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Wednesday, May 30, 2018

New guideline for HER2 testing in breast cancer


Published today, a Focused Update to the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guideline for human epidermal growth factor receptor 2 (HER2) testing in breast cancer brings new levels of clarity that will benefit patients and clinical teams alike.
An ASCO-CAP expert panel of pathologists and oncologists developed this Focused Update to address new information made available since the guideline’s previous update in 2013. Notably, the 2018 Focused Update addresses uncommon clinical scenarios and improves clarity, particularly for infrequent HER2 test results that are of uncertain biologic or clinical significance.
For patients with invasive breast cancer, accurate determination of HER2 status of the tumor is essential to ensure that those most likely to benefit are offered a HER2-targeted therapy. At the same time, those who are unlikely to benefit can avoid side effects and costs associated with those drugs.
As primary predictors of how a patient with breast cancer may respond to HER2-targeted therapy, pathologists use in situ hybridization (ISH) tests to assess HER2 gene amplification and can assess protein overexpression by immunohistochemistry (IHC) tests.
“Now, a growing body of clinical outcomes literature and survey data enables us to recommend how to best evaluate some of the less common patterns in HER2 results emerging from ISH,” said Expert Panel co-chair for CAP, Elizabeth Hammond, MD, FCAP, an emeritus professor of pathology at the University of Utah School of Medicine and consultant pathologist at Intermountain Healthcare.
According to ASCO Expert Panel co-chair Antonio Wolff, MD, FACP, FASCO, a professor of oncology at Johns Hopkins, “It is well documented that greater communication among providers-;oncologists and pathologists-;leads to improved results. This update demonstrates that both the CAP and ASCO are committed to collaboration that not only guides best medical practices, but that also serves as a model for other specialties.”
Updated findings of note include:
  • Revision of the definition of IHC 2+ (equivocal) to the original FDA-approved criteria.
  • Repeat HER2 testing on a surgical specimen if the initially tested core biopsy is negative is no longer stated as mandatory. A new HER2 test may (no longer should) be ordered on the excision specimen on the basis of some criteria (such as tumor grade 3).
  • A more rigorous interpretation criteria of the less common patterns that can be seen in about 5% of all cases when HER2 status in breast cancer is evaluated using a dual-probe ISH testing. These cases, described as ISH groups 2 to 4, should now be assessed using a diagnostic approach that includes a concomitant review of the IHC test, which will help the pathologist make a final determination of the tumor specimen as HER2 positive or negative.
  • The Expert Panel also preferentially recommends the use of dual-probe instead of single-probe ISH assays, but it recognizes that several single-probe ISH assays have regulatory approval in many parts of the world.
The guideline Focused Update is available online at the ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE. Additionally, the CAP and ASCO developed RESOURCES TO HELP PATHOLOGISTS AND ONCOLOGISTS review and implement the guideline, including a summary of recommendations, a teaching presentation, and testing algorithms.
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New Reference Ranges: How Many Kids Really Have High Blood Pressure?


New pediatric blood pressure (BP) clinical practice guidelines were released in 2017 by the American Academy of Pediatrics (AAP).[1] The new guidelines aimed to establish better reference BP ranges for normal-weight children and adolescents by excluding children who were overweight or obese. The new guidelines also changed some of the terminology and definitions of “normal” and “elevated” BP used in the earlier guidelines (Table). The term “prehypertension” is no longer used.
Table. American Academy of Pediatrics Blood Pressure Definitions
AGE 1-13 YEARSAGE ≥13 YEARS
Normal blood pressureSystolic and diastolic < 90th percentile< 120/< 80 mm Hg
Elevated blood pressure≥ 90th to < 95th percentile or 120/80 mm Hg to < 95th percentile120/< 80 mm Hg to 129/< 80 mm Hg
Stage 1 hypertension≥ 95th percentile to < 95th percentile + 12 mm Hg or 130/80 mm Hg to 139/89 mm Hg(whichever is lower)130/80 mm Hg to 139/89 mm Hg
Stage 2 hypertension≥ 95 percentile + 12 mm Hg or ≥ 140/90 mm Hg (whichever is lower)≥ 140/90 mm Hg

How Many Kids Are Reclassified?

