American Cancer Society/American Society of Clinical Oncology Breast Cancer Survivorship Care Guideline

The purpose of the American Cancer Society/American Society of Clinical Oncology Breast Cancer Survivorship Care Guideline is to provide recommendations to assist primary care and other clinicians in the care of female adult survivors of breast cancer. A systematic review of the literature was conducted using PubMed through April 2015. A multidisciplinary expert workgroup with expertise in primary care, gynecology, surgical oncology, medical oncology, radiation oncology, and nursing was formed and tasked with drafting the Breast Cancer Survivorship Care Guideline. A total of 1,073 articles met inclusion criteria; and, after full text review, 237 were included as the evidence base. Patients should undergo regular surveillance for breast cancer recurrence, including evaluation with a cancer-related history and physical examination, and should be screened for new primary breast cancer. Data do not support performing routine laboratory tests or imaging tests in asymptomatic patients to evaluate for breast cancer recurrence. Primary care clinicians should counsel patients about the importance of maintaining a healthy lifestyle, monitor for post-treatment symptoms that can adversely affect quality of life, and monitor for adherence to endocrine therapy. Recommendations provided in this guideline are based on current evidence in the literature and expert consensus opinion. Most of the evidence is not sufficient to warrant a strong evidence-based recommendation. Recommendations on surveillance for breast cancer recurrence, screening for second primary cancers, assessment and management of physical and psychosocial long-term and late effects of breast cancer and its treatment, health promotion, and care coordination/practice implications are made.

This guideline was developed through a collaboration between the American Cancer Society and the American Society of Clinical Oncology and has been published jointly by invitation and consent in both CA: A Cancer Journal for Clinicians and Journal of Clinical Oncology. Copyright © 2015 American Cancer Society and American Society of Clinical Oncology. All rights reserved. No part of this document may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without written permission by the American Cancer Society or the American Society of Clinical Oncology.

ASCO Backs Bone Drugs for Myeloma

Recommended for patients with or without evidence of lytic damage

Patients with symptomatic multiple myeloma should receive bone-modifying therapy irrespective of evidence of lytic destruction or spinal compression fracture, according to an updated guideline from the American Society of Clinical Oncology (ASCO).

Treatment options consist of the intravenous bisphosphonates pamidronate and zoledronic acid (Zometa) or, alternatively, the RANK ligand inhibitor denosumab (Xgeva). Denosumab might be preferred over zoledronic acid for patients with renal impairment, as the RANKL inhibitor has been associated with fewer renal adverse events.

 The primary purpose of the update, and associated expert-panel review, was to determine whether the 2007 recommendations remain valid. ASCO initially published clinical guidance about the use of bone-modifying agents in myeloma in 2002.

“These recommendations are consistent with the previous recommendations, with new information on denosumab,” the guideline authors stated. “Additional modifications were made to some of the recommendations on the basis of recent data to better clarify the indications for treatment, duration of treatment, and associated complications of treatment.”

The panel, chaired by Kenneth Anderson, MD, of Dana-Farber Cancer Institute in Boston, and Robert A. Kyle, MD, of the Mayo Clinic in Rochester, Minnesota, updated the ASCO recommendations after examining 35 relevant studies identified by means of a targeted systematic literature review. The review included randomized controlled trials, systematic reviews, meta-analyses, clinical practice guidelines, and observational studies.

Key recommendations included:

  • Initiate bone-modifying therapy for patients with imaging-based evidence of lytic disease and for patients with osteopenia in the absence of lytic disease
  • Use bone-targeted agents as adjunctive therapy for controlling pain associated with osteolytic disease and for patients receiving other interventions for existing or impending fractures
  • Initiate intravenous bisphosphonates in patients with normal radiographs or osteopenia by bone mineral density measurements
  • Do not use bone-modifying agents in patients who have monoclonal gammopathy of undetermined significance, except when osteopenia exists
  • Reduce the dose of zoledronic acid in patients who have pre-existing mild or moderate renal impairment
  • Consider denosumab as an alternative to zoledronic acid for patients with compromised renal function
  • Use serum creatinine monitoring before each dose of a bisphosphonate, in accordance with FDA labeling
  • Perform intermittent evaluation of all bisphosphonate-treated patients for presence of albuminuria

The updated guideline also includes a table with the estimated cost of bone-modifying agents. Pamidronate and zoledronic acid had per-dose costs of $30.67 and $53.64, respectively, whereas each dose of denosumab cost $1,995.48. The estimated 1-year costs were $398.71 for pamidronate, $214.56 for zoledronic acid administered every 12 weeks, $697.37 for zoledronic acid every 4 weeks, and $25,9341.24 for denosumab every 4 weeks.

A compendium of ASCO recommendations related to bone-modifying therapy in myeloma is available on the organization’s website. The update was also published in the Journal of Clinical Oncology.

Locally Advanced, Unresectable Pancreatic Cancer: American Society of Clinical Oncology Clinical Practice Guideline.

PURPOSE: To provide evidence-based recommendations to oncologists and others for treatment of patients with locally advanced, unresectable pancreatic cancer.

METHODS: American Society of Clinical Oncology convened an Expert Panel of medical oncology, radiation oncology, surgical oncology, gastroenterology, palliative care, and advocacy experts and conducted a systematic review of the literature from January 2002 to June 2015. Outcomes included overall survival, disease-free survival, progression-free survival, and adverse events.

RESULTS: Twenty-six randomized controlled trials met the systematic review criteria.

