GENE SIGNATURES IN BREAST CANCER

Results of a 70-gene signature assay (70-GS) can influence recommendations about adjuvant treatment for patients with early breast cancer classified as intermediate risk by a 21-gene assay (21-GA), researchers say.

“The use of genomic assays in early stage ER-positive, HER2-negative breast cancer has become a standard practice for determining who should get adjuvant chemotherapy,” Dr. Hatem Soliman of Moffitt Cancer Center in Tampa, Florida, told Reuters Health.

“There are still some situations where the initial genomic test doesn't provide a clear answer. In these cases, the provider and patient may require additional information - almost like a second opinion - to guide them,” he said by email.

“However,” he added, “this is costly and should be done only in cases where the clinicopathologic information and initial genomic test are equivocal.”

To investigate, Dr. Soliman and colleagues enrolled 840 patients (mean age, 59; 87% white) with early-stage breast cancer and a 21-gene assay recurrence score of 18 to 30 (intermediate risk). All patients also were classified with the 70-GS, and results were given to physicians before adjuvant treatment was started.

As reported in JAMA Oncology, online October 26, on the basis of 21-GA result (before 70-GS assessment), 382 patients (45.5%) were recommended to receive adjuvant chemotherapy and 458 (54.5%) were recommended not to receive it.

The 70-GS reclassified the intermediate-risk patients as low-risk in 374 cases (44.5%) and high-risk in 466 cases (55.5%).

Receiving the 70-GS classifications significantly influenced adjuvant treatment assessment. Among the low-risk patients, 108 (28.9%) had chemotherapy removed from their treatment recommendation, whereas 171 (36.7%) high-risk patients had chemotherapy added.

The 70-GS results were significantly associated with the physician’s adjuvant treatment recommendation: 88% of high-risk patients were recommended to receive adjuvant chemotherapy, and 91% of low-risk patients were recommended not to receive it.

After receiving the 70-GS results, physicians reported having greater confidence in their treatment recommendation in 79% of cases.

Dr. Soliman said, “The information provided by the 70-GS assay had a significant clinical impact on adjuvant therapy recommendations. So in cases where there is initial uncertainty regarding the use of adjuvant chemotherapy, the 70-GS assay can aid in identifying patients with an excellent prognosis using endocrine therapy alone.”

Experts in cancer genetics weighed in on the findings in emails to Reuters Health.

Dr. Sofia Merajver, Scientific Director of the Breast Cancer Program and Director of the Breast and Ovarian Cancer Risk Evaluation Program at the UM Comprehensive Cancer Center in Ann Arbor said, “It is unknown whether survival would be improved by the change in therapy for those patients, and that is the gold standard.”

“Plus, the total expression of proteins is not sufficient to define the signaling processes inside cells, nor is a single static measure robust enough to predict long-term survival or time to recurrence, the outcome variables patients are truly interested in,” she observed.

“In essence, this paper just proves what doctors and patients are willing to do. The hope is that the value of adjusting the therapy was not overstated during this research, since so much (outcomes) data still needs to be collected.”

Dr. Dana Zakalik, Director of the Beaumont Cancer Genetics Program at Beaumont Hospital in Royal Oak, Michigan, commented, “The 70-gene assay seems to ‘simplify’ the genomic risk score into two categories (high vs. low) and addresses the uncertainty of the ‘intermediate’ risk score of the 21-gene assay, for which we still await data.”

“We need more data and validation to answer whether this is a better assay or whether it merely simplified it by just having a high versus a low group,” he added.

“There has not been a head-to-head comparison between the different assays, so we need more research and longer follow-up. Hopefully,” he said, “we will soon have data on the ‘intermediate’ group of the 21-gene assay, and perhaps that will resolve some questions.”

Dr. Glenn Gerhard, Chair of the Department of Medical Genetics and Molecular Biochemistry at Temple University in Philadelphia said, “Risk stratification for breast cancer for the significant number of patients classified as intermediate risk by the 21-GA assay is problematic; thus, other approaches are needed.”

“More comprehensive genomic testing using the 70-GS assay provides important additional information in a setting in which physicians use limited clinical data and other more traditional information to guide decision making,” he added.

Like Dr. Merajver, Dr. Gerhard noted that “recurrence and survival data were not collected as part of the study; thus, whether the changes in treatment decisions altered outcomes has not yet been determined.”

“The results were also restricted to patients with ER-positive, HER2-negative cancers, to those with a designated range of 21-GA results, and to a largely white population,” noted. “Thus, the extent of generalizability is not known.”

The study was sponsored by Agendia, a molecular diagnostics company that employs four of the authors.

