Patients with human papilloma virus—positive oropharyngeal cancer (HPV-OPC) and their spouses may find some reassurance in a recent study by researchers at the Johns Hopkins Bloomberg School of Health. The study found that partners are no more likely to be infected by HPV than the general population, and their risk of contracting HPV-OPC remains low.

Findings of this pilot study—the first large study to examine oral HPV infection among patients with HPV-OPC and their partners&mdash;were announced in a press briefing at the 2013 ASCO Annual Meeting. The majority of oropharyngeal cancers in the United States are now caused by HPV, and the incidence of HPV-related oropharyngeal cancer is increasing significantly, noted the study’s lead author, Gypsyamber D’Souza, PhD, MPH, MS, associate professor of Epidemiology at the Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland.

“Some of the patients with this diagnosis worry about oral HPV transmission and the cancer risk to their partners or spouses.” To better understand this possible increased risk, D’Souza and colleagues enrolled a total of 166 patients with HPV-OPC; 94 of them had spouses or long-term partners who were also enrolled in the study. DNA samples were collected from both groups, following administration of a 30-second mouth rinse and gargle. Samples were obtained at the time of diagnosis and 1 year later.

Median age of the HPV-OPC patients was 56 years; 89% were male, 92% were white, non-Hispanic, and 94% had performed oral sex. Their partners were predominantly female (94%) and white, non-Hispanic (92%), with a median age of 53 years. Patients were significantly more likely to have had >10 oral sex partners over their lifetime (39%), versus their spouses/partners (11%). Samples were analyzed for the presence of 36 subtypes of HPV DNA, among them, the most prevalent type found in the majority of HPV-OPC cancers—HPV16.

DNA is considered the “gold standard” for determining presence of HPV in the tumor, D’Souza explained. She noted that for individuals without cancer, examining exfoliated oral cells from the rinse/gargle samples is the best available option for measuring oral HPV infection, since there is currently no validated, US Food and Drug Administration-approved test. Researchers found that nearly two-thirds of the cases (65%) had HPV DNA in their oral exfoliated cells, and a little over half (54%) of these cases had HPV16, said D’Souza. After 1 year and completion of treatment, analysis of the oral rinse samples from the HPVOPC cases demonstrated that a “vast majority of these cases no longer had any HPV16 DNA detectable,” she added.

The prevalence of HPV among the long-term female partners of patients was 5%, which is comparable to the 4% prevalence among women in the general population, based on previously published data. HPV16 was found in just 2.3% of female partners and in none of the small number of male partners. In addition, no precancers or cancers were detected in the 60 partners/spouses who underwent a visual oral exam.

“These findings provide assurance that prevalence of oral HPV infection is not increased among partners [of patients with HPV-OPC], and their risk of HPV-OPC remains low,” said D’Souza. “Couples who have been together for several years have likely shared whatever infections they have, and no changes in their physical intimacy are needed.”

D’Souza concluded her presentation by noting that while oral HPV infection remains common, “many individuals who become infected are able to clear these infections and not get cancer.” “HPV is responsible for thousands of cases of cancer of the oropharynx, cervix, and other sites every year,” noted Gregory Masters, MD, ASCO spokesperson and moderator of the press briefing. “This study improves our understanding of HPV risk among the partners of patients with HPV-positive oropharyngeal cancers. I’m sure this news will provide long-awaited reassurance for patients, as well as their spouses and partners.” 1. D’Souza G, Gross ND, Pai SI, et al. Oral HPV infection in HPV-positive oropharyngeal cancer cases and their spouses. J Clin Oncol. 2013;31 

Articles

Evidence-Based Oncology

For Partners of HPV-Positive Throat Cancer Patients, Good News in Studies

Bevacizumab (Avastin) combined with either of 2 chemotherapy backbones improved overall survival (OS) by 3.7 months versus chemotherapy alone in patients with advanced cervical cancer, according to data from the phase III GOG 240 study. The likely practice-changing results were presented at a press briefing at the 2013 ASCO Annual Meeting.

“This is the first time that an overall survival benefit [with a targeted drug] has been shown in cervical cancer. This is a paradigm shift—patients live longer and feel better,” said moderator and ASCO spokesperson Jyoti D. Patel, MD, an oncologist at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University in Chicago, Illinois.

The standard of care for newly diagnosed cervical cancer is cisplatin plus paclitaxel, and some patients are cured when treated with radiation plus cisplatin-based chemotherapy. However, the treatment options are highly limited for those patients whose disease progresses. These patients often become resistant to cisplatin, and “Unlike some other solid cancers, cervical cancer doesn’t really respond to different chemotherapies…so we need some new therapeutic options,” said lead GOG 240 study author Krishnansu S. Tewari, MD, a professor of Obstetrics and Gynecology at the University of California, Irvine, who presented the results at the ASCO press conference.

Researchers decided to test the antiangiogenic VEGF inhibitor bevacizumab in this setting because “angiogenesis is very active in cervical cancer,” according to Tewari. In the 4-armed GOG 240 trial, 452 women with recurrent or metastatic cervical cancer were randomized to 1 of 2 chemotherapy regimens alone or combined with 15 mg/kg of bevacizumab. The chemotherapy regimens were cisplatin (50 mg/m2) plus paclitaxel (135-175 mg/m2) and topotecan (0.75 mg/m2 days 1-3) plus paclitaxel (175 mg/m2 day 1). Treatment was administered on 21-day cycles until complete response, unacceptable toxicity, or disease progression.

	The researchers included the noncisplatin chemotherapy arm with their analysis because of the resistance concern with repeated cisplatin treatment. Topotecan plus paclitaxel was selected because a phase II trial in this population showed that the regimen is active in this population. Patient characteristics in the four GOG 240 study arms were comparable with regard to age, histology, performance status, previous use of platinum as a radiosensitizer, and recurrent, persistent, or advanced disease. Overall, there was a significant improvement with the primary endpoint of OS for patients receiving bevacizumab.

	At a median follow-up of 20.8 months, OS with bevacizumab plus chemotherapy was 17.0 months versus 13.3 months with chemotherapy alone (hazard ratio = 0.71; 95% CI, 0.54-0.94; P= .0035). The survival rate did not vary significantly between the two chemotherapy arms. Response rates (level of tumor shrinkage) were better for patients receiving bevacizumab: 48% versus 36%, respectively (P = .00807).

	Tewari said bevacizumab also improved progression-free survival (PFS), but did not present the PFS data at the press briefing. We feel [these results] are clinically meaning in a population of patients that doesn’t respond to chemotherapy very well,” said Tewari. Regarding toxicities, higher rates of grade 3-4 bleeding (5% vs 1%), thrombosis/embolism (9% vs 2%), and gastrointestinal fistula (3% vs 0%) were reported with combination bevacizumab treatment versus chemotherapy alone. Additionally, there were four fatal adverse events in both the bevacizumab and nonbevacizumab treatment groups.

	Discussing the toxicity profile, Tewari said, “We found no new toxicities associated with bevacizumab. The toxicities were similar to what had been previously reported [with bevacizumab treatment] in other types of cancers.” GOG 240 also used patient-reported outcomes to compare quality of life between the treatment groups and found little variance. “The [QoL] assessment indicates that the survival gains associated with bevacizumab did not come at a decrease in quality of life,” said Tewari.

	Regarding the next steps for the GOG 240 study, Tewari said that the manuscript for the study has been written and will soon be submitted for review and publication. He said that he does not know the specific timeline for when Genentech, which manufactures bevacizumab, might submit an application to the FDA for a cervical cancer indication for bevacizumab. He did note, however, that it is likely that Genentech will begin communicating with the FDA soon about the potential to expand the drug’s indication.

1. Tewari KS, Sill M, Long III HJ. Incorporation of bevacizumab in the treatment of recurrent and metastatic cervical cancer: a phase III randomized trial of the Gynecologic Oncology Group. J Clin Oncol. 2013;31(suppl; abstr 3). 