Using data from the National Health and Nutrition Examination Survey (NHANES) collected from 1999 through 2014, a recent study[2] aimed to find out how these new reference values might change the proportion of children diagnosed with hypertension. The data included more than 15,000 children (with representative sampling of minority populations) with a median age of 13.4 years. Using NHANES criteria, 35.9% of the sample children were overweight, with 10.3% defined as obese.
Using the updated AAP definitions, 5.8% of the cohort would have been classified “upward,” in terms of BP classification. About one third of those children were reclassified from “normal” BP to either elevated BP or stage 1 hypertension. Approximately one half of that group had “prehypertension” under the old designation but were now classified as having stage 1 hypertension. Only about 5% of those classified upward moved from stage 1 to stage 2 hypertension.
The reclassified children were more likely to have elevated body mass index, lipid abnormalities, or abnormal A1c levels, representing a high-risk population who may require more thorough evaluation for cardiovascular risk.
The population estimate of elevated blood pressure or hypertension increased from 11.8% to 14.2% with the new blood pressure reference values.

Viewpoint

The fact that 14% of the US child and adolescent population would be classified as having elevated BP or hypertension is an amazing statistic and should cause us to all consider how accurately we measure, assess, and treat abnormal BP in children. There are a couple of cautionary notes. First, the NHANES data collected only a single BP measurement, although presumably it was done in a proper manner. The guidelines suggest measuring BP two or three times in the clinic, especially after having the child sit quietly for 5 minutes. Subsequent BPs after the initial measurement in a clinical setting are often lower, and the average BP should be used.
Even if the 14% figure is an overestimate because the children were classified on the basis of a single BP measurement, the true proportion of children with elevated BPs could still be somewhere around 10%—a high figure.
A full review of the guidelines is beyond the scope of this report, but practitioners should avail themselves of the recommended sequence for lifestyle modification, follow-up intervals, indications for beginning medication, and when to initiate more intense management of hypertension.[1]
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Anticholinergics and Dementia: It’s the Drugs


Hello. I’m Dr Charles Vega, and I am a clinical professor of family medicine at the University of California at Irvine. Welcome to Medscape Morning Report, our 1-minute news story for primary care.
It is well known that anticholinergic medications affect cognition, with long-term exposure linked to dementia. Guidelines indicate that they are to be avoided in frail, elderly patients. However, it has been unclear whether the increased risk is specific to the anticholinergic or to the underlying conditions being treated.
A case-control study involving over 300,000 patients suggests that it is the drugs. Antidepressants, drugs for Parkinson’s, and urologic meds increase the risk of developing dementia for up to 20 years after exposure.
The data are observational and the associations were moderate, with an odds ratio ranging from 1.1 to 1.6 for exposure to drugs with a known risk for short-term cognitive dysfunction. However, given the high incidence of dementia, the investigators contend that this represents an appreciable risk to patients.
This study reinforces the need for a thorough drug history in our older patients because drugs with anticholinergic properties are out there in many forms.
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States Continue Push to Restrict Abortion