SURVEILLANCE OF PATIENTS WITH MIDGUT NEUROENDOCRINE TUMOURS

In a study reported in the Journal of the National Cancer Institute, Cives et al found that postsurgical relapse occurred in 31% of patients with stage I to III midgut neuroendocrine tumors over long-term follow-up, with liver, mesentery, and pelvic lymph nodes being the main sites of relapse.

Characteristics of Recurrence

The retrospective study included 129 patients treated at the Moffitt Cancer Center between 2000 and 2010 who underwent R0/R1 resection. Median postoperative follow-up was 81 months (range = 1–295 months). Recurrence was found in 40 patients (31.0%). Most recurrences were metastatic, with the liver (52.5%) and pelvic lymph nodes (15.0%) being the most common sites of distant relapse. Locoregional recurrences were observed in 13 patients (33.5%), with 11 observed in the mesentery and 2 in the small intestine.

Median disease-free survival was 138 months. Resection of ≤ 17 lymph nodes predicted relapse (P = .01) and shorter disease-free survival (median = 134 months vs not reached, P = .04). Among patients with relapse, the cumulative risk of recurrence at 1, 5, and 10 years was 15.0%, 50.0%, and 85.0%, respectively. No recurrences were observed among 6 patients with stage I disease, whereas similar rates of relapse were noted among the 118 with stage II (35.7%) or III disease (31.7%).

The investigators concluded: “An annual surveillance interval may allow early detection of recurrence. Given the apparent decline in recurrence after 8 years from surgery, a decade-long duration of active surveillance may be proposed.”

HPV+ CANCERS AND SURVIVAL

Survival with human papillomavirus (HPV)-associated cancers differs significantly between blacks and whites, men and women, and people in different age groups, according to findings from the Centers for Disease Control and Prevention (CDC) National Program of Cancer Registries (NPCR).

“We found racial and gender disparities,” Dr. Mona Saraiya from CDC, Atlanta, Georgia told Reuters Health by email. “A black person with an HPV-associated cancer was likely to die sooner than a white person with the same cancer. And we were surprised that men with an HPV-associated anal cancer were likely to die sooner than women with the same cancer.”

HPV DNA is present in an estimated 91% of cervical cancers, 75% of vaginal cancers, 69% of vulvar cancers, 91% of anal cancers, 63% of penile cancers, and 71% of oropharyngeal cancers. Little is known about survival with these HPV-associated cancers.

Dr. Saraiya and colleagues used NPCR data from 2001 through 2011 to study survival among patients diagnosed with HPV-associated cancers, as well as survival disparities by sex, race, and age.

The 5-year age-standardized relative survival was highest for vulvar (66%) and anal (65.9%) squamous cell carcinomas (SCCs) and lowest for penile (47.4%) and oropharyngeal (51.2%) SCCs, according to the November 6 Cancer online report.

Survival consistently declined with increasing age for cervical, penile, and oropharyngeal carcinomas, whereas survival increased slightly among patients diagnosed between age 40 and 49, compared with those diagnosed before age 40, for vaginal and vulvar SCCs.

Most HPV-associated cancers were diagnosed among whites, and 5-year age-standardized relative survival was consistently higher for whites compared with blacks for all HPV-associated cancers. The lowest survival and the greatest differences by race were for oropharyngeal carcinomas (32.4% for blacks vs. 53.5% for whites) and penile carcinomas (34.7% vs. 48.4%, respectively).

For cancers that occur among both men and women, more than half of the anal and rectal SCCs occurred among women, compared with only 20% of oropharyngeal SCCs. Five-year relative survival for anal carcinomas was higher among women (69.3%) than men (59.8%), as it was for rectal carcinomas (61.2% vs. 45.5%, respectively). But survival for oropharyngeal carcinomas was lower among women (49.8%) than men (51.7%).

Overall survival rates were higher for all HPV-associated cancers diagnosed at localized stage and lower for cancers diagnosed at regional and distant stages.

When population characteristics and disease stage at diagnosis were combined, the poorest 5-year relative survival was observed for men who had rectal SCCs (6.9%) and for patients age 60 or older who had rectal and vulvar SCCs (10.5% and 10.9%, respectively) diagnosed at distant stage.

“HPV vaccination and improved access to screening and treatment, especially among groups that experience higher incidence and lower survival, may reduce disparities in survival from HPV-associated cancers,” the researchers concludeFor many HPV-associated cancers (besides cervical cancer), there is no routine screening recommended,” Dr. Saraiya said, “so one major initiative to reduce disparities would be to focus on prevention - namely, HPV vaccination.”

“Cervical cancer screening is a proven strategy that works, but in order for it to be successful in improving outcomes, clinicians can work with their patients to ensure they get the correct follow-up after an abnormal screening result,” she said. “For other cancers, screening strategies are limited - but more research in good screening strategies and tests is needed for anal and oropharyngeal cancers. For example, there are trials underway to examine the role of anal cytology in screening for anal cancer in high-risk populations, and also research being done on the role of cytology or other strategies in screening for oropharyngeal cancers.”