Bevacizumab Aids Survival in Cervical Cancer

Researchers highlighted the latest developments in the treatment of multiple myeloma at the 2013 ASCO Annual Meeting. Noteworthy abstracts included updated data on pomalidomide (Pomalyst), which the US Food and Drug Administration (FDA) recently approved, as well as research involving the promising novel agents daratumumab and elotuzumab. 

New Standard of Care in Relapsed/Refractory MM

Pomalidomide plus low-dose dexamethasone “should become the standard of care for patients with relapsed/refractory multiple myeloma (MM) after treatment with lenalidomide and bortezomib,” said Katja C. Weisel, MD, associate professor at University Hospital Tuebingen in Germany, reflecting the views of an international group of investigators taking part in the large MM- 003 trial.

The phase III MM-003 study enrolled 455 patients with relapsed or refractory MM. Eligible patients were refractory to their last prior therapy, had progressive disease during therapy or within 60 days, and had failed lenalidomide and bortezomib after two or more cycles of each therapy alone or in combination. 

Patients were randomized 2:1 to a combination of pomalidomide plus low-dose dexamethasone (n = 302) or to high-dose dexamethasone (n = 153). At a median follow-up of 4 months, when the primary analysis was performed, patients receiving the combination of pomalidomide plus low-dose dexamethasone had significantly longer edian progression-free survival (PFS), at 3.6 versus 1.8 months (hazard ratio [HR] = 0.45; P <.001) and overall survival (OS; not reached vs 7.8 months; HR = 0.53; P <.001) compared with patients receiving high-dose dexamethasone.

		analysis after a median follow-up of 10 months. At this time, PFS and OS continued to favor treatment with pomalidomide plus low-dose dexamethasone, with median PFS of 4 versus 1.9 months (HR = 0.48; P <.001) and median OS of 12.7 versus 8.1 months (HR = 0.74; P = .028). The investigator-assessed overall response rate for patients in the pomalidomide arm was 31% versus 10% in the high-dose dexamethasone arm (P<.001), and 24% versus 3% for patients who were randomized 6 months or more after enrollment (P <.001).

		The most frequent grade 3/4 adverse event for the pomalidomide combination was neutropenia (48%). Commenting on this rate of neutropenia, Weisel noted that there were only a few febrile complications. On February 8, 2013, the FDA approved oral pomalidomide for the treatment of patients with MM who have received at least 2 prior therapies, including lenalidomide and bortezomib, and who have had disease progression on or within 60 days of completion of the last therapy.

CD38 Monoclonal Antibody Yields “Unprecedented” Early-Stage Data

		The investigational monoclonal antibody (mAb) daratumumab targets the CD38 molecule, which is highly expressed on the surface of multiple myeloma (MM) cells. Daratumumab has been shown to have broad-spectrum cytotoxic activity; it acts by mediatingkilling of CD38-expressing tumor cells via antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity, and apoptosis.

		In a phase I/II dose-escalation study reported by Henk Lokhorst, MD, PhD, from UMC Utrecht, The Netherlands, for an international group of researchers at ASCO 2013, the performance of daratumumab in patients with relapsed/refractory MM was described as “unprecedented unprecedented for a single-agent mAb treatment of multiple myeloma.”

		In early May, the FDA granted Breakthrough Therapy Designation for daratumumab for the treatment of patients with MM who have received at least 3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent, or for patients who are doublerefractory to both classes of drugs.

		Following on previously published safety and efficacy data, an international group of researchers reported finalized part 1 and preliminary safety data from an ongoing part 2 of the study, which enrolled patients 18 years and older with MM that was relapsed or refractory to at least 2 prior lines of therapy. Patients must also have been ineligible for transplant. At the ≥4-mg/kg At the ≥4-mg/kg dosage (n = 12), daratumumab induced a marked reduction in paraprotein and bone marrow plasma cells in the group of heavily pretreated patients. In addition, in patients receiving the ≥4-mg/kg dosage, 5 partial responses and 3 minor responses were observed; 7 of these patients had a 50% to 100% concomitant reduction in bone marrow plasma cells. Median PFS in the

		≥4-mg/kg dosage group was not reached by a data cutoff of 3.8 months.

		No antidrug antibodies were detected among enrolled patients. The most common reported adverse events were infusionrelated and occurred predominantly during the first full infusion. A total of 44% of patients across all dosage groups had infusion-related events of grade 1 to 3. Other adverse events were anemia (n = 1), thrombocytopenia (n = 1), bronchospasm (n = 2), cytokine release (n = 1), and AST increase (n = 1).

Latest Results Promising for Elotuzumab Combo

		The combination of the humanized anti-CS1 monoclonal antibody (mAb) elotuzumab plus lenalidomide/dexamethasone was generally well tolerated and resulted in a high objective response rate and encouraging PFS in patients with relapsed/refractory multiple myeloma (MM), according to Sagar Lonial, MD, Winship Cancer Institute of Emory University, Atlanta, Georgia, in an update of phase II and phase I/II long-term safety results.

 Lonial reported these findings for a large international group of investigators at ASCO 2013.

		Elotuzumab is a humanized anti-CS1 mAb that enhances natural killer-cell mediated, antibody-dependent cellular toxicity of CS1-expressing MM cells. The study included a dose-finding phase I cohort (N = 28) and a phase II cohort (N = 73), with patients treated until disease progression, unacceptable toxicity, or death. (Data for patients treated with 1 or more [phase I] or 1 to 3 [phase II] prior therapies who received elotuzumab plus lenalidomide/dexamethasone were previously published [J Clin Oncol. 2012;30(16):1953-1959; Blood. 2012;120(21):Abstr 202].

		The objective response rate in the phase II cohort (median age, 63  years) was 84%: 92% with 10 mg/kg (n = 36) and 76% with 20 mg/kg (n = 37). At a median follow-up of 20.8 months, median PFS was not reached for the 10-mg/kg group and was 18.6 months for the 20-mg/kg group.

		The most common treatment-emergent grade ≥3 adverse events were lymphopenia (19%), neutropenia (18%), thrombocytopenia (16%), and anemia (14%). In general, grade 3/4 adverse events that were emergent after 18 months were consistent with those reported during the initial 18 months.

The observed OS benefit included 29% of patients who received pomalidomide after experiencing progressive disease on high-dose dexamethasone. Weisel reported data from an updated

1. San-Miguel JF, Weisel KC, Moreau P, et al. MM-003: a phase III, multicenter, randomized, openlabel study of pomalidomide (POM) plus low-dose dexamethasone (LoDEX) versus high-dose dexamethasone (HiDEX) in relapsed/refractory multiple myeloma. J Clin Oncol. 2013;31(suppl; abstr 8510).

2. Lokhorst HM, Plesner T, Gimsing P, et al. Phase I/II dose-escalation study of daratumumab in patients with relapsed or refractory multiple myeloma. J Clin Oncol. 2013;31(suppl; abstr 8512).

3. Lonial S, Jagannath S, Moreau P, et al. Phase (Ph) I/II study of elotuzumab (Elo) plus lenalidomide/dexamethasone (Len/dex) in relapsed/refractory multiple myeloma (RRMM): updated ph III results and ph I/II long-term safety. J Clin Oncol. 2013;31(suppl; abstr 8542). 

Studies Highlight Newly Approved and Novel Multiple Myeloma Treatments

An oral targeted drug already approved by the US Food and Drug Administration for the treatment of kidney cancer and soft tissue sarcoma has been found to extend disease-free survival in women with advanced ovarian cancer, according to study results presented at the 2013 ASCO Annual Meeting.

The phase III, randomized, multicenter clinical trial (AGO-OVAR16) showed that pazopanib (Votrient), following initial successful chemotherapy, extended disease-free survival by an average of 5.6 months compared with a placebo in patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer (AEOC).

The goal of treatment with pazopanib would be to maintain the successful but typically short-lived response experienced by these patients after initial treatment, said the study’s lead author, Andreas du Bois, MD, PhD, a professor of Gynecologic Oncology at Kliniken Essen Mitte in Essen, Germany. Since there is no test available to predict a patient’s risk for relapse, a maintenance therapy such as this one would be used for most patients in this population, experts at the ASCO meeting noted.