RECOMMENDATIONS: A multiphase computed tomography scan of the chest, abdomen, and pelvis should be performed. Baseline performance status and comorbidity profile should be evaluated. The goals of care, patient preferences, psychological status, support systems, and symptoms should guide decisions for treatments. A palliative care referral should occur at first visit. Initial systemic chemotherapy (6 months) with a combination regimen is recommended for most patients (for some patients radiation therapy may be offered up front) with Eastern Cooperative Oncology Group performance status 0 or 1 and a favorable comorbidity profile. There is no clear evidence to support one regimen over another. The gemcitabine-based combinations and treatments recommended in the metastatic setting (eg, fluorouracil, leucovorin, irinotecan, and oxaliplatin and gemcitabine plus nanoparticle albumin-bound paclitaxel) have not been evaluated in randomized controlled trials involving locally advanced, unresectable pancreatic cancer. If there is local disease progression after induction chemotherapy, without metastasis, then radiation therapy or stereotactic body radiotherapy may be offered also with an Eastern Cooperative Oncology Group performance status ≤ 2 and an adequate comorbidity profile. If there is stable disease after 6 months of induction chemotherapy but unacceptable toxicities, radiation therapy may be offered as an alternative. Patients with disease progression should be offered treatment per the ASCO Metastatic Pancreatic Cancer Treatment Guideline. Follow-up visits every 3 to 4 months are recommended.

‘Huge’ Survival Benefit, New Standard of Care in Glioma

Results were released early and are leading to talk about a new standard of care in glioma after an interim analysis showed a “huge difference” in survival between patients who received temozolomide in addition to radiotherapy, compared with those who received radiotherapy alone.

“It completely took us by surprise,” said lead author Martin van den Bent, MD, professor of neuro-oncology at the Erasmus MC Cancer Center in Rotterdam, the Netherlands.

Previous trials in glioma have not shown any difference after 5 to 6 years after randomization, but in this study there was a significant difference even at 2 years, and at 5 years the difference was “huge,” he said.

The findings come from the CATNON trial, conducted in 745 patients with grade 3 anaplastic glioma, all of whom did not have the 1p19q deletion, a genetic abnormality that is associated with better prognosis and chemosensitivity. In order to find the patients for this trial, more than 1400 patients were screened in 12 countries across three continents, and enrolment took 8 years, Dr van den Bent reported.

The results from the interim analysis, after a median follow-up of 27 months, show that 43% of patients treated with both temozolomide and radiotherapy were alive after 5 years, compared with 24% in the radiotherapy-alone group.

Put another way, the 5-year survival was 56% in those who received both temozolomide and radiotherapy, compared with 44% in those treated with radiotherapy alone (hazard ratio, 0.67; P = .003)

In this portion of the trial, temozolomide was administered after radiotherapy.
Dr Martin van den Bent
Two other groups in this trial are evaluating temozolomide given concurrently and temozolomide given both concurrently and after radiotherapy. “Further follow-up is required” to obtain answers on this, Dr van den Bent said. At the interim analysis, the efficacy boundary was not met, he said.
The required number of events for a full analysis of the results are likely not be collected until about 2024, which is when he will be retiring, Dr van den Bent joked.

“Adjuvant temozolomide clearly improves survival,” Dr van den Bent concluded, and he also emphasized that this was the first randomized clinical trial to show an overall survival benefit in glioma.

In answer to a question from a clinician in the audience, who asked whether this was practice changing and how he should treat his glioma patients now, Dr van den Bent emphasized that the result for adjuvant temozolomide is clear, and that it should now be used together with radiotherapy in patients such as the participants in this trial. “That is now evidence-based medicine,” he added. However, with the question remaining over concurrent temozolomide, he said that he remained hesitant, because it increases long-term toxicity.

An American expert not involved in the trial agreed that it was practice changing. In fact, adjuvant temozolomide plus radiation will become a standard of care in glioma, commented Brain Michael Alexander, MD, PhD, disease center leader for radiation oncology at the Center for Neuro-Oncology, Dana-Farber Cancer Institute, and associate professor of radiation oncology at Harvard Medical School in Boston.

Temozolomide plus radiation is already a standard of care in glioblastoma multiforme, he noted, on the basis of phase 3 trial results reported in 2005 (N Engl J Med. 2005;352:987-996).

Many clinicians have extrapolated from this to also use the chemoradiation combination in glioma, he told Medscape Medical News, but this has not been supported by direct data until now.

New Standard of Care

Adjuvant temozolomide is a new standard for these patients, David Reardon, MD, clinical director at the Center for Neuro-Oncology, told the meeting in his discussion of the abstract.

He congratulated the researchers on their “truly labor-intensive efforts,” and noted the significant difference in survival, with an increasing separation of the curves with time.

But he also added that the finding was “not too unexpected,” as the addition of chemotherapy to radiotherapy improving survival is a “recurring theme in neuro-oncology.”

In fact, a recently published study shows that the addition of the chemotherapy combination of procarbazine, lomustine, and vincristine to radiotherapy also prolonged survival in glioma (N Engl J Med. 2016;374:1344-1355).

Dr Reardon also noted that a question remains over the use of concurrent temozolomide in glioma, and he said he was looking forward to the final analysis from this trial, even if it takes until 2024.

Temozolomide was supplied free of charge by Schering-Plough/MSD. The study was funded by an unrestricted grant from Schering-Plough, and also grants from the European Organisation for Research and Treatment of Cancer (EORTC) and Cancer Research UK. Dr van den Bent reports a consulting or advisory role with Merck, Roche, Celldex, Novocure, AbbVie, Amgen; honoraria from Roche, Actelion, Celldex, Bristol-Myers Squibb, Merck, AbbVie, Novocure; and research funding from AbbVie and Roche. Dr Reardon reports honoraria from AbbVie, Bristol-Myers Squibb, Cavion, Celldex, Genentech/Roche, Inovio Pharmaceuticals, Juno Therapeutics, Merck, Midatech, Momenta Pharmaceuticals, Monteris Medical, Novartis, Novocure, Oxigene, Regeneron, Stemline Therapeutics; a consulting or advisory role with Bristol-Myers Squibb, Cavion, Celldex, Genentech/Roche, Inovio Pharmaceuticals, Juno Therapeutics, Merck, Midatech, Momenta Pharmaceuticals, Monteris Medical, Novartis, Novocure, Oxigene, Regeneron, and Stemline Therapeutics; and research funding from Celldex (Inst), Incyte (Inst), and Midatech (Inst).


