥61 days after surgery had a 74% and 54% increased risk of death, respectively, compared with the ≤30 days group, but RFS and DRFS were not impacted by TTC in these patients.

For patients who were HER2-positive but not treated with trastuzumab (n = 551), outcomes were not adversely affected by longer TTC, but a statistically significant increase in death risk was observed in the trastuzumab- treated group (n = 591) when chemotherapy was initiated ≥61 days after surgery versus ≤30 days (HR = 3.09; 95% CI, 1.49-6.39). A trend toward worse RFS and DRFS was also reported for this group.

The researchers concluded that for patients with stage II and III breast cancer, those with TNBC, and those with HER2-positive tumors, “Every effort should be made to avoid postponing the initiation of adjuvant chemotherapy. This may lead to an improvement in outcomes for these subsets of patients.”

de Melo Gagliato D, Gonzalez-Angulo AM, Lei X, et al. Clinical impact of delaying initiation of adjuvant chemotherapy in patients with breast cancer [published online January 27, 2014]. 

Articles

Breast cancer patients whose chemotherapy is initiated >60 days following surgery experience worse survival outcomes

Breast Cancer Patients Fare Worse When Adjuvant Chemotherapy Is Delayed

The use of immunotherapy for pancreatic cancer has had limited exposure, but Aduro BioTech, Inc, has had phase II success with an approach in which two vaccines are administered. The vaccines, GVAX Pancreas and CRS-207, are administered to patients sequentially.

“It has been shown previously in the vaccine field that when combining two vaccine modalities that immune responses are superior to a single vaccine modality,” said Dirk Brockstedt, PhD, senior vice president of Research and Development at Aduro Biotech, in an interview with 

This knowledge, along with positive analyses from preclinical and phase I research, led to Aduro’s phase II investigation of the vaccine combination.

Results from the phase II study demonstrated that treatment with GVAX Pancreas and CRS-207 improved overall survival (OS) and doubled the 1-year survival probability for patients with previously treated, metastatic pancreatic ductal adenocarcinoma. The findings were presented by lead author Dung T. Le, MD, an assistant professor of Oncology of the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, during an oral presentation at the 2014 Gastrointestinal Cancers Symposium in San Francisco.

In the study, patients were randomized to receive either the combination of GVAX Pancreas and CRS-207 (Arm A), or the GVAX Pancreas vaccine only (Arm B). Researchers reported that patients in Arm A demonstrated a median OS of 6.1 months compared with 3.9 months in Arm B (HR = 0.54; 

 = .011). One-year survival probability for patients in Arm A was 24% as compared to 12% in patients in Arm B. According to the Aduro, the study was stopped early because it had met the primary efficacy endpoint at a preplanned interim analysis.

A phase IIb trial was initiated shortly after data from the phase II study were presented.

The company reported that the phase IIb study, ECLIPSE trial (Efficacy of Combination Listeria/GVAX Immunotherapy in the Pancreatic Cancer Setting), will enroll approximately 240 adults with previously-treated metastatic pancreatic cancer, involving more than 20 clinical trial sites in the United States and Canada. Safety, immune response, and efficacy will be evaluated.

In this three-arm trial patients will be randomized to receive GVAX Pancreas, low-dose cyclophosphamide, and CRS-207; CRS-207 only; or chemotherapy. The primary endpoint is OS.

“The goal of the study is to confirm results from the previous study and to compare overall survival to currently used therapy,” said Brockstedt. “We’re interested in assessing whether the combination therapy is truly required. From the previous phase II study, it’s clear that if you compared the combination therapy to just GVAX alone, the combination treatment is superior and led to an increase in overall survival,” Brockstedt said.

Eventually, the company would like to determine if GVAX is actually contributing to this improved survival rate. Brockstedt said that “from a business perspective, developing a single biologic is a simpler development path than developing two biologics.” He noted that there are regulatory challenges, as well. “In a combination treatment, the manufacturer has to demonstrate the contribution of each modality to safety and efficacy. So we’re addressing this in the phase IIb study now, so that we have a relatively straightforward phase III study moving forward.”

According to Aduro, the GVAX family of vaccines is derived from human cancer lines that are genetically modified to secrete GM-CSF, an immune-stimulatory cytokine.

CRS-207 is based on attenuated Listeria monocytogenes strains that have been genetically modified to induce potent innate and T cell-mediated immunity, specific for tumorassociated antigens. CRS-207 has been engineered to express the tumor-associated antigen mesothelin, which is overexpressed in many cancers, including non-small cell lung, ovarian, and gastric, as well as mesothelioma.

Aduro BioTech Immunotherapy Duo Shows Promise in Pancreatic Cancer

	Member, Fred Hutchinson Cancer Research Center

The Long-Term Follow-Up (LTFU) Clinical Program at Seattle Cancer Care Alliance (SCCA) has expanded its scope of services to assist in the hands-on management of patients who develop complex conditions more than 100 days after their peripheral blood hematopoietic stem cell transplant procedure.