If approved in this setting, pazopanib would be the first maintenance therapy for the treatment of ovarian cancer in the United States, although bevacizumab (Avastin) is registered for use concurrently with chemotherapy and subsequently as maintenance therapy in Europe.

“Our findings show that we finally have a drug that can maintain control over ovarian cancer growth achieved through initial treatments,” du Bois said. “If pazopanib is approved for ovarian cancer, many patients will experience longer disease-free and chemotherapy free periods. During this time, the patient keeps control over the disease instead of the disease having control over the patient’s life.”

Pazopanib is an oral, multikinase inhibitor of VEGFR-1, -2, -3, PDGFR-a (alpha) and -ß, and c-Kit that blocks several targets involved in tumor angiogenesis, which “plays a major role” in AEOC, du Bois said. Ovarian cancer is the fifth-leading cause of cancer death among women in developed countries, and has the highest mortality risk among all gynecological tumors. At the time of diagnosis, 70% of patients already have advanced disease, which is associated with a cure rate of only 20% to 25%, according to ASCO.

While 70% to 85% of patients are free of their tumors after initial treatment with surgery and chemotherapy, three-fourths of them experience recurrences, and half of those recurrences take place within the first year, du Bois said. Such patients typically live 2 to 4 years from the time of diagnosis, and can receive up to 5 lines of treatment during the course of their disease, he said. The study was designed to evaluate the efficacy, safety, and tolerability of pazopanib maintenance therapy in patients who had not progressed after first-line platinum-taxane chemotherapy for AEOC, with a primary end point of progression-free survival (PFS). Secondary end points included overall survival, safety, and quality of life.

In the study, 940 patients, most of whom had stage III/IV AEOC (91%), were randomized 1:1 to receive either pazopanib or placebo daily for 24 months. All patients had prior surgery and 5 or more rounds of chemotherapy that prevented the disease from worsening. Patients in the pazopanib arm had a prolonged PFS vs placebo (HR = 0.766; 95% confidence interval, 0.64-0.91; P =.0021; median 17.9 vs 12.3 months, respectively). The first interim analysis for overall survival (189 patients) showed no difference between arms, but those data will not be considered mature until it includes 551 events, du Bois noted.

As compared with a placebo, pazopanib treatment was associated with a higher incidence of adverse events (AEs) and serious AEs (26% vs 11%), several of them class-specific, including elevated liver enzymes. The most common were hypertension, diarrhea, nausea, headache, fatigue, and neutropenia, du Bois said. Fatal AEs were reported in three patients on pazopanib and one patient on placebo.

An immediate goal for this research is to combine pazopanib with other targeted drugs and personalize therapy according to patient and tumor characteristics according to an ASCO press release. “Relapses remain all too common for women with advanced ovarian cancer. This large trial shows us that targeting multiple molecular cancer drivers can have a substantial impact on this cancer’s ability to grow, giving our patients significantly longer time before relapse.

This study offers a realworld example of how the precision medicine era of cancer research is paying off in areas where no alternate approved drugs exist,” said Carol Aghajanian, MD, ASCO spokesperson and gynecologic cancers expert and chief of Gynecologic Medical Oncology Service at Memorial Sloan-Kettering Cancer Center in New York City. While bevacizumab (Avastin) is approved in Europe as a maintenance therapy for these diseases, it was studied in combination with chemotherapy, and then as a continuation therapy, which “was not a pure maintenance therapy setting. We don’t know which part of the bevacizumab trial [sparked] the efficacy,” du Bois said. “This differs from the population we have, since ours had successful primary treatment and 85% had no residual tumors.”

The study of pazopanib—along with previous unsuccessful attempts to combine it with chemotherapy in this population&mdash;suggests that the drug will be best used as maintenance therapy in this population, du Bois said. Future studies, he said, should address the optimal sequencing of pazopanib and chemotherapy.

1. du Bois A, Floquet A, Kim JW, et al. Randomized, double-blind, phase III trial of pazopanib versus placebo in women who have not progressed after first-line chemotherapy for advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer: results of an international Intergroup trial (AGO-OVAR16). J Clin Oncol. 2013;31(suppl; abstr LBA5503). 

Pazopanib Maintenance Therapy Delays Relapse of Advanced Ovarian Cancer

Low-dose weekly paclitaxel is as effective as and has fewer side effects than the standard biweekly schedule for patients with early-stage breast cancer, according to the results of a phase III study presented at the 2013 ASCO Annual Meeting.

Paclitaxel is typically prescribed in either weekly or biweekly regimens. This is the first study to formally compare the 2 dosing schedules. The low-dose weekly administration of the  chemotherapy agent paclitaxel resulted in equal disease-free survival (DFS) in patients with early-stage breast cancer when compared with biweekly administration of the drug, and although each dosing regimen resulted in a different set of side effects, the weekly dosing schedule appeared to offer a slightly more favorable side-effect profile.

“It’s important to give these drugs in an optimal way,” said G. Thomas Budd, MD, a medical oncologist at the Cleveland Clinic in Cleveland, Ohio, and lead author of the study. Budd noted that paclitaxel used to be given in higher doses every 3 weeks in the treatment of breast cancer until studies showed that the weekly and biweekly schedules in this study yielded superior results.

In this phase III trial, 3294 patients with node-positive or high risk node-negative operable breast cancer first received treatment with one of 3 different regimens of doxorubicin and cyclophosphamide, after which they were randomized to receive either a low-dose regimen of paclitaxel weekly for 12 weeks or a standard-dose regimen of paclitaxel every 2 weeks for 12 weeks with pegfilgrastim support. As of April 2013, DFS was essentially the same with both schedules of paclitaxel (hazard ratio = 1.05; 95% confidence interval, 0.89-1.25). “It appears from these data that either way of giving paclitaxel produces a similar outcome,” Budd said. “An investigator and a patient or a doctor and a patient could choose either one of these schedules.”

The rate of any grade 3/4 toxicity was similar across the 2 arms, occurring in 36% of patients receiving the biweekly regimen and 35% of patients receiving the weekly regimen. However, researchers found that the different dosing schedules were characterized by different types of side effects of different severities. Allergic reactions were more common in the biweekly dose (14%) compared with the lower dose (6%), as were symptoms of bone and muscle pain (11% vs 3%, respectively). Neurologic toxicity was also more frequent in the biweekly dose of paclitaxel compared with the low-dose regimen (17% vs 10%, respectively), but Budd noted that patients received 6 cycles of the biweekly regimen instead of the standard four cycles for the purposes of scientific comparison, which may have slightly affected the frequency of these side effects.

The rate of hematologic toxicity was higher in the weekly dose arm (17%) than the biweekly dose arm (6%), as was the rate of leukopenia (6% vs 1%, respectively) and neutrophils (11% vs 2%, respectively). However, the rate of neutropenic fever was low in both groups (0.4% vs 0.1%, respectively) and the difference was not statistically significant (P = .29). Budd explained that the higher rates of hematologic toxicity in the weekly schedule could have been a result of ascertainment bias, since patients had toxicities measured on a weekly basis rather than the biweekly basis of the other study arm. “In this study, the weekly schedule seemed to be less toxic for most patients,” Budd said.

1. Budd GT, Barlow WE, Moore HCF, et al. S0221: comparison of two schedules of paclitaxel as adjuvant therapy for breast cancer. J Clin Oncol. 2013;31(suppl; abstr CRA1008). 

Optimal Paclitaxel Schedule Identified for Early-Stage Breast Cancer

Older adults represent the majority of the more than 1.5 million people diagnosed with cancer each year. Unfortunately, significantly fewer older adults are enrolled on clinical trials, resulting in limited information regarding the risks and benefits of standard cancer therapies in the elderly. While chemotherapy is offered increasingly as part of cancer treatment to older adults, it is known that chemotherapeutic side effects can increase significantly with age.