American Society of Clinical Oncology (ASCO) 2016 Annual Meeting:

Big Difference in Colorectal Cancer on Right vs Left Side

There is a big difference in colorectal cancer when it occurs on the right side compared with the left side, according to a new analysis of data from a large, federally funded trial. There is also a suggestion that the position of the primary tumor could influence treatment choice.

Survival was significantly longer for patients with primary tumors that originated on the left side of the colon (in the descending colon, sigmoid colon, and rectum) than for patients with primary tumors that originated on the right side of the colon (in the cecum and ascending colon).

The median overall survival (OS) was 19.4 months for patients with right-sided tumors vs 33.3 months for patients with left-sided tumors.

“While previous studies had suggested that tumor location may impact clinical colorectal cancer outcomes, the effect we observed in this analysis appears to be far greater than we expected,” said lead study author Alan Venook, MD, professor of medicine at the University of California, San Francisco.
“These findings will likely change the way we approach colorectal cancer treatment and research, even as we seek to more deeply understand the biology,” he said in a statement.

Dr Venook will present the new data at the forthcoming American Society of Clinical Oncology (ASCO) 2016 Annual Meeting. He was discussing the findings at a premeeting presscast.

New Analysis of Data

The new findings derive from a further analysis of data from the CALGB/SWOG 80405 (Alliance) study, conducted in 1137 patients with metastatic colorectal cancer. The trial compared first-line treatment with two different chemotherapy regimens ― oxaliplatin, 5-fluorouracil, and leucovorin (FOLFOX), and irinotecan, 5-fluorouracil, and leucovorin (FOLFIRI) ― and two targeted agents, bevacizumab (Avastin, Genentech, Inc) and cetuximab (Erbitux, ImClone Systems Incorporated).
The main results from this trial, presented at ASCO 2014, showed no difference in either progression-free survival (PFS) or overall survival (OS) between any of the treatment arms, leading to the conclusion that either chemotherapy regimen and either targeted agent could be used as first-line therapy.

A follow-up to this, showing how a consideration of costs changes the conclusion, was reported at ASCO 2015.

This new analysis looks at patient outcomes with respect to where the original cancer was found.

Dr Venook reported that 293 patients had right-sided primary tumors, and 732 patients had left-sided primary tumors. An additional 66 patients had transverse tumors; these patients were excluded from the analysis, inasmuch as it made no difference to the results whether they were included among either the patients with right-sided tumors or those with left-sided tumors, Dr Venook explained. An additional 46 patients had tumors that were designated as uncertain; these patients were also excluded.

All the patients in this analysis had tumors without a mutated KRAS gene, which is a known biomarker of response to certain colorectal cancer therapies, including cetuximab (in fact, cetuximab is approved only for use in such patients).

The primary analysis showed that patients with colorectal cancer that originated on left side had better outcomes and longer survival than patients with cancer that originated on the right, regardless of the treatment they received.

However, a further exploratory analysis found differences that were related to treatment.

During the presscast, Dr Venook highlighted the finding that among patients who received cetuximab, those with left-sided tumors had a median OS of 36 months vs 16.7 months for patients with right-sided tumors.

 The magnitude of this difference was “surprising to us,” he said. He noted that this 16-month survival of patients with right-sided tumors who received cetuximab is “quite different” from what was seen in all the other subgroups. “It is clearly an outlier.”

The exploratory analysis also showed that among patients who received bevacizumab, overall survival for those with left-sided tumors was 31.4 months vs 24.2 months for those with right-sided tumors.

“It appears that patients with right-sided colorectal cancer, broadly speaking, do not get benefit from cetuximab,” Dr Venook said. He suggested that this finding will change clinical practice. “This could very well represent a shift,” he said. Other factors need to be taken into consideration, but for now, these data argue strongly against using cetuximab and other EGFR antibodies in patients with colorectal cancer originating on the right side, he said.

 He noted that further work is underway. Detailed, ongoing analysis is being conducted on 44,000 tumor samples taken from patients enrolled in this trial, and he hopes that this work will show that “sidedness” is a surrogate for biological markers. He said that for the time being, “The side can help us make decisions in the context of all the other information we gather.”

A coauthor of the abstract was a little more cautious. “These are preliminary data and need confirmation,” commented Richard Schilsky, MD, ASCO chief medical officer and former chief of the Section of Hematology-Oncology at the University of Chicago.

The new data suggest that left-sided and right-sided colorectal cancers are both biologically and anatomically different, he commented. “There have been some data trickling through that these differences may exists, but this was quite a large trial and is more definitive evidence to suggest that these are real differences that we should be paying attention to,” he told Medscape Medical News.

“The bottom-line conclusion is that in the future, clinical trials for colon cancer should stratify patients by ‘sidedness,’ so we can better understand this issue,” Dr Schilsky commented.

“We’re not ready yet to make treatment decisions on real-world practice based on this information, but it’s pretty provocative…given that the overall results show that the choice of targeted therapy doesn’t really matter. This new info suggests that it does matter, depending on sidedeness,” he added.

Another expert also urged caution in acting upon the findings. Julien Taieb, MD, head of the gastroenterology and gastrointestinal oncology department of the Georges Pompidou European Hospital, Paris, pointed out that the new findings come from a post hoc analysis of subgroups of patients, which does not theoretically allow definitive conclusion. “From a scientific point of view, we now have to meet the standards for evidence-based medicine with a randomized controlled trial on that topic,” he said.

“I think that these are very interesting findings on a huge clinical trial, but in my opinion, these results are not sufficient to change our practice,” Dr Taieb told Medscape Medical News.

In addition, although talk of sidedness is interesting, it is not accurate enough in the current era of genetic and genomic medicine, he commented, adding: “We are now trying to move to international consensual molecular classifications to better define and treat the different types of colon cancer.” He noted that it is already known that the two anatomic sites have different concentrations of some biological markers that may be involved in anti-EGFR resistance, including BRAF and RAS mutations.