The Transitional Transplant Clinic (TTC) started in September 2012 and offers specialized posttransplant care from a dedicated team of SCCA physicians and nurses. The TTC takes pressure off the early posttransplant care teams and referring physicians by providing temporary care for patients with complex medical conditions until they are ready to return to the care of their local oncologists or primary care physicians. The TTC also opens up capacity at SCCA, ensuring that new patients get access to life-saving transplants without delay, and improving the continuity of care for patients with lingering complications.

Most patients who have a bone marrow transplant at SCCA initially receive care in a dedicated posttransplant clinic for 2 to 3 months and then return to the care of their primary physician. Once patients are discharged from this early posttransplant service, they become LTFU patients. The LTFU clinical program provides telemedicine and onsite clinical consultation to its patients. If a patient develops a typical, mild transplant-related problem, or if the primary provider has a question, clinicians in the LTFU program consult with them over the phone to provide advice or, if needed, coordinate a return to SCCA for an evaluation or clinical care.

Today, the LTFU program has more than 5000 patients who were transplanted between 100 days and 42 years ago at either Fred Hutchinson Cancer Research Center or SCCA. This growing LTFU population attests to the expanding use and improved long-term outcomes of modern bone marrow transplant techniques used at SCCA.

Even with safer and more effective transplants, some patients will develop severe posttransplant complications that prevent them from being discharged to their primary provider at the expected 100 days after transplant. Other patients who have already been discharged also sometimes experience new or recurrent posttransplant complications that are difficult for a primary provider to handle.

These are often recipients of allogeneic transplants with new or poorly controlled late acute or chronic graft-versus-host disease. Or, they might be patients with serious or recurrent infections, poor graft function, or other— perhaps multiple&mdash;medical conditions that require extensive ongoing management. These types of patients require prolonged and frequent clinic visits that are hard for a busy oncology clinic to handle. The TTC at SCCA provides this complex level of posttransplant care.

The LTFU Clinical Program continues to offer its full range of services. What’s new is that the TTC now fills the gap in continuity of care for the high-acuity patients with complex posttransplant-related problems beyond 2 to 4 months after transplantation.

According to Paul V. O’Donnell, MD, PhD, past medical director of SCCA’s Adult Transplant Service, the TTC provides an essential backup service to referring physicians. “A private oncologist in the community may see three patients every hour, so caring for one of these patients with chronic or complicated issues can be extremely difficult,” O’Donnell said. “The TTC will take care of these patients and help them transition back to the referring physician over a period of a few months.”

Ensuring Capacity for New Transplant Patients Until recently, transplant patients with late-developing chronic or serious problems typically received care at SCCA’s early posttransplant clinic or the hematological clinic, located at the University of Washington Medical Center and Seattle Children’s Hospital. But increasing demand for transplants has reduced the capacity of these core clinics to keep or readmit patients with chronic problems.

“If these patients with late acute problems stay too long in the allogeneic or the autologous posttransplant care clinics, the clinic volumes build and build,” O’Donnell said. “We need those inpatient clinics for about five new patients each week.” If our transplant team is overloaded with complex patients, it makes it difficult to take new patients,” he said. “The TTC was designed to help us maintain this capacity for new incoming patients.”

Another primary motivation for creating the TTC was to establish a seamless continuity of care from a dedicated, expert medical team. The acute posttransplant team’s monthly staff rotation hampered their ability to provide continuity of care to patients with lingering complications beyond 3 months after transplant. The TTC has solved this problem, which is another novel aspect of SCCA’s transplant program.

The TTC team consists of two attending physicians— Merav Bar, MD, assistant member, Fred Hutchinson Cancer Research Center, and Laura S. Connelly-Smith, MBBCh, DM, SCCA staff physician&mdash; along with one dedicated midlevel practitioner, one dedicated nurse, and one support staff. The TTC team’s goal is to improve or stabilize the patient’s posttransplant medical conditions and eventually transfer their primary medical care back to their referring physicians with periodic follow-up by the LTFU team.

To date, 50 patients have received care at the TTC, which is more than originally projected. Approximately half of these patients required hospital admissions. The average duration of medical care received by TTC patients is 3 months.