These side effects may result in loss of independence and impaired quality of life. However, among older adults of the same chronologic age, an individual patient’s ability to withstand the rigors of cancer treatment may differ widely. As a result, some older adults may tolerate and benefit from aggressive therapies similar to younger patients, while others may not. Measurable patient characteristics that predict better tolerance have not been widely studied and are desperately needed in clinical practice to inform treatment decision-making and individualize care for each older adult. The field of geriatric oncology has developed in part to address this need.

A major research focus within the field is to develop and test the utility of practical assessment strategies that predict tolerance and benefit to standard therapies. Nowhere is the uncertainty regarding optional treatment for older adults more prominent than in the setting of acute myelogenous leukemia (AML). Due to the morbidity of the disease and intensity of treatment, AML represents one of the most dramatic examples of age-related outcome disparity in oncology. Older adults represent more than half of new cases of AML and experience significantly inferior outcomes with higher rates of treatment-associated morbidity and mortality and lower overall survival. However, clinical trials have shown repeatedly that selected older adults can tolerate intensive therapy and experience long-term survival when treated in a similar fashion to middle-aged adults. The difficulty is identifying those patients who are likely to benefit from intensive treatments at the time of diagnosis.

Treatment recommendations for older adults range widely and are often based to a larger extent on chronologic age. Research focused on identifying those older adults more likely to benefit from treatment has primarily focused on age-related alterations in tumor biology. Few studies have evaluated patient-specific characteristics such as comorbid conditions, functional status, and cognitive status, all of which may be equally important in determining treatment tolerance.

To address this issue, we designed a study focused specifically on older adults with AML to test the utility of bedside geriatric assessment in predicting treatment outcomes. This study drew on the strengths of Wake Forest Baptist Health as a leukemia referral center, with robust geriatric and cancer research programs. In this observational study of 74 older adults who were treated intensively for their AML, we investigated the predictive value of a bedside geriatric assessment on overall survival. The geriatric assessment was composed of several brief questionnaires and physical performance tests, which were designed to measure physical function by self-report and objective evaluation, cognition, mood (depression and distress), and comorbidity.

We were particularly interested in the utility of objective physical function testing, which minimizes biases associated with self-report and allows for standardization of measurements. The physical performance measures used included the short physical performance battery (a brief 4-meter walk, repeated chair stands, and balance testing) and grip strength. The entire assessment was administered in approximately 30 to 40 minutes by a nurse prior to initiation of intensive chemotherapy. The primary outcome of the study was overall survival. After adjusting for clinical and biological factors known to be associated with survival in older patients with AML, we found that both impairment on the cognition screen and impaired objectively measured physical performance were independently associated with worse survival in this cohort.

This is the first study to evaluate the role of cognition or physical performance in this setting. It is important to note that all patients enrolled on this study were already highly selected and deemed fit for intensive therapy by standard oncology assessment strategies. In this setting, assessments of cognition and physical performance were able to detect vulnerability that might otherwise be undetected and yet is clinically significant. Multisite studies to validate the utility of geriatric assessment in the setting of therapy for AML are ongoing in the Alliance cooperative group. If validated, simple assessment measures of physical function and/or cognition may be used to help further individualize treatment decision making for older adults in clinical practice. Identifying characteristics that predict vulnerability to excessive toxicity may inform future clinical trial design by facilitating the development of treatment strategies specifically for vulnerable or frail older adults.

Finally, this research may inform interventions to address vulnerability. Building upon our observational study that showed the prognostic significance of lower physical performance at diagnosis, we have developed a physical activity intervention to minimize functional decline associated with intensive therapy. The goal of this work is to develop active strategies to prevent functional decline during treatment that will maximize treatment benefits and quality of life.

Predicting Treatment Outcomes in Older Adults With AML

A British study has confirmed that 10 years of adjuvant tamoxifen substantially reduces late breast cancer recurrence and mortality among women with estrogen receptor (ER)-positive disease, supplying what investigators believe is the final piece of evidence supporting long-term use of the endocrine therapy.

The randomized, phase III aTTom study helps settle the question of whether 10 years of tamoxifen provides a benefit versus the more standard 5 years, said lead author Richard G. Gray, MA, MSc, discussing the findings at the 2013 ASCO Annual Meeting. The research was featured at a press conference and during the plenary session. “There has been quite a remarkable improvement in the benefits of tamoxifen,” said Gray, a professor of Medical Statistics at the University of Oxford in the United Kingdom, during his presentation. 

“What is really impressive is the effect on breast cancer mortality.” Gray said prior research has shown that 5 years of tamoxifen reduces breast cancer recurrence and mortality by approximately one-third over a 10- to 15-year period following diagnosis. The benefits of longer treatment emerge later on, with reductions in recurrence starting to unfold after year 7 and reductions in mortality becoming evident after year 9, Gray indicated. He said the continued use of tamoxifen resulted in an additional 24% reduction in mortality after year 10.

“So, 10 years of tamoxifen compared to no tamoxifen reduces breast cancer mortality by a third in the first decade and a half in the second decade,” he said. The results of the aTTom study mirror those of the international ATLAS trial, which Gray presented at the 2012 CTRC-AACR San Antonio Breast Cancer Symposium last December. Together, the study results “provide proof beyond reasonable doubt” about the benefits of continuing tamoxifen treatment, Gray said. In the aTTom trial, 6953 women with breast cancer who had been taking tamoxifen for 5 years were randomized to continue receiving tamoxifen for another 5 years or stop taking the drug.

With follow-up of more than 10 years, there were 580 recurrences among women who had taken tamoxifen for 10 years,compared with 672 recurrences in the shorter-term treatment arm (P = .003). Moreover, there were 392 breast cancer deaths after recurrence among participants who had taken the drug for a decade, compared with 443 deaths among those in the 5-year arm (P = .05). When the results of the aTTom study and the ATLAS trial, which included 6846 women, are combined, the statistical significance of the benefits of longer tamoxifen administration are enhanced, with improvement in recurrence rates (P <.0001), breast cancer mortality (P = .002), and overall survival (P = .005), according to the aTTom abstract. 

The disadvantages of taking tamoxifen for 10 years may include continuing menopausal symptoms such as night sweats and hot flashes, and rare adverse events such as an increased risk of endometrial cancer. In the aTTom trial, there were 102 cases and 37 deaths (1.1%) attributed to endometrial cancer in the 10-year tamoxifen arm, compared with 45 cases and 20 deaths (0.6%) in the 5-year group. In the United States, the trial results likely will change the standard of care for women who are premenopausal at diagnosis to include 10 years of tamoxifen, said Sylvia Adams, MD, an associate professor at New York University School of Medicine who provided commentary on the study during the press conference. US women who are postmenopausal at diagnosis typically receive an aromatase inhibitor as adjuvant treatment but they may now consider incorporating extended tamoxifen into their treatment plan, Adams said. 1. Gray RG, Rea D, Handley K, et al. aTTom: long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 in 6,953 women with early breast cancer. J Clin Oncol. 013;31(suppl; abstr 5). 

More Evidence for 10 Years of Tamoxifen in ER+ Breast Cancer

 OncLive, a sister news portal to Evidence-Based Oncology, on July 26, 2013, unveiled the inaugural class of “Giants of Cancer Care.” An advisory panel of eminent oncologists chose 12 honorees to be recognized for their remarkable achievements in research and/or clinical practice. The Giants of Cancer Care awards recognize and celebrate individuals who have achieved landmark success within the field of oncology.

The inaugural class of “Giants” was announced at a reception during the 14th International Lung Cancer Congress, hosted by Physicians’ Education Resource, LLC, an affiliate of MJH Associates, the parent company of OncLive. Each of the winners will be individually profiled in a special edition of OncologyLive and prominently featured on OncLive.com. MJH Associates Chairman and CEO Mike Hennessy said, “We’re proud to honor these exemplary members of the oncology profession. These ‘Giants’ have dedicated their lives to improving the quality and quantity of life for cancer patients. Our enormous gratitude is the foundation of this program.”