“However, sidedness remains an easy factor to identify, either by colonoscopy or on a CT scan, and it is something that is ‘doable’ in every country in the world, where sophisticated genomic/genetic analyses may not be possible,” he said.

He noted that the original trial found no difference between cetuximab and bevacizumab, whereas two smaller studies had found a significant difference, with improved OS on anti-EGFRs compared with bevacizumab in patients with wild-type disease who had undergone full RAS testing (which was not available for the whole population of the present trial).

Calcium Channel Blockers Don’t Promote Breast Cancer

Massive study finds no link between antihypertensive class and malignancy.

A long-simmering controversy over long-term use of calcium channel blockers to control high blood pressure and the effect that has on development of breast cancer may be settled, with researchers here reporting there is no link.

An adjusted hazard ratio for breast cancer among 107,337 women on calcium channel blockers was 0.96 when compared with 165,815 women not taking these agents (95% CI 0.90-1.03), a nonsignificant difference, said Sara Soldera, MD, a medical oncology fellow at McGill University Health Center, Montreal.

“We found that the long-term use of calcium channel blockers is not associated with an increased risk of breast cancer,” she told MedPage Todayat her poster presentation during the annual meeting of the American Society of Clinical Oncology. “Our finding is that this is just null — calcium channel blockers do not reduce your risk of breast cancer or increase your risk. They have no impact.”

Soldera and colleagues accessed the United Kingdom Clinical Research Datalink and included women enrolled in that database from 1995 to 2009 and then followed through the end of 2010. In that time period, 3,002 women who were not taking calcium channel blockers developed breast cancer over 1,075,336 person-years compared with 1,512 cases among the women whose records indicated treatment with this class of antihypertensive drug, over 491,768 person-years.

Soldera said that there had been a controversy over whether calcium channel blockers have an impact on breast cancer. “I got the idea to do the study when some of my patients brought up the question. I think that when a women is diagnosed with breast cancer, they look back to see if there is something that might have caused it,” Soldera said. “And they ask whether it was the calcium channel blockers.”

So she hit the medical literature books and “when I researched it, there was a lot of disparity — a lot of papers saying yes, and a lot of papers saying no. But these studies had small sample sizes and poor methodology.

“So we decided to do a larger study,” she said. “We thought that with the numbers of patients and patient-years in this study, if there was a signal, we would find it. We hoped that we could kind of settle the question with this study.”

Soldera noted that many women who develop breast cancer are overweight and may be taking calcium channel blockers to combat hypertension. She suggested they can be assured that taking the medication will help control blood pressure, but won’t be causative for breast cancer.

Tufia Haddad, MD, assistant professor of oncology at the Mayo School of Medicine, Rochester, Minn., told MedPage Today, “There has not been much discussion in the community of the possible link between calcium channel blockers and risk of breast cancer given that the study results to date have yielded such mixed results.

“There have been a number of small cohort or case-control studies evaluating this possible association, and some study results have suggested there is a possible association between usage and increased breast cancer risk while other study results suggest there is no association,” Haddad said.

“A recent meta-analysis of 17 studies evaluating this association did not find an increase in breast cancer risk between calcium channel blockers users and non-users. However, in subgroup analysis, long-term use — greater than 10 years of calcium channel blockers — [was] associated with an increase in breast cancer risk. That meta-analysis evaluated the data of approximately 150,000 women of whom over 53,000 were calcium channel blocker users,” she said.

“The current abstract is a well-designed, population-based cohort study of about 270,000 women who were newly started on an antihypertensive medication,” she said.

“Regardless of type of calcium channel blocker prescribed, long- or short-acting formulation of calcium channel blocker, or duration of calcium channel blocker use, there was no observed increase in the risk of breast cancer,” Haddad said. “The results were adjusted for other important breast cancer risk factors, and there was good long-term follow-up of these patients — more than 1.5 million person years.

“So there are no consistent data to support an association between calcium channel blocker use and breast cancer risk,” she said. “The negative findings of this contemporary, large, population-based cohort study are in agreement with that.”

Soldera, in her study, found that the hazard ratio of taking calcium channel blockers for less than 5 years was 0.96; the risk or taking the anti-hypertensive for 5 to10 years was 1.05, and the risk for taking calcium channel blockers for 10 or more years was 0.61 — but in none of these calculations was the finding statistically significant.

Axillary evaluation still frequent in breast DCIS, against guidelines

Axillary lymph node evaluation is performed frequently in patients with ductal carcinoma in situ (DCIS) undergoing breast-conserving surgery (BCS) despite international guidelines recommending against its use, a recent study reveals.

Although axillary lymph node evaluation is the standard of care in the surgical management of invasive breast cancer, a benefit has not been shown in DCIS. Therefore, the American Society of Clinical Oncology and the National Comprehensive Cancer Network guidelines recommend against axillary lymph node evaluation in women with DCIS undergoing BCS. [J Clin Oncol 2005;23:7703-7720; NCCN Clinical Practice Guidelines in Oncology, Breast Cancer: Version 1, 2015:]

Despite the recommendations, researchers recently found that almost one-fifth of women in the US who had BCS between 2006 and 2012 underwent an axillary lymph node evaluation. [JAMA Oncol 2015, doi: 10.1001/jamaoncol.2015.0389]

In their analysis of 35,591 US women with DCIS, 17.7 percent of those undergoing BCS and 63.0 percent of those undergoing mastectomy were found to have undergone an axillary evaluation. The rate of axillary evaluation increased from 56.6 percent in 2006 to 67.4 percent in 2012 with mastectomy, but remained relatively stable with BCS (18.5 percent in 2006 and 16.2 percent in 2012).

In patients undergoing mastectomy, those treated at non-teaching hospitals in urban areas had a higher rate of axillary evaluation. In patients undergoing BCS, a higher rate of axillary evaluation was observed in those treated at non-teaching hospitals by low-volume surgeons (defined as having one DCIS operation per year).