“We were not able to examine in detail what disparities exist for treatment of these cancers; further investigation of those is needed,” Dr. Saraiya added.

Dr. Patti Gravitt from George Washington University's Milken Institute School of Public Health, Washington, DC, who has researched trends in HPV infection and cancer mortality rates, told Reuters Health by email, "The consistent trend for lower relative survival from HPV-associated cancers in black versus white men and women points to an important disparity that deserves more detailed understanding.”

“I think the research community needs to evaluate both behavioral and biological causes of the survival disadvantage in blacks,” she said. “While it is important to ensure that these don't reflect differential access to care (screening, diagnosis, and treatment), we should also consider other biological factors that may result in different responses to the HPV infection.”

“Oral and female genital microbiomes differ quite significantly by race and may modify the immune response to the virus or the effectiveness of treatment,” Dr. Gravitt said. “Research to understand the ecology of the oral and anogenital tracts on HPV infection and cancer risk and survival by gender, race, and age using systems approaches may be particularly informative.”

“Recent reports from the CDC show an increasing trend of non-viral sexually transmitted infections, such as chlamydia and gonorrhea, suggesting that the risk of sexually transmitted HPV continues to be high in the United States,” she added. “Unequivocally, the best strategy to reverse these trends is for providers to make strong recommendations for HPV vaccination in adolescence before the age of sexual debut.”

HIGH FIBER INTAKE INCREASE SURVIVAL IN COLORECTAL ACNCER

High fiber intake is associated with improved survival among patients diagnosed with colorectal cancer (CRC), even among those who increase their fiber intake after the diagnosis, the results of an analysis of two prospective studies indicate.

In a study that included more than 1500 healthcare professionals who had been diagnosed with CRC, researchers found that each 5 g/d increase in fiber intake was linked to a 22% reduction in cancer-specific mortality and a 16% reduction in overall mortality, with the greatest effect seen with whole-grain foods. Notably, no association was seen with daily fruit fiber intake.

The study, which was published online November 1 in JAMA Oncology, found that the survival benefit occurred even among those patients who increased their fiber intake after diagnosis. The maximum effect seen for patients who consumed about 24 g/d.

Study author Andrew T. Chan, MD, MPH, of Massachusetts General Hospital and Harvard Medical School, Boston, said that the findings may influence advice given to CRC patients as well as our understanding of the disease.

The possibility that fiber or related substances may be protective "does give us some interesting biological insights into the process by which colon cancer may spread, and as result, it may provide us some new targets for new disease interventions," he told Medscape Medical News.

"The mechanism could be related to some of the effects that fiber has, for example, on insulin pathways, and this may be a potential target for treatment in the future. It's also possible that fiber may form a substrate for bacteria in the gut to produce anti-inflammatory compounds and metabolites," said Dr Chan.

Previous studies have indicated that dietary fiber protects against the development of CRC. Potential mechanisms include a reduction in exposure to intestinal carcinogens; systemic benefits on insulin sensitivity and metabolic regulation; and the fermentation of fiber in the gut into short-chain fatty acids that have tumor-suppressive effects.

However, no studies have examined the impact of fiber intake on survival in patients already diagnosed with CRC.

The researchers collated data from the prospective Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS). The NHS recruited 121,700 US registered female nurses aged 30 to 55 years in 1976; the HPFS enrolled 51,529 US male healthcare professionals aged 40 to 75 years in 1986.

In both studies, the participants completed a medical history and lifestyle questionnaire, which included information on CRC status, at baseline and then every 2 years. Dietary data were also collected, and a food frequency questionnaire was completed every 4 years.

For those reporting a CRC diagnosis, the team asked for consent to acquire their medical records and pathologic test reports. A total of 1575 individuals diagnosed with stage I-III CRC completed the questionnaire, including 963 women from the NHS and 612 men from the HPFS.

The mean age of the patients was 68.6 years. During a median follow-up period of 8 years, there were 773 deaths, of which 174 (22.5%) were deemed to be CRC specific. The overall 5-year survival rate was 83% for stage I disease, 82% for stage II disease, and 72% for stage III CRC.

After taking into account potential confounding factors, fiber intake was inversely associated with mortality, at a multivariate hazard ratio (HR) per 5 g/d increase in intake of 0.78 for CRC-specific mortality (P = .006) and 0.86 for all-cause mortality (P < .001).

The team also found that mortality was lower for patients who increased their fiber intake after diagnosis: each 5 g/d increase was associated with an 18% reduction in CRC-specific mortality (P = .002) and a 14% reduction in all-cause mortality (P < .001).

The relationship between fiber intake after diagnosis and CRC-specific mortality was linear, reaching a maximum at approximately 24 g/d, beyond which there was no further mortality reduction.