In evaluating criteria for selection to the inaugural class of Giants, the Advisory Panel considered “pioneers,” characterized by individuals who have amassed a large body of work and have already accomplished their most notable contributions to oncology; and separately, “innovators,” those who recently (within the past 10-15 years) have made a significant contribution to patient care, clinical trials, or translational research.

For more information, visit us online at giants.onclive.com.

Breast: Bernard Fisher, MD University of Pittsburgh Pioneer in our understanding of the biology and treatment of breast cancer

Gastrointestinal: Bert Vogelstein, MD Johns Hopkins Medicine Pioneer who discovered the molecular basis of colorectal cancer

Genetics: Elizabeth H. Blackburn, PhD University of California, San Francisco Innovator and Nobel Prize winner for her discoveries of the genetic composition and function of telomeres

Genitourinary: Lawrence H. Einhorn, MD Indiana University Pioneered the development of life-saving treatment for testicular cancer

Head & Neck: Everett E. Vokes, MD University of Chicago Innovator of concomitant chemoradiation therapy and curative treatment approaches for head and neck cancers

Leukemia: Brian J. Druker, MD Oregon Health & Science University Innovator of targeted therapies for chronic myeloid leukemia

Lung: Thomas J. Lynch, Jr, MD Yale Cancer Center Pioneered the use of molecular testing for EGFR mutations in lung cancer

Lymphoma: Vincent T. DeVita, Jr, MD Yale Cancer Center Innovator of combination chemotherapy regimens for large cell lymphomas

Melanoma: Steven A. Rosenberg, MD National Cancer Institute Pioneered the use of adoptive immunotherapy in melanoma

Myeloma: Robert A. Kyle, MD Mayo Clinic Pioneer and respected leader in myeloma research, treatment, and education

Prostate: Charles L. Sawyers, MD Memorial Sloan-Kettering Cancer Center Innovator of novel androgenreceptor inhibitor for treatment of advanced prostate cancer

Scientific Advances: Judah Folkman, MD (deceased) Harvard/Massachusetts General Hospital Father of angiogenesis

Inaugural 'Giants of Cancer Careâ€ Announced: Oncology Luminaries Selected by Peers for Prestigious National Honor

An antibody that targets the programmed death ligand 1 (PD-L1) to unleash the body’s immune system has demonstrated a 21% response rate in a phase I study of patients with multiple solid tumors, setting the stage for an advance in immunotherapy with broad implications for treatment. MPDL3280A produced durable responses with no dose-limiting toxicities and a favorable adverse-event profile in heavily pretreated patients, according to Roy S. Herbst, MD, PhD, a professor of Medicine at Yale Cancer Center and chief of Medical Oncology at Smilow Cancer Hospital at Yale-New Haven in Connecticut.

“This therapy has the potential to be used in almost every tumor type,” Herbst said in an interview. “It’s just the tip of the iceberg so far. We’re still figuring out exactly what the right biomarker is going to be to predict the most responsive population.”

Herbst previewed the findings during a press conference held in advance of the 2013 ASCO Annual Meeting. In the study, MPDL3280A was administered intravenously every 3 weeks to patients with metastatic tumor types including non—small cell lung cancer (NSCLC), melanoma, colorectal cancer, gastric cancer, and renal cell carcinoma. Responses were assessed with computed tomography scans every 6 weeks for 6 months, and then every 12 weeks.

In all, 29 of 140 evaluable patients (21%) exhibited tumor shrinkage according to RECIST criteria, with the highest overall In all, 29 of 140 evaluable patients (21%) exhibited tumor shrinkage according to RECIST criteria, with the highest overallMoreover, only 2% of the participants (4 patients) experienced grade 3/4 AEs that were deemed to be immune-related, and only 1 patient discontinued treatment because of an immune-related AE. 

“We didn’t see any high-grade pneumonitis, which makes us feel very optimistic that this drug, because it’s hitting only the PD-L1, is probably sparing some of the mechanisms that would allow for the lung to become inflamed,” Herbst said in the interview. “We saw a couple of episodes of hepatitis and liver inflammation, but really, it’s a very mild toxicity profile.”

MPDL3280A is the latest example of the checkpoint blockade anticancer strategy pioneered with the development of ipilimumab (Yervoy), which unlocks the power of the immune system by targeting CTLA-4. The US Food and Drug Administration approved the melanoma drug in 2011. One of the highlights of the ASCO meeting last year was research into BMS-936558, now called nivolumab, which targets PD-1. Research into the agent was also presented at this year’s meeting.

Herbst said the efficacy demonstrated thus far in attacking PD-L1 and other immune checkpoints “gives us the opportunity to open up a whole new avenue of therapy in cancer.” Tumor cells express PD-L1, which in turn binds to the T-cell receptors PD-1 and B7.1, Herbst said. “As long as there’s PD-L1 on the surface of the tumor, the T cell PD-1 sees it as a friend,” he said. “It is cloaked and it doesn’t recognize the tumor as a foreign body and it doesn’t kill it. But as soon as that PD-L1 goes away—by blocking it with an antibody&mdash;the tumor becomes visible, the target can be lit up, you go after it, and the Tcell attacks and kills it.”

Herbst said the therapeutic strategy could apply to a variety of cancers. “Any tumor type that has mutations is going to have the potential to be immunogenic and to work in this way to activate the immune system,” he said, adding that “a lot of patients don’t have a driver mutation that’s easily targetable.”

Since MPDL3280A has been engineered for enhanced safety, the agent could potentially be combined effectively with targeted therapies or with chemotherapy, Herbst noted. “The ability to combine this is going to be extraordinary,” he said.

The MPDL3280A study is continuing with an expanded cohort of patients with a larger range of solid tumors and blood cancers; more than 275 patients have been enrolled, according to an ASCO press release. Genentech, which is developing the drug, also is investigating MPDL3280A in separate phase I trials in combination with vemurafenib (Zelboraf) in patients with BRAF V600 mutation-positive metastatic melanoma and in addition to bevacizumab (Avastin) with or without chemotherapy in advanced solid tumors, as well as in a phase II study as monotherapy in PD-L1-positive locally advanced or metastatic NSCLC.

1. Herbst RS, Gordon MS, Fine GD, et al. A study of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic tumors. J Clin Oncol. 2013;31(suppl; abstr 3000).

Early Results Robust for New Immunotherapy Agent

One in 5 African-American women with breast cancer carries an abnormality in at least 1 gene associated with breast cancer susceptibility, according to results of a genomic profiling study by researchers at The University of Chicago, suggesting a need for increased genetic screening among a population group which previously has been understudied.

The research represents the first comprehensive examination of all known breast cancer susceptibility gene variations among African-American women, a group disproportionately affected by early onset and triple-negative breast cancer, a difference researchers have hypothesized may have a genetic component. However, prior studies have focused on BRCA1/2 gene mutations rather than on all of the 18 inherited clearly damaging mutations currently known to be associated with an increased risk of breast cancer. Results of the study were announced at a press briefing during the 2013 ASCO Annual Meeting.

Overall breast cancer survival is worse among African-American women than it is for white women, and the gap continues to widen, noted the study’s lead author, Jane E. Churpek, MD, assistant professor of medicine. “For those of us here in Chicago, [this study] is particularly relevant, because we have one of the worst disparities in the country.” The incidence of advanced breast cancer also is on the rise among young women, especially young African-American women, she added.

For the study, researchers analyzed DNA from 249 unrelated African-American women at The University of Chicago’s Cancer Risk Clinic, using the targeted genomic capture and next-generation sequencing assay known as BROCA. This approach allows investigators to look at multiple genes at once and identify multiple types of mutations in those genes all at the same time, Churpek explained. The average age of the women included in the study was 43 years.The researchers found that 22% of these patients (n = 56) inherited a clearly damaging mutation, 79% of which were BRCA1 (n = 26) or BRCA2 (n = 20). Investigators also found mutations in other genes with defined cancer risks, including ATM (n = 5), CHEK2 (n = 3), PALB2 (n = 3), and PTEN (n = 1).