While the researchers suggested a need for prospective evaluation of the clinical benefit of axillary evaluation in women with DCIS, Dr. Kimberly Van Zee of the Evelyn Lauder Breast Centre, New York, NY, US, attributed the unexpectedly high rate of axillary evaluation in BCS-treated patients to hospital and surgeon factors. “Only low-volume surgeons and non-teaching hospitals were associated with the greater use of nodal assessment, suggesting that such surgeons are less aware of or less able to adopt current recommendations,” she pointed out in an accompanying editorial.

Body Image After Cancer

Everyone has a picture in their mind of the way they look. Good, bad, or somewhere in between, we can’t help but feel something in connection with our body image. However, body image goes beyond our perceived level of attractiveness. How comfortable we feel in our bodies and how in control we feel over their functions play an important role in how we see ourselves. When that changes because of something like cancer, a person’s entire identity can seem to be altered as well.

In this video, produced as part of the “Moving Forward” video series by the American Society of Clinical Oncology (ASCO) and the LIVESTRONG Foundation, young adult survivors discuss how cancer and cancer treatment has affected their bodies and their lives.

Watch the video. URL:

New guideline takes on tough HER2 cases.

In HER2 testing for breast cancer, the term “equivocal” verges on being afour-letter word. If the patient has a clearly positive test result, therapies targeting HER2 become a treatment option, and a highly successful one at that. If the result is clearly negative, HER2-targeting drugs are off the table; the patient isn’t expected to benefit from the drugs, which are expensive and can be cardiotoxic.

But if the result isn’t clear? David Hicks, MD, can still remember the first time he reported a HER2 breast cancer result as “equivocal.”

Dr. Antonio Wolff says that over the years, many physicians have asked about the so-called best, most accurate test for HER2. In the new guideline, “We have taken the tack that it’s not an issue of which test is right, among those linked with clinical outcome, but whether the test selected is done right.”

Dr. Antonio Wolff says that over the years, many physicians have asked about the so-called best, most accurate test for HER2. In the new guideline, “We have taken the tack that it’s not an issue of which test is right, among those linked with clinical outcome, but whether the test selected is done right.”

“The medical oncologist called me and said, ‘I liked it much more when it was positive or negative,’” recalls Dr. Hicks, professor of pathology and laboratory medicine and director of surgical pathology, University of Rochester (NY) Medical Center.

Dr. Hicks is also a practicing breast pathologist and thus no stranger to the difficult HER2 cases that bedevil his physician colleagues and patients. Equivocal results aren’t the only challenges. What’s the best way to handle tumor heterogeneity? What about HER2 genotypic abnormalities, like aneusomy of chromosome 17; colocalization of HER2 and CEP17 signals that affect HER2/CEP17 ratio in dual-signal in situ hybridization assays; and genomic heterogeneity?

Such “rogue” cases, as Dr. Hicks calls them, should become easier for both pathologists and medical oncologists to manage with the arrival of a newly updated HER2 testing guideline issued by the American Society of Clinical Oncology and the CAP. The guideline, published online Oct. 7 in Archives of Pathology & Laboratory Medicine ( and Journal of Clinical Oncology (, updates the previous guideline, which appeared in 2007.

“We provide clear instructions and clear recommendations on how to handle difficult cases and how to reduce areas of uncertainty,’’ says Antonio Wolff, MD, who was the principal oncologist author of both guidelines.

The guideline also simplifies fixation time for HER2 specimens, bringing requirements in line with those for ER/PgR assays. This is a change that Dr. Hicks—another of the guideline’s authors—predicts will be “helpful and welcome news” for pathologists. And it defines bright-field ISH as a valid test platform for assessing HER2 amplification.

Dr. Hicks

Dr. Hicks

All these highly specific recommendations bring a new level of harmoniousness to HER2 testing—one that took considerable effort to achieve. HER2 testing puts in sharp relief two of medicine’s rival geometries. Medical oncologists, naturally, prefer to travel in a straight line, from test result to treatment. Pathologists, just as naturally, find it difficult to stick to that unswerving path. As Elizabeth Hammond, MD, the principal pathologist author of both the new guideline and the earlier one, says, “Unfortunately, cancer biology doesn’t work in a straightforward manner.” But with their latest guideline, the authors hope the odds that both parties will arrive together at agreeable answers have just gone up.

Above all, the guideline emphasizes the need for action. HER2 testing acts as a traffic light for HER2-targeted therapy, and idling at a yellow light indefinitely is not an option.

Yet pathologists are understandably leery of expressing a higher level of certainty than they feel, says Dr. Hammond, professor of pathology, University of Utah School of Medicine, and consultant pathologist, Intermountain Healthcare, Salt Lake City. For them, an “equivocal” result, for example, may well be not only an accurate answer but also the responsible one. But on its own, it doesn’t help the oncologist much. “The result you give needs to be something that helps the clinician make treatment decisions for the patient.”

In that sense, the guideline underscores the notion that test results can be seen as the start of a treatment, not the end of an assay, and that the role of the pathologist in patient care is an active one. Or, as Dr. Hicks puts it, “We’re not just someone who generates a result and throws it over the fence.”

As the guideline’s authors began their discussions in early 2012, they had plenty to talk about.

There has been, for example, no shortage of concern or confusion about how in situ hybridization tests were being counted, says Dr. Hammond. As a result, she says, “We spent a lot of time as a panel dealing with this.”

The guideline’s writers had a tough challenge. According to Dr. Hicks, their first thought was to set HER2 positive at 10 percent of cells with strong staining. But the definition for FISH was an average number over 40 or 60 nuclei. The two methods—cell-by-cell evaluation versus counting multiple nuclei—aren’t necessarily simpatico, however. Because of heterogeneity, a FISH result will depend on which nuclei are being counted. If 10 percent are amplified and 90 percent are not, but nuclei in the nonamplified area are counted, the result will be a 10 percent IHC positive with a HER2-negative FISH result.

The current authors recognized that earlier guidance was not specific enough in cases where tumor heterogeneity was an issue. “The method that we were advocating before was not the right method for finding small populations of tumor cells that might be amplified,” Dr. Hammond says, given that those small populations might have important implications.