More information about SCCA’s LTFU care can be found at 

www.seattlecca.org/diseases/bmt-long-term-follow-up.cfm

The Long-Term Follow-Up (LTFU) Clinical Program at Seattle Cancer Care Alliance (SCCA) has expanded its scope of services to assist in the hands-on management of patients who develop complex conditions more than 100 days after their peripheral blood hematopoietic stem cell transplant procedure

Filling a Gap in Posttransplant Care: The Transitional Transplant Clinic

		Lymphoma Division Chief John Theurer Cancer Center at HackensackUMC

		Chief Science Officer and Director of Research and Innovation Regional Cancer Care Associates

The concept of linking chromosomes to cancer was first proposed by Boveri in 1902. The notion that cells carry surface receptors was established in 1905 by Ehrlich, who also coined the term chemotherapy. At that time, however, surgery and radiation were the only strategies used in the treatment of tumors, including in lymphosarcoma. The era of cancer chemotherapy did not officially begin until the 1940s, with the first use of nitrogen mustard in lymphoma (after its declassification as a warfare agent) by Gilman and Goodman at Yale and folic acid antagonists by Sidney Farber in Boston.

From then on, many new compounds (mostly cytotoxics) were established using the standard clinical trial approach. Combination regimens appeared in the mid-1960s, thanks to Holland, Freireich, and Frei, who hypothesized that cancer chemotherapy should follow the strategy of antibiotic therapy for tuberculosis. Subsequently, all combination chemotherapy regimens were developed empirically by using drugs with distinct mechanisms of action affecting DNA (directly or indirectly) or cells’ microtubules. Retrospectively, it seems oncologists had hit a wall in terms of results for several decades, though dramatic progress was being made toward understanding the mechanisms underlying cancer.

The enormous progress of cell biology applied to cancer cells led to the publication of the initial classic six hallmarks of cancer in 2000, which then appeared much more complex in the updated version a decade later (Cell. 2011;144[5]:646- 674). Meanwhile, it was conceptualized then that cancer cells relied on deregulated pathways—particularly either loss of tumor suppressor genes or gain of oncogenes function, leading to the concept of oncogene addiction&mdash;which in itself provided an obvious rationale for targeted intervention.

The Human Genome Project, completed in 2003, mapped the 25,000 genes in the genetic code and ushered in the era of personalized medicine. The era of targeted therapy was launched with targeting HER2 with trastuzumab in breast cancer (Slamon et al. N Engl J Med. 2001;344[11]:783-792.) and with targeting BCRABL with imatinib in chronic myeloid leukemia (Druker et al. N Engl J Med. 2001;344[14]:1031-1037). Since then, an impressive number of targeted approaches have been developed that either help pick a drug (eg, crizotinib for ALK-positive NSCLC, erlotinib for EGFR-positive NSCLC, PARPi in BRCA1/2-mutated malignancies, vemurafenib in BRAF V600E-positive melanoma) or identify patients for whom a drug is unlikely to benefit (eg, patients with KRAS-positive colorectal cancer are unlikely to benefit from anti- EGFR therapy).

Though these examples are quite dramatic, unfortunately they represent only a true minority of patients. The Human Genome Project will definitely remain as a landmark in the evolution of medicine at large, though a dramatic acceleration has taken place since then. The high throughput technologies developed then have led to the genomics of cancer, which have revealed a daunting diversity, both interpatient, but also within a patient (clonal heterogeneity).

The heterogeneity of cancer arises in large part from genetic variation, where the random mutation frequency in human cancer cells is over 100- to 500-fold greater than in adjacent tumor cells. The mutational landscape (insertions, deletions, fusions, etc) of cancer is extremely complex (beyond the point of this editorial) and multilayered -omics have emerged from DNA, RNA, and epigenetic differences, to metabolomics and eventually, functional proteomics. This remarkable tumor heterogeneity will likely represent a major challenge to personalized medicine and biomarkers development.

It is clear, however, that even for tumors with thousands of mutations, a limited number of them are critical in cancer cell behavior—driver mutations&mdash;while many others are considered passenger mutations&mdash;potential noise in data interpretation. While the price of whole genome sequencing has dramatically improved&mdash;Illumina launched its HiSeq X Ten sequencer this year, which delivers the first $1000 genome at 30x coverage&mdash; the difficulty resides in the interpretation of the data from complex bioinformatics to actionable items in routine practice. Massive parallel sequencing or next generation sequencing offers a platform that can deliver answers (profiles) within 2 weeks and usually focuses on mutations (a few hundred) believed to be relevant in cancer cell biology.

While the technology keeps evolving rapidly and might make it easier (smaller amount of materials needed or profiles based on circulating tumor cells [CTCs]), it becomes clear that an enormous effort is needed to implement these changes in the current and future management of cancer patients. The goal is to ultimately be able to integrate all these -omics data through more crossdisciplinary biology approaches and computational science—the foundation of the promising and elegant field of systems biology led by Leroy Hood (see our upcoming “Applications of Systems Biology in Cancer” conference on May 12, 2014, at the John Theurer Cancer Center).