Almost all of the identified gene mutations were different, noted Churpek, which has important implications for genetic testing programs. “For some populations, we can use tests which look at only a few sites in a few genes, and we can identify the majority of mutations, but that technique will not work for this population with such great genetic diversity.”

The researchers also looked at how these mutations were distributed according to personal and tumor characteristics. Damaging mutations were carried by 30% of women with a family history of breast or ovarian cancer, 30% of those with triple-negative breast cancer, and 27% of women who were young (aged ≤45 years) at diagnosis. Churpek added that even among those patients with no family history of breast or ovarian cancer, over 10% still carried a mutation, which, she stressed, “reminds us that family history is not the only criterion that we should think of.”

“This work highlights the critical role of improved awareness and access to genetic counseling and testing services for all women, especially African-American women, who have unfortunately not utilized these services well in the past,” said Churpek. Demonstrating the cost-effectiveness and efficiency of next-generation sequencing assays—which allow for the comprehensive screening of multiple genes from multiple people in 1 test in a single visit&mdash;represents another important aspect of the study, added Churpek. “These tools will allow us to identify who’s at risk before they develop cancer, so we can begin to focus on prevention and eventually impact public health,” she concluded. Churpek JE, Walsh T, Zheng Y, et al. Inherited mutations in breast cancer genes in African American breast cancer patients revealed by targeted genomic capture and next-generation equencing. J Clin Oncol. 2013;31(suppl; abstr CRA1501). 

More Genetic Screening Needed for African-American Breast Cancer Patients

Last month, The American Journal of Managed Care (AJMC) hosted a panel discussion on current issues in breast cancer treatment. Participants were the moderator, Michael E. Chernew, PhD, co-editor-in-chief of  AJMC, Professor of Health Care Policy, Harvard Medical School; and panelists, Sandra M. Swain, MD, immediate past president of the American Society of Clinical Oncology (ASCO) and medical director of the Washington Cancer Institute, MedStar Washington Hospital Center, and Lee N. Newcomer, MD, MHA, senior vice president for Oncology, Genetics and Women’s Health at United-Healthcare.

The panel continued a 2012 AJMC discussion regarding pertuzumab (Perjeta) which had been just received approval by the US Food and Drug Administration as a first-line treatment for HER-2 positive metastatic breast cancer in combination with trastuzumab (Herceptin). Concerns have arisen about market access, as the cost of this combination therapy is more than $180,000 for an 18-month course. The July panel opened with an overview of a new combination therapy. This article presents highlights from the panel’s recent discussion of the cost of new treatment therapies in breast cancer.

 Today, we would like to examine the use of another combination therapy, trastuzumab and [panzene] which is [Typhila] and pertuzumab, which is Perjeta. So, as we talk through this issue, concerns about which patients get these different therapies, their relative cost, and implications for outcomes will become important. I will start with Dr Swain…to understand the current treatment landscape and overview. Who are the patients eligible for these different types of therapies, and how big is the patient population?

 As far as the use of pertuzumab, the current indication is for the patient to either present with metastatic HER-2 positive breast cancer, or for the patient who has had adjuvant treatment and then a recurrence, so it is first-line treatment for HER-2 positive breast cancer. The indication is for the use with trastuzumab and a taxane. For TDM-1, the indication is in patients who have had previous treatment already with HER-2 targeted therapy and usually chemotherapy, and so it is not the first-line treatment; it is either second or third-line or later-line treatment. We probably have about 8000-9000 patients that either have recurrent disease in the first-line setting or present with stage IV disease. Of those 8000 or 9000 patients, approximately 4000-5000 would actually be eligible to get pertuzumab with trastuzumab in the first-line setting. Many of those patients will have ER-positive disease also, and the physician may not want to start with chemotherapy. Not all would get chemotherapy in the first-line setting, but it could be higher.

And that number of patients is basically over the course of a year nationwide?

Yes. For TDM-1, I don’t know the exact numbers; Dr Newcomer, if you know those numbers, it may be somewhat higher.

 I couldn’t give you an exact number either, but I sure agree with your estimate of 8000-9000 as a nation.

And so, either of you, Dr Newcomer if you want to start or Dr Swain, can you provide a brief overview of the EMILIA trial?

Sure, I would be happy to do that. This trial, EMILIA, involved almost 1000 patients who were randomized to either get lapatinib and capecitabine or to get TDM-1; this was after they had previous treatment with HER-2 targeted therapy. This trial had incredible results. The TDM-1 group had a statistically significant improvement and progression-free survival of about 3 months. The difference was 6.4 months with the lapatinib/capecitabine compared with 9.6 months with TDM-1. And, not only did the trial show these results, but there was a survival benefit, and the survival for the TDM-1 was almost 31 months versus 25 months. That’s a really significant increase of survival of 5 months with the use of TDM-1.

That’s probably one of the best responses we have seen in breast cancer in almost a decade; that would that be a fair statement.

 I think also with the CLEOPATRA data, which was the first-line study with pertuzumab, trastuzumab and docetaxel versus the combination with the placebo without the pertuzumab, also a very significant progressionfree survival of 6 months and a survival benefit, too. So, I think both of them are pretty spectacular results.

How are physicians, particularly oncologists, using these agents in practice? Is the information of the trial filtered through the practice?

I would have Dr Newcomer answer this, but I think what I see is that the doctors are not necessarily using the docetaxel with pertuzumab first line but they are also using paclitaxel, and interestingly, most recently at the ASCO meeting (May 31-June 4 in Chicago) there was a study from Memorial Sloan-Kettering using weekly paclitaxel with pertuzumab and trastuzumab showing a very high response rate. I think it was about 50%, so it was a very high response rate. So, I think the taxane really doesn’t matter there. The issue is it is very effective dual-targeted therapy with trastuzumab and pertuzumab.

And we did see an immediate request for those drugs as soon as they became available on the market. We are limiting the use to the actual trial from the label, so the paclitaxel would not be authorized by us, but certainly the docetaxel is and usage was immediate. I think people are very aware of these studies, because it is such a significant drug and the breast cancer patients were following this news just as closely as the physician.

 That’s wonderful. Maybe one of you can provide an overview of the Marianne trial.

 This was a trial that was also on HER-2 positive breast cancer, the same as the other ones that we have already discussed, and it was over 1000 patients who had been randomized. The study actually closed, I think, last year, so it hasn’t been reported yet; it is predicted to be reported in 2014. This was a 3-arm study and the patients were randomized to get trastuzumab with either docetaxel or paclitaxel; the paclitaxel was weekly and the docetaxel every 3 weeks. Arm B was the TDM-1 plus pertuzumab. And arm C was the TDM-1 plus a placebo for pertuzumab. So I think this is a really important study, too, to see if the TDM-1 can be moved to first line.

 Genentech has applied for approval for the use of pertuzumab regimen before surgery…So I gather there are 2 other trials that’s based on, the NEOSPHERE study and the TRYPHAENA study.

Right, and we have seen in several of the neoadjuvant trials, which are fairly small trials, you know, several hundred patients, that dual-targeted therapy really does give a much higher pathologic CR, and pathologic CR means that there is no tumor in the breast and sometimes no tumor in the nodes depending on how you define it. But, for example, in the NEOSPHERE study, when they used the pertuzumab, trastuzumab, and docetaxel, the pathologic CR rate was 46%. When you only used trastuzumab and docetaxel, it was 30%. So it is much higher with the dual-targeted therapy. I was a co-chair of an FDA workshop in March addressing this question of whether pathologic CR could be used as a surrogate for approval, so (Genentech) is the first one going in to try to see if they can get approval for the pertuzumab in the neoadjuvant setting.

 Just to make sure, because I am not sure everyone understands this, pathologic CR is associated with much better survival rates in other studies, correct?