Dr. Hammond

Dr. Hammond

In the past, pathologists were mostly doing a random counting of the tumor population, she says. Now, per the new guideline, the pathologist needs to scan the entire ISH slide prior to counting at least 20 cells; areas of potential amplification must be included; and those areas of amplification must be separately counted and reported. “This gives a much better chance that a patient will have an opportunity to get a positive result if there are any amplified or heterogeneous elements in their tumor by this FISH or ISH test method,” Dr. Hammond says.
Dr. Hicks, who has been using the new approach, says it should eliminate discordant cases due to intratumoral heterogeneity. “I think we got that right. Time will tell.” Panel members wanted the guideline to be as evidence-based as possible. “But sometimes, even when there are limitations in our knowledge, guidance needs to be provided. You have to start someplace. As Liz finally said, ‘Well, I think this is the best we can do,’” until more data become available.

Tumor heterogeneity appears to occur more frequently than previously thought, and there’s been concern and plenty of questions about how physicians can be certain the tumor block selected for testing is representative of the patient’s tumor. Dr. Hammond says, “We can never know that. So you have to make a rational decision about how much of a tumor you need to examine to get the right answer.”

The new guideline also takes on the equivocal category. Most notably, it aligns the ASCO/CAP equivocal category with that recommended by the FDA.

When the first guideline was written, says Dr. Hammond, “Our principal concern with HER2 testing was false-positives.” That concern led to one of the more vexing issues in HER2 testing. In the clinical trials for Herceptin, patients were considered positive for HER2 if their tumors contained more than 10 percent cells staining 3+ for HER2. The 2007 guideline writers chose a higher cutoff—more than 30 percent of cells because the panelists unanimously felt that almost all truly positive cases would have higher percentages of staining cells. Says Dr. Hammond: “We felt that tightening the threshold and being more specific about what constituted a positive would help limit the numbers of false-positives.”

Even as they did so, they knew the differing cutoffs might be confusing for practitioners, says Dr. Wolff, professor of oncology, Johns Hopkins University, Baltimore. But they had reasons for doing so.

Dr. Hammond calls setting the threshold at 30 percent “highly conservative. I still believe that’s the case.” In fact, she says, if proper specimen handling procedures are followed, the group of patients who fell into the previous equivocal category (that is, between 10 and 30 percent staining as 3+ positive) would be quite low. One retrospective paper (Perez EA, et al. J Natl Cancer Inst. 2012;104:159–162) considered patient eligibility for one of the trastuzumab adjuvant trials using both cutoffs and found that 3.7 percent of patients who met the FDA cutoff would have been declared ineligible by the ASCO/CAP criterion. “This high percentage would happen, though, only if recommendations from the 2007 guideline were ignored and reflex testing wasn’t done,” she says.

Therefore, Dr. Wolff says, physicians can set those concerns to rest. In a letter published in JNCI last year (Wolff AC, et al. 2012;104:957–958), he says, “We reanalyzed those data, and the actual number of patients affected would be about 0.2 percent of all patients newly diagnosed with breast cancer”—less, he adds, than the observed variability of various commercial assays in clinical use.

Dr. Hammond points out that the study population in the Perez paper consisted of patients who were put on clinical trials in the early 2000s before any specimen handling requirements were implemented. Wide acceptance of those requirements has lowered the false-positive rate since publication of the guideline in 2007. “We don’t believe this [the new guideline] is going to make any significant increase in the number of false-positives,” she says. It may even help curb them further, she adds.

Likewise, laboratories have shown a “meaningful increase” in participating in HER2 proficiency testing, Dr. Wolff says, adding that efforts to improve HER2 testing have gone beyond pathologists and oncologists, with health systems at large increasingly comprehending the need to provide the resources to implement accurate, standardized, and reproducible predictive biomarker testing, including proper handling of tissue specimens before they reach the pathology lab.

Might such improvements alone have led to a drop in equivocal cases, even without changing the threshold?

“That’s a great question, and I wish I knew the answer to it,” Dr. Hammond says. “Data from some large centers suggest so, and in my own laboratory, that is in fact the case.” Implementing careful specimen handling has had a dramatic effect on producing better pathology results at Intermountain, both by IHC and FISH, she says. In the past, perhaps up to 10 percent of cases would need a repeat FISH test. Her lab also has a “very, very small” number of patients who fell into the equivocal categories under the old guideline either by FISH or IHC, she says.
Nevertheless, she agrees using consistent criteria will help create standardized behavior. And, she adds, “We don’t want to create confusion.”

Concerns were raised about the 2007 guideline’s equivocal category for FISH, Dr. Hammond says. In the FDA guideline and in the clinical trials, a threshold of 2.0 was set to qualify patients for treatment. In the ASCO/CAP guideline, however, the authors said that, based on package inserts provided by assay manufacturers, a HER2/CEP17 ratio of 1.8 to 2.2 would be better considered equivocal rather than positive or negative, since they were within two standard deviations of the standard error of that measurement, says Dr. Hammond.

Now, the result is considered equivocal when the dual-probe HER2/CEP17 ratio is < 2.0 with an average HER2 copy number  4.0 and < 6.0 signals/cell.
As an example, Dr. Wolff says confusion occurs in cases in which there is evidence of coamplification in the region recognized by the CEP17 probe. “If that happens,” he says, “you could end up in

a situation where you have, say, an average HER2 signal copy number of six or seven, but also an increase of the average number of CEP17 copies detected to, say, four.” The result will be a ratio of less than two. Relying solely on that ratio, the pathologist runs the risk of calling the tumor nonamplified. “When in reality, we now recognized the occasional coamplification of the CEP17 region identified by the centromere probe. The new guideline mandates that such cases will have another HER2 test performed.

“The biggest message,” Dr. Wolff continues, “is that we ask physicians not only to look at the ratio alone, but actually to look at the individual average number of HER2 copies, which is provided in the numerator, because this can help with difficult cases.”