Consumption of fiber from cereals was associated with a significant reduction in CRC-specific mortality, at an HR for each 5 g/d increase of 0.67 (P = .007 for trend), and all-cause mortality, at an HR of 0.78 ( P < .001 for trend).

There was no association between daily fruit fiber intake and CRC-specific or all-cause mortality. Vegetable fiber intake was associated with a significant reduction only in all-cause mortality, at an HR per 5 g/d of 0.83 increase (P = .009 for trend).

Whole-grain consumption was linked to lower CRC-specific mortality, at an HR per 20 g/d increase of 0.72 (P = .002 for trend). This was attenuated after taking into account total fiber intake, at an HR of 0.77 (P = .02). A similar effect was seen for all-cause mortality.

The researchers write: "Our present study adds to the existing literature and suggests that the effect of high fiber intake may extend beyond protection against cancer incidence and contribute to better prognosis after cancer is established."

While acknowledging that there are a number of potential limitations to their study, including the self-reported nature of the information on fiber intake and sources and lack of detailed treatment data, they note that the findings are in accord with those of previous studies.

They conclude: "Our findings provide support for the nutritional recommendations of maintaining sufficient fiber intake among CRC survivors."

Is It Fiber or Phytochemicals?

Approached for comment, Elizabeth Ryan, PhD, assistant professor, College of Veterinary Medicine and Biomedical Sciences at Colorado State University in Fort Collins, said that there have been many studies of the intake of fiber from various food sources, but the results have been mixed.

She told Medscape Medical News that one of the major limitations of such studies is their reliance on diet logs, which are yet to be fully validated.

Dr Ryan explained: "There are not a lot of biomarkers that I could look at in your blood or my blood and say: 'You've eaten oats today.' It's based on your writing, 'I ate oats yesterday,' and that's sometimes difficult when we want to make sure we want to hold people accountable for reporting what they're eating."

Nevertheless, she said that in the current analysis, the researchers address the limitations of their methodology and that the results support what is already known about the beneficial effects of fiber, particularly fiber from whole grains.

For Dr Ryan, the outstanding question is, "Do we suggest one particular type of whole grain over another? Because, is it just about meeting the [recommended] fiber intake, or are there other phytochemicals in those foods that [are also] protective against colorectal cancer?"

Do we suggest one particular type of whole grain over another? Dr Elizabeth Ryan

She believes that the best approach would be to ensure that patients eat a variety of cereals, rather than rely on a fiber supplement. However, the lack of data to support that recommendation means that the picture for patients is "confusing."

Dr Ryan also believes that individual patients are likely to respond differently to different levels of fiber intake: "Maybe I have colorectal cancer and I increase by 5 g/d. How am I going to find out if maybe it should have been 10 g/d for me, because I didn't respond as well to the 5 g/d?"

She added: "There may be a lot of individual variation in how we would respond to increased fiber intake."

LONG TREM SAFETY OF HERCEPTIN

As reported by Ganz et al in the Journal of Clinical Oncology, long-term follow-up of patients in the National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol B-31/NRG Oncology trial showed no worsening of cardiac function or quality of life with the addition of adjuvant trastuzumab (Herceptin) to anthracycline and taxane chemotherapy in patients with node-positive HER2-positive early breast cancer.

Study Details

Patients in NSABP Protocol B-31 received adjuvant doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab. In the current analysis, patients who were alive and disease-free were evaluated for left-ventricular ejection fraction using multigated acquisition scans and for patient-reported outcomes using the Duke Activity Status Index (DASI), Medical Outcomes Study questionnaire, and review of current medications and comorbid conditions.

Long-Term Follow-up

Median follow-up was 8.8 years among eligible patients. Overall, 5 of 110 patients (4.5%) in the control group and 10 of 297 (3.4%) in the trastuzumab group had a > 10% decline in left-ventricular ejection fraction from baseline to a value < 50%. Lower DASI scores were associated with use at follow-up of medications for hypertension (P < .001), congestive heart failure (P < .001), diabetes (P = .02), and hyperlipidemia (P =003).

On a multivariate analysis, lower DASI scores were associated with increasing age at study entry (odds ratio [OR] = 1.10, P < .001) and use of hypertension medication at baseline (OR = 2.38, P = .007) but not with treatment group (OR = 0.59, P = .07, for trastuzumab vs control group). No significant differences were found between treatment groups in any individual cardiac symptom or condition or for overall comorbidity score.

The investigators concluded: “In patients without underlying cardiac disease at baseline, the addition of trastuzumab to adjuvant anthracycline and taxane-based chemotherapy does not result in long-term worsening of cardiac function, cardiac symptoms, or health-related quality of life. The DASI questionnaire may provide a simple and useful tool for monitoring patient-reported changes that reflect cardiac function.”