Well, it is associated with survival rates and that was a big discussion that we had, and it is really not absolutely proven that survival will be better, because the neoadjuvant trials that have been done haven’t really [proven this] except for 1 trial. The NOAH trial did show a better outcome for those patients who had the highest path CR, but the other ones really don’t have that outcome data. So that was a big discussion and I am sure with this, if (Genentech) gets approval, it will be an accelerated approval, meaning that this is a surrogate endpoint and that they need to have a follow-up study that relates to the outcome data, as you mentioned, like survival or disease-free survival benefit.

So as a non-physician, what I hear from this discussion is it’s an extremely exciting time in this particular clinical area and I was wondering, first, do you agree? It seems like the pace of innovation is quite rapid, but…the fiscal consequences can be substantial. Second, I was wondering what your broad thoughts are; specifically, for Dr Newcomer, how are payers assessing the value of these agents, and how are they addressing when there are other options that are available for lower cost?

 I think we should begin with the fact that these drugs are having a very significant clinical effect. These are not drugs that help just a tiny bit, but they are making a substantial impact on both survival and how long the tumor stays away. So that has very real value. The question is, how much we can afford to pay for those kinds of responses? There are 2 things, though, that help make this more plausible for both UnitedHealthcare and for society in general. This is not a large number of patients, as Dr Swain said, 8000-9000 a year, and not all of those are eligible for therapy. So, as you spread that cost over a large population of insured patients, it isn’t very big. So, I think it will cost more money, there is no question about that, these are extremely expensive medications when they are successful and we are going to have to pass that cost on to others, but again because of the very real and significant response rate, there is value there.

So, does that imply that both the small population and the value of the treatment are encouraging plans in some ways to promote access to these medications because of the health benefit, as opposed to discouraging access because of the cost?

Well, I don’t know that any health plan that I am aware of is discouraging access to these drugs. If a patient is seeing a medical oncologist with HER-2 overexpressed disease, they are going to hear about these options. I believe, and I will ask if Dr Swain agrees, but I can’t imagine oncologists not talking about this to their patients, and I can’t imagine a health plan telling an oncologist not to talk about it. The key question is just how we budget so that we have enough money to pay for these therapies.

 I think it is not only that the insurance plans pay for it, but with the huge high drug cost, the copays are really high for these patients. So, a lot of them can’t afford that. So I think we really do need to look at this and address the exorbitant cost of these drugs.

So are they being placed on a specialty tier?

They aren’t at United-Healthcare, and I would point out at least in our plans that the maximum out-of-pocket expense is met by every one of these patients. So plans typically have an amount of money where once you have paid that amount, everything else is covered 100%. That amount will be set by the employer; it can vary fromas little as $1000 to as high as $10,000, but there is a limit. And at that point, the patient doesn’t have to pay any more. So $10,000 out of pocket may seem like a lot of money, but when you are considering the fact that this is a life-prolonging therapy, it should be worth that both to the patient and to their family.

And that out-of-pocket limit for a breast cancer patient, it is just what they are paying for drugs, or their overall treatment? It might be that the added cost of these medications for the patient is relatively small, because they would come close to hitting their maximum out-of-pocket anyway. Or am I wrong about how I have done that math?

The maximum out-of pocket applies to all of their healthcare for all of their family. So once their family has paid that amount of money, they no longer have any more coinsurance or any other expenses. And you can’t have breast cancer in today’s modern age without hitting that maximum out-of-pocket.

Yes. Because by the time you finish your surgery, radiation, other medications, it doesn’t take very long to hit $10,000.

So, in fact, although the person with an out-of-pocket max is paying $10,000, they are going to be paying $10,000 whether or not they have access to these particular new medications; so if I understand correctly, what the specialty tiers do or some of the other cost-share requirements, is they push you up for someone who happens to get breast cancer, they push you up for that out-of-pocket max, but they wouldn’t really influence your treatment decisions because pretty much any treatment decision you make is going to take you to that out-of-pocket max in most cases.

 So there are 2 things we should add to that. First, these drugs are given in physicians’ offices as infusions, and specialty tiers, rarely if ever apply to those. Second, I have been talking about UnitedHealthcare plans and there may be other plans out there that put more of a burden on the patient, but the reason those plans are structured that way is to get the cost of the insurance down. So the less you cover, the cheaper the insurance, and that’s a decision in a triad that the people make when they buy their insurance or their employer does. So, we would encourage good insurance plans but they are expensive, there is no question about that today in the United States.

And what about with Medicare, do they still have that $10,000 out-of-pocket limit?

 They don’t. Medicare patients are clearly disadvantaged there, and they are paying coinsurance or copayments forever.

Depending on their Part D plan or their MAPD plan, if they are in United Medicare Advantage Plan, then there would be some differences?

Medicare Advantage Plan looks a lot more like a traditional, commercial insurance plan, in that there would be maximum out of pocket so there would be better benefits than standard Medicare. Standard fee-forservice, Medicare, that Dr Swain was talking about, their coinsurances go on indefinitely.

 And those are the patients who really will be hurt by the high prices because we know about two-thirds of patients with cancer actually are in the Medicare range. So a lot of these patients that we are talking about would be getting Medicare.

So those people of course would have (insurance)…90% of them are on some sort of Part D or other supplemental plan, but it raises a question about another population—the Medicaid population. What are states doing, if anything, related to access to these medications?

 I can just talk for DC and we only get a set amount of money, which is very, very low for anything we give, we give Cytoxan or we give TDM-1, we get X amount of dollars, which is very little. So they don’t do it by drug here in DC, and I don’t know what other plans do.

Each individual state has its own Medicaid rules. So, there is no common answer. It is very clear, though, that each state in the country right now is facing a budget crisis in Medicaid. So I wouldn’t be surprised to hear that other states are putting up the same kind of problems that Dr Swain just described. 

 And are you worried about access to these medications for people in the Medicaid population?

 I am very worried about it. I am in a safety net hospital and we do give it to the patients that need it but we also have 340B pricing. So we basically can cover some of it but it is a big problem, it is a huge loss for us.

: So it would probably be useful if you said something about 340B pricing.

 I just can say it this way: At our hospital, a safety net hospital, we do have a substantial number of Medicaid patients and there are big losses for us when we use these drugs, but we do use them in the patients that need them.

I think it is worth pointing out that 340B was—the original intent of that regulation was&mdash;to address this kind of situation that when states couldn’t pay properly for the drugs that there would be a discount for safety net hospitals, and that was the intent of the program. The hope was it would help defray the cost that Dr Swain was talking about.

And because it does probably affect 60 million people or more, who are going to be on Medicaid, I think it is a really good question.

Absolutely. To what extent do you think the patchwork of payers and financing will impede the access to patients who might benefit from these novel therapeutic agents?

I think it will affect them greatly, because what we are already seeing is the patients are coming to hospital settings who are on Medicare and are not being treated in their doctor’s office and their infusion center because the doctors can’t afford to do it, they actually lose money, so they are coming to a higher-price facility, a hospital, to get their infusion. So I think it is really going to affect, not on the patients but the economy in general.

There are some paradoxical things that arise in our financing system where we may end up spending more money in efforts to save money.

Current Issues in Breast Cancer Treatment: Chernew Leads Discussion with Swain, Newcomer on New Agents, Cost of Care

The decision about whether to get tested for a genetic mutation that may predispose a person to certain cancers is a difficult one for many patients to make. Even more difficult for mutation carriers is deciding whether to undergo a prophylactic surgical procedure.

How would cancer genetics specialists themselves make these tough choices? Have their perspectives changed over the years, with increased knowledge about genetic testing, surveillance, and treatment?

Ellen T. Matloff, MS, CGC, director of the Yale Cancer Genetic Counseling Program at the Yale School of Medicine/ Yale Cancer Center, in New Haven, Connecticut, is getting more interest than ever in these questions in light of the June 13, 2013, US Supreme Court decision involving Myriad Genetics, in which she was a plaintiff. Myriad had vigorously enforced patents to control a monopoly in genetic testing for mutations of the BRCA1 and BRCA2 genes, indicators of the likelihood of developing breast or ovarian cancer.