Again, the 2007 authors had their reasons for choosing the cutoffs they did. The equivocal category was created not to exclude patients from treatment, but to trigger additional testing. Unfortunately, it also led to confusion and controversy.

“Because it was within the error of the measurement,” says Dr. Hammond, “we felt it was useful for oncologists and pathologists to understand that the accuracy of a FISH estimate in that range might be affected by variability. But many of our colleagues later expressed concerns and preferred that we follow that same threshold provided in the clinical trial.”
Their desire is simple to understand, she says. “They want so much to find patients who are going to be HER2 positive.”

Medical oncologists might have been happier if the authors had just bid adieu to the equivocal category with this latest guideline. “We actually tried to get rid of it,” Dr. Hammond says. “But we could not do so. There always is an equivocal category, but we think we narrowed it considerably.”

That might have a bright side. The problem might not be with an equivocal result per se, but with viewing it as a final answer or the end of the discussion. As the authors of the new guideline emphasize, some difficult cases (including those with an equivocal result) will continue to exist and should start conversations.
Indeed, that’s what happened when they began to revise the guidelines and tried to answer the tough questions they face routinely in their own practices. “Most of us are practicing oncologists and practicing pathologists” as well as researchers, Dr. Wolff says.

Dr. Hammond calls the discussions “lively” but says they led to a strong document. It wasn’t unusual, she says, for her and Dr. Wolff to disagree about a subject initially or to reflect the differing opinions between medical oncologists and pathologists. “But when we talked it through, we were very much aligned, because both of us just wanted an accurate test result for the patient.” Yes, these conversations take time, and yes, they can be—temporarily—disconcerting. “But it’s worthwhile,” says Dr. Hammond. “It’s better than talking to yourself.”

Fortunately, not every case requires donnish oversight. “The cases we struggle with are very rare—one, two, three percent of the breast cancer population,” says Dr. Hicks. But little wonder the discussions were animated—there are few data on how to help this small subset of patients with unusual tumors.

Dr. Hicks would like to see those discussions continue in clinical practice. “It would be wonderful if after the guidelines are out, at every tumor board across the country, a pathologist sat up there and presented the changes and led a discussion about how this is going to affect the management of breast cancer in that institution going forward.”

As physicians familiarize themselves with the new guideline, they’ll be able to ask better questions about what test results mean. Dr. Hicks draws attention to the language in the guideline that asks medical oncologists and pathologists to confer on difficult cases, including thinking about HER2 results in the context of the patient’s histology. It’s a new spin on personalized medicine, distilled to answering a basic question: Does this make sense for this particular patient?

That may sound like an obvious question to ask, but in practice it wasn’t happening enough. “We describe the importance of ensuring that the assay results are concordant with the other histopathologic features,” Dr. Wolff says. Take a tubular breast cancer that is low grade and ER/PgR positive, for example. If the HER2 result for the tumor is positive, “those data don’t match in principle,” he says. In situations with such apparent histopathologic discordance, “We ask the pathologist and the oncologist to look back and examine the case as a whole” and consider additional testing if appropriate.

How have discordant results been handled up to now? “It really varied,” Dr. Wolff says. More experienced practitioners would catch the discrepancy, he says, and realize “something wasn’t quite right.” By formalizing this as a recommendation, even those who don’t specialize in breast pathology or breast oncology will know what to do.

Conversation is critical, says Dr. Wolff, but it “doesn’t happen as easily as we would like it to happen. By putting it in the document, we want to make that the norm.”

Similarly, the guideline gives specific recommendations listing the individual steps that pathologists and oncologists need to take as HER2 testing unfolds. “You can’t duck responsibility,” says Dr. Hammond.

It also provides specific guidance for patient and clinician conversations about HER2 testing. “Words matter,” says Dr. Wolff. “We spent a lot of time going over the meaning of everything we wrote.” Nothing, it seems, was left to chance.

That being said, tough cases, like the equivocal category, aren’t disappearing anytime soon. And just as this guideline reflects better knowledge and growing experience, so, too, will future changes create more challenges.

“We tried to do our best, but we’re very honest in saying we may not have covered everything,” Dr. Wolff says, “and we may not have gotten everything right. We did our best with the information available.” It’s inevitable that new classes of HER2 test results not covered in the guideline will become apparent once more data are available. Hence the need to keep the conversation going.

Some of those conversations will be sparked by new technologies, another topic that’s taken up in the new guideline.

While there’s plenty of interest in HER2 serum testing and RT-PCR, the only new platform endorsed in the guideline is FDA-approved bright-field in situ hybridization. The evidence for other methods was insufficient to warrant a recommendation right now. Conversely, the guideline notes, bright-field ISH measures gene amplification, which has clear clinical utility—it was the biological criterion used in prospective clinical trials. It shows high concordance levels with other ISH methods using FISH, and it appears to be reproducible across laboratories.
Bright-field offers another option for labs that currently offer only IHC testing. “That might be a much more interesting way for pathologists to operate,” Dr. Hammond says. While it brings challenges, it will also allow such labs to thoroughly examine the tumor in a way they likely didn’t before, she says.

Labs will also have more flexibility in specimen handling, thanks to other changes in the guideline.

Recognizing the need to further standardize preanalytical variables, the authors have extended the fixation time for HER2 specimens. Now, the fixation time is six to 72 hours, bringing it in line with the times used for ER/PgR testing. In the 2007 guideline, the time was six to 48 hours.

Another change addresses sample procurement. While the 2007 guideline implied that a tumor excisional sample was preferable because it provided more cells for study, says Dr. Hicks, HER2 testing on needle core biopsies has increased in recent years. The new guideline says the needle core biopsies are acceptable, though with clearly defined caveats.
“I think what’s been happening is people are doing the HER2 on the needles—if they’re negative, they’re calling them HER2 negative, and they’re not repeating the test,” says Dr. Hicks. “That may be fine 90, 95 percent of the time. But for that small number of patients who really are HER2 positive, and the needle didn’t get to that part of the tumor, they’re missing an opportunity to have a potentially life-prolonging or life-saving treatment.”