Emerging efforts to develop molecularly relevant clinical trials still face a lot of challenges: from access to tissue (with repeat biopsies critical to understanding clonal evolution and resistance), to defining relevant subsets of important mutations (to reduce noise and improve feasibility), to eventually analyzing pathways/ networks that hopefully will guide our decisions in the future. There is no question that the era of precision medicine has arrived, and we need to embrace it and resolve together the challenges that come with it, including at the regulatory level.

The ultimate integration of -omics data at large will help improve cancer patients’ outcome at several levels: (1) early detection (before any symptoms or clinical abnormality) using, for example, CTCs, serum proteins, or exosomes signatures (2) patient stratification at diagnosis (eg, identify patients who will do well with a classic regimen versus offering a new option) (3) build clinical trials that are molecularly relevant (eg, adaptive trials) (4) assessment of disease progression, response, or resistance to therapy (5) eventually redefining the classification of the tumor itself through the ongoing work of large consortia (TCGA and ICGC).

Implementing precision medicine requires a global effort from clinicians, insurance providers, government regulators, and the pharmaceutical industry. Finally simplifying the drug development process (away from phase III trials) by focusing on targeted populations will help reduce costs, while giving the right drug to a given patient, and will translate into a better “mileage.” This in itself will help control cancer care cost by reducing the use of empiric and palliative ineffective therapies. “Smarter medicine is better medicine!”

There is no question that the era of precision medicine has arrived, and we need to embrace it and resolve together the challenges that come with it, including at the regulatory level.

Precision Medicine-An Inevitable (Though Challenging) Goal!

Founded in 1987, Gilead Sciences made a name for itself in 1996, when it launched Vistide, a treatment for cytomegalovirus retinitis in patients with AIDS. The company has expanded its understanding of the complexities of the immune system and is firmly focused on oncology.

Its lead oncology agent idelalisib is undergoing phase III investigation as a treatment for indolent non-Hodgkin lymphoma (iNHL) and chronic lymphocytic leukemia (CLL). Idelalisib, the prized asset that was acquired from Calistoga Pharmaceuticals in 2011, is aimed at a target identified as the “delta” variation of the PI3 kinase pathway. The target is involved in proliferation, growth, migration, and cell survival. When the pathway is switched into an overactive mode, it can lead to cancer and inflammatory diseases. Idelalisib is being developed both as a single agent and in combination with approved and investigational therapies.

“Idelalisib has produced impressive responses in clinical trials for both indolent NHL and CLL, and we believe that it may offer an important new treatment option for patients with these cancers,” said Roger Dansey, MD, vice president of Clinical Research at Gilead, in an interview with 

Combination treatment with idelalisib and rituximab (Rituxan) was associated with a >70% improvement in overall survival (OS) in patients with high-risk relapsed/refractory CLL, according to phase III data from Study 116 (Abstract LBA-6) presented at the 55th Annual Meeting of the American Society of Hematology. “This study was stopped early because of the overwhelming improvement in progression-free survival among patients receiving idelalisib plus rituximab versus those receiving rituximab alone,” said Dansey.

In the phase II Study 101-09 presented during an oral session of the same meeting (Abstract #85), “[heavily-pretreated] patients with refractory iNHL who received idelalisib had a 57% overall response rate, with a median duration of response of 12.5 months,” said Dansey.

The company reports that the FDA has granted priority review to a New Drug Application (NDA) for idelalisib for the treatment of relapsed CLL. A target review date under the Prescription Drug User Fee Act (PDUFA) has been set for August 6, 2014. Previously, the FDA granted idelalisib a Breakthrough Therapy designation in relapsed CLL. The designation is given to drug candidates that may offer major advances in treatment over existing options.

Separately, the FDA has accepted an NDA for idelalisib for the treatment of patients with iNHL. The FDA has granted a standard review for the iNHL NDA, with a target review date under PDUFA set for September 11, 2014.

Rounding out the company’s other oncology offerings are momelotinib, simtuzumab, GS-9973 (a Syk inhibit or), GS-9820 (a PI3K delta inhibitor), and GS-5745 (an MMP9 mAb inhibitor).

Momelotinib, an investigational JAK inhibitor that has shown promise for the treatment of myelofibrosis, is in phase III development and the others are in earlier stages.

		*Being developed as a single agent and in combination with idelalisib

Founded in 1987, Gilead Sciences made a name for itself in 1996, when it launched Vistide, a treatment for cytomegalovirus retinitis in patients with AIDS.

March 2014 | Oncology & Biotech News

Breast Cancer Patients Fare Worse When Adjuvant Chemotherapy Is Delayed

Aduro BioTech Immunotherapy Duo Shows Promise in Pancreatic Cancer

Filling a Gap in Posttransplant Care: The Transitional Transplant Clinic

Precision Medicine-An Inevitable (Though Challenging) Goal!

Gilead Sciences Moves Ahead on Idelalisib Filings