In light of the ruling, Matloff’s research on the willingness of genetic specialists to be tested for mutations, or even undergo surgery, seems even more timely. She discussed her results at the March 2013 annual meeting of the American College of Medical Genetics and Genomics in Phoenix, Arizona. She presented findings of a follow-up survey of 216 active members of the National Society of Genetic Counselors’Special Interest Group in Cancer.

 In late June, Matloff offered a presentation to members of the medical community in New York City, portions of which were broadcast nationally on FOX News.

“We originally conducted this study in 1998, when cancer genetic testing and counseling was in its infancy, and we had little or no data to tell us what would be the efficacy of prophylactic surgery, surveillance, or chemoprevention for carriers,” Matloff explained in Phoenix. The follow-up, Internet-based, anonymous survey was conducted in July 2012; male respondents were asked to answer questions as they would for a close female relative. 

Much has changed in the 14 years since the 1998 survey—notably, the fact that now 58.3% of the specialists surveyed said that they would opt for bilateral prophylactic mastectomy if they tested positive for a deleterious BRCA mutation at age 35. When that question was asked in 1998, only approximately 25% said that they would choose to have their breasts removed if they were found to be BRCA mutation carriers. Decreased risk (57.9%) and avoidance of fear/worry (49.1%) were cited most often by respondents who said they would choose mastectomy if found to be mutation carriers. Twelve percent indicated that a lack of confidence in surveillance would be a factor in their decision to have their breasts removed.

“This was a very controversial issue in 1998, and it still is to some extent in 2012,” said Matloff. Those who would choose not to have the prophylactic procedure listed confidence in surveillance (33.3%), negative impact of surgery on body image and sexuality (22.2%), and the fact that the surgery would not provide 100% protection against recurrence (10.6%). On the question of whether to undergo BRCA testing if risk for the mutation was determined to be 50%, a large majority of respondents to both surveys said that they would choose to be tested: 84.5% of those responding to the 1998 survey and all but 2 of the respondents in 2012 (99.1%). Among the reasons 2012 respondents gave for choosing to be tested were that the information would aid in medical management, it would be helpful to their families, and it would lessen uncertainty; 55.6% of the affirmative respondents said they would choose to be tested for the 50% probability that they would test negative.

Matloff added that she did not present data on whether BRCA mutation carriers would have their ovaries removed, because the percentage was high in both surveys and not statistically significant. The researchers also found statistically significant differences in attitudes toward prophylactic surgery for Lynch syndrome between the 2 surveys. When asked if they would choose prophylactic colectomy if positive for a deleterious HNPCC mutation at age 35, only 16 respondents to the 2012 survey (7.4%) said they would, compared with 27 people (17.4%) who answered affirmatively in 1998.

Respondents in 2012 indicated confidence in colonoscopy, lowered quality of life and body image, and a willingness to postpone surgery until detection of a lesion or polyp as reasons for this choice. However, when the same question was asked with regard to removal of the uterus or ovaries due to an elevated Lynch syndrome risk, participants were more inclined to respond affirmatively.

Nearly 80% of 2012 respondents said they would have their uterus removed if found to carry the HNPCC mutation at age 35, compared with 54.1% in 1998. Similarly, nearly 78% of respondents in 2012 indicated that they would have their ovaries removed versus 52.4% in 1998. The survey also explored the issue of anonymity in genetic testing with respect to health insurance, and the results indicate that respondents are for the most part confident that billing their insurance company for testing would not be detrimental, with 94.9% of the 2012 respondents replying that they would, compared with just 23.9% in 1998. “I find this particularly interesting because I’m not sure we would even think to ask these questions in 2012, but these were top of mind in 1998,” Matloff observed.

Matloff explained that gauging the perspectives of experts on issues related to genetic testing and possible interventions is especially important, insofar as the specialists surveyed “arguably have the most education and clinical experience in cancer genetic counseling and testing.”

“We now know that genetic testing is well established, as compared with 1998, and that more clinicians know about BRCA and Lynch syndrome,” said Matloff. She added that more clinicians are treating patients who carry mutations, and they can see both the natural progression of disease and also the stress inherent for people who test positive, as well as the stress among unaffected carriers, as they undergo surveillance, chemoprevention, and prophylactic surgery.

Another factor that may affect genetic testing is cost, which Matloff expects will come down in light of the Myriad decision. Within the next few years, Matloff believes that the costs associated with testing will decline from $4000 for 2 genes to under $1000 to sequence the entire exome. This decrease in costs will bring genetic testing into the average marketplace with broad applications for reimbursement, Matloff believes.

As more competitors enter the testing marketplace, choices and costs will improve for consumers, she explained. 

1. Matloff E, Bonadies D, Brierley K, Moyer A. Changes in specialists’ perspectives on cancer genetic testing, prophylactic surgery and insurance discrimination: then and now. Presented at the Annual Clinical Genetics Meeting of the American College of Medical Genetics and Genomics; March 19-23, 2013; Phoenix, AZ; Abstract 27.

2. http://www.onclive.com/onclive-tv/Ellen-Matloff-on-the-Supreme-Court-Gene-Patenting-Decision/ 

Yale's Matloff Reports Shift in Views on Genetic Testing, Prophylactic Surgery: Sees Drop in Costs After Supreme Court Ruling

These days, talk about “quality” factors into every discussion of healthcare. So how do the nation’s 449 accountable care organizations (ACOs) and ACO-like entities sponsored by hospital systems, physicians groups, insurers, and community organizations

There’s no shortage of data and metrics surrounding how effectively hospitals and doctors’ groups claim to be delivering care, yet pinning down what it means to deliver quality care is difficult. Trying to define quality may well prove elusive, as ACOs are less rooted in amending the patient experience than they are in turning industry work flows and hierarchies upside down.

“ACOs are not an attempt to change the patients, but an attempt to change the (healthcare) delivery system,” said Jeffrey Brenner, MD, founder and executive director of the Camden Coalition of Healthcare Providers.

Under the 2010 Affordable Care Act (ACA), the nation’s healthcare system bears financial risk for delivering better care, and the industry is experimenting by rearranging the relationship between those who provide care—doctors, nurses, specialists and technicians&mdash;and those who pay for it, such as insurance companies, major employers who self-insure, and federal and state governments.

ACOs, which integrate care across healthcare providers, are catching on, and ACOs and ACO-like entities operate in as many as 45 states.

 Between 25 million and 31 million Americans are receiving healthcare services through an ACO, and more than 40% of Americans—126 million people&mdash;live in areas with at least 1 ACO, estimate Rick Weil, partner, and Niyum Gandhi, associate partner, in the Health and Life Sciences Practice of the consulting firm Oliver Wyman.

As of November 1, 2012, there were 328 ACOs, up from 221 at the end of May 2012, and 164 in September 2011, according to Leavitt Partners.

While the near-term growth of ACOs seems assured, the jury is still out on the question of whether ACOs can deliver the requisite quality of care to have any measurable impact on long-term costs. Even if there is no consensus about what quality care entails, initiatives in the marketplace hold clues to the future of how ACOs plan to deliver better care.

Future healthcare quality can’t be improved unless hospitals and doctors know how well or poorly they are performing today. It’s no surprise, then, that ACOs are sticklers for metrics. Nationwide Children’s Hospital (NCH) in Columbus, Ohio, a sponsor member of the Partners for Kids ACO, which serves more than 300,000 children, tracks its metrics with impressive granularity.

Drug errors, surgical infections, bloodborne infections, and rates of pneumonia associated with ventilator use are reported quarterly and monthly. Even staff compliance with washing hands is plotted on a graph.

The hospital, which serves a pediatric Medicaid population in a 34-county area in central and southeastern Ohio, reports that the number of catheterassociated bloodstream infections has dropped to 0.5-per-1000 catheter days in the first quarter of this year, from an average of 5.1 per 1000 in 2004.

July/August