As with other difficult cases, the authors spent plenty of time grappling with this issue. Ultimately, they called for repeat testing in cases where the tumor is high grade; if there’s a limited amount of tissue on the needle core biopsy; if the needle core result falls into the equivocal range; or if the excisional sample contains a different component from that found on the core. The guideline also specifies the type of case when repeat testing is not warranted: if the test is negative and the tumor is grade one and strongly ER/PgR positive.

Even as the new guideline aims for clarity, no one expects it to be the final word on HER2 testing.

If anything, pressure to improve testing will only grow down the road. New studies are exploring the possibility of treating patients with HER2-targeted antibodies without chemotherapy, Dr. Wolff says. “In that situation we have to be incredibly clear and certain that the tumor is HER2 positive or not. Because we could be in a situation where a patient might only receive HER2-targeted treatments in the future.”

When it comes time for another update, the authors will have a good model to follow, says Dr. Hicks: this most recent panel. “More than anything, we are grateful for all the hard work by the guideline panel members and staff from CAP and ASCO.”

No one expects guidelines to be chiseled in stone like commandments. Even if nothing changed— and when was the last time that happened in medicine?—“At some point people start saying, ‘This is an old guideline. It can’t be valid anymore,’” says Dr. Wolff. With the 2007 guideline, “We knew all along that at some point we would need to update the document. And we’ve been more or less waiting for that moment. Now was the time.”


Source:  CAP TODAY 

New tools automatically match patients with clinical trials.

The majority of Americans—72%—say they would take part in a clinical trial recommended by their doctor, according to a survey released last month by the Alexandria, Virginia-based science advocacy group Research!America. Despite that enthusiasm, though, there’s a shortage of enrollment. According to US government estimates, only about 3% of patients with advanced cancer enroll in phase 1 trials. Part of the problem, experts believe, comes down to a lack of awareness: the general public doesn’t know about investigational trials, and few physicians discuss the option with their patients.


New tools unveiled this year that automatically prescreen patients for trials based on their electronic medical records and email matches to doctors could help solve the problem. “We’ve needed these kinds of tools for a long time,” says Eric Topol, a cardiologist and director of the Scripps Translational Science Institute in La Jolla, California. “Physicians are really busy, and there are so many clinical trials that no human could track them all.”

The US federal registry,, currently lists more than 145,000 trials in all 50 states, as well as 184 foreign countries. Wading through those listings is a daunting task for individuals interested in signing up for a study, assuming that they know of the resource to begin with. Ultimately, problems with patient recruitment delay clinical trials by 4.6 months, on average, according to the Center for Information and Study on Clinical Trial Research Participation, a nonprofit organization in Boston. That holdup means it takes longer for treatments to reach the market.

To increase enrollment, some patient-advocacy groups have started playing matchmaker. A year ago, the Michael J. Fox Foundation for Parkinson’s Research launched the Fox Trial Finder, a web portal designed to help pair people with Parkinson’s with clinical studies (see Nat. Med. 18, 837,2012). The Alzheimer’s Association’s TrialMatch, meanwhile, has been up and running since 2010. Anyone can register online or by phone and see if he or she—or a patient or loved one—is a good fit for any of the 153 trials in 621 locations. To date, there have been 11,166 referrals, says Heather Snyder, the Chicago-based association’s director of medical and scientific operations.

In addition to the Fox Trial Finder and TrialMatch, for-profit companies have unveiled web portals to link people with studies. New York’s EmergingMed helps connect individuals with cancer trials, and in late May, Michigan-based CureLauncher unveiled a clinical-trial-matching service for a range of disorders. But tools such as these rely on the gumption of patients and doctors to wade through web listings. A new wave is emerging of automated tools that do away with the need for patients or physicians to manually enter information.

On alerts

Earlier this year, the Virginia Commonwealth University’s Massey Cancer Center in Richmond unveiled two new tools that work with its Clinical Trials Eligibility Database, which stores information about patients and clinical trials at the center. Since February, its MD Alert Notification System has automatically prescreened the list of scheduled patients each morning and emailed physicians when it finds that one of those individuals is eligible for one or more of 75 open trials at the center.

“If the patient is interested, one click by the physician refers them to the research nurse associated with that trial,” says Lynne Penberthy, director of the Massey Cancer Center’s informatics core who oversees the tracking and matching tools. Another new computer application there, the Automated Matching Tool, has been available since January. It screens all patients in the system on a scheduled basis, not just those coming in for a visit.

An algorithm known as Trial Prospector offers even greater automation for clinical trial enrollment. In a pilot study presented at last month’s American Society of Clinical Oncology meeting in Chicago, the program reached into the medical records of 60 people with gastrointestinal cancer who had scheduled appointments at the University Hospitals Seidman Cancer Center of the Case Comprehensive Cancer Center in Cleveland, Ohio. It pulled out 15 pieces of information—including age, diagnosis and blood count—that it compared to eligibility criteria of the 300-plus trials in Cases’s database. It then emailed doctors lists of any matches, and it also shows the studies for which the patient didn’t qualify and explains why; for example, some factors, such as low red blood cell count, might be easily fixed with a transfusion. The algorithm was 100% accurate, and 11% of the patients ended up enrolling in a trial suggested to the doctor by the algorithm.

“In theory this could be readily adapted anywhere, but we’ve still got a long way to go,” says Neal Meropol, associate director for clinical research at the Case Comprehensive Cancer Center. His team plans to refine Trial Prospector over the next 6 to 12 months, expand it to other cancers, and test it in a community-practice setting, where physicians aren’t highly specialized and may not have as much knowledge of open trials.

Penberthy similarly sees automated trial matching tools as a way to reach a more diverse set of participants. “We’re hoping that this is going help increase the equity,” she says. “It may help to increase minority patients enrolled in clinical trials,” an underrepresented population.

Topol, who isn’t involved with the programs, says that although automated matching programs are in their infancy, “eventually they could build something that’s extraordinary.”

Source: Nature