Arkansas’ law adding more regulations on providers of medication abortions is but one example of the increased restrictions that states are seeking to put on abortion providers, according to advocates on both sides of the abortion debate.
The law, which was passed in 2015, requires clinics that provide medication abortions to have a contract with a provider that has admitting privileges at a local hospital. The law was challenged by abortion rights advocates and wound its way through the legal system, eventually making its way to the Supreme Court, which on Tuesday declined to hear the case.
As a result, the ruling of the 8th Circuit U.S. Court of Appeals in favor of the law still stands, although Planned Parenthood has said it will seek a temporary injunction to block the law from taking effect. In the meantime, however, Planned Parenthood has said it will stop providing medication abortions in the state.
The practical effect is that women in Arkansas who are seeking an abortion will now only have one place to go, said Elizabeth Nash, senior state issues associate at the Guttmacher Institute, a pro-abortion rights organization. “There were [originally] three clinics … and two of those clinics only provided medication abortions,” she said in a phone interview. “Those two clinics are closed, and the remaining clinic can only provide — for now — surgical abortions.”
Numbers Down
Arkansas now joins a handful of states that have only one abortion clinic; the others include North Dakota, South Dakota, Wyoming, Mississippi, Kentucky, and West Virginia, Nash said. “In some states, that has curtailed access dramatically,” Nash said. “Women may end up going to other states to access abortion there … or they may be delayed because they found out that they wanted an abortion early in the pregnancy, but they have to arrange an appointment several weeks in advance [since] there is only one clinic to go to.”
Kelly Marcum, legislative assistant at the Family Research Council, a pro-life organization, said in a phone interview that “numerous pro-life bills are moving at the state level.” For example, this past week, Louisiana legislators passed a bill to effectively defund Planned Parenthood in their state; while not mentioning the organization by name, the bill says that abortion providers in Louisiana will not be able to receive Medicaid funds.
And legislation at the federal level — even if it’s not successful — helps move things along in the states, she continued. “Even if a bill at the federal level doesn’t pass,” such as a ban on abortions after 20 weeks that was passed in the House but not the Senate — “we see momentum in the states to get [similar bills] across the finish line. With an administration that’s friendly to the pro-life moment, there is more momentum at the state level” to get these bills through.
In addition, Marcum said, “[President Trump] is putting in strict constitutionalist judges in various circuits, and that will help when these bills get bottled up in the courts.”
New Kind of Restriction
Currently, 43 states have laws that restrict abortion after a certain period of gestation, according to a report by the Guttmacher Institute. In addition, 19 states require an abortion to be performed in a hospital after a specified point in the pregnancy.
The Arkansas law is a relatively new kind when it comes to medication abortions, according to Shivana Jorawar, state legislative counsel, at the Center for Reproductive Rights, a pro-abortion rights group. “We are seeing restrictions on medical abortion and telemedicine, but the requirement of admitting privileges being needed is a little unique,” Jorawar said during a phone interview at which a public relations person was present.
On the other hand, “I do think we’re going to continue seeing more pre-viability abortion bans,” she said. “We’ve been seeing 15-week bans in Louisiana and Mississippi. Those are new in that we haven’t seen 15-week [limits] before, but we have seen gestational bans for as early as 6 weeks, and I do think that more states are going to introduce these blatantly unconstitutional bans,” despite the cost to taxpayers of having to defend them.
In the end, however, the courts will end up protecting a woman’s right to choose, she predicted. “At the end of the day, if this makes it to the Supreme Court, every justice is obligated to respect and follow precedent, and there is a very firm precedent when it comes to abortion,” Jorawar said.
“Less than 2 years ago, [the Supreme Court] reaffirmed [abortion rights] in the Whole Women’s Health case. They made it clear that states can’t have laws that … impose burdens on this very fundamental right with no corresponding benefit, and the existing restrictions we see here fail that test.”
With the closing of Planned Parenthood clinics in states like Arkansas, more crisis pregnancy centers likely will appear, said Marcum. “We’ve seen in numerous states where abortion clinics have closed down that crisis pregnancy centers have grown nearby in response to the fact that there are still women who need help, and they are seeking organizations that will actually help them. What we’d like to see is Title X and Medicaid funds diverted from Planned Parenthood go to crisis pregnancy centers and community health centers that are equipped to empower women.”
Trump Effect
Steven Aden, chief legal officer and general counsel at Americans United for Life, a pro-life organization, agreed that for now, many of these state laws regulating abortion will continue to have a tough time in the courts, including a recently enacted bill in Iowa that would outlaw abortion after a fetal heartbeat is detected, which is usually at around 6 weeks. “We don’t anticipate early-term abortion limits … will make much headway in federal courts at this time,” he said in a phone interview. “We do think [the Iowa law] has an uphill battle.”
However, things could start to change as the Trump administration continues to appoint conservative judges, he added. “At this rate, you’d have to think that the drive to appoint constitutional conservatives/originalist judges will have an impact at some point down the road … just as [more liberal] judges appointed by [President] Obama had an impact.”
For now, there seems to be continued interest among states “to regulate abortion like any other outpatient procedure,” Aden said. “You’ll see principally bills going to surgical center regulation, chemical abortion regulations, and perhaps non-discrimination provisions outlawing abortion based on the baby’s gender or prenatal genetic characteristics.”
There is definitely a need for these types of bills, Aden continued. “In some states it has been shown that up to 90% of babies with Down syndrome are aborted,” he said. “There is certainly genetic counseling and genetic discrimination based on disabilities in the womb.”
“And with respect to gender science, it’s pretty well established that at least internationally and in many metropolitan areas in the U.S. where there’s a high number of immigrants, that there’s a market for abortion based on the gender of the baby, principally because the baby is a girl, so I think that’s important protective legislation,” he added.
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J&J revamps baby products and message to appeal to millennial moms


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A first look at J&J’s revamp of its baby care product line with updated looks, formulations and an upcoming ad campaign. (Johnson & Johnson)
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AbbVie Is a Great Short-Term Investment but Long-Term Is More Complicated


Over the last five years, AbbVie shares are up about 130 percent. It’s generally viewed as a volatile stock—although to be fair, almost all biopharma stocks are—but some have argued that although AbbVie is a great stock short-term, other, less-volatile stocks, like Pfizer, would be better investments long-term. Dividend Sensei, writing for Seeking Alpha, makes the argument that AbbVie will dominate the market for the next decade or longer.
Dividend Sensei notes that the company has a strong executive team, especially Rick Gonzalez, the company’s chief executive officer, and Bill Chase, its chief financial officer. “The reason that such deep industry experience is essential is because top quality management is capable of navigating the treacherous and fast-changing waters of this industry and generating strong returns on capital for shareholders.”
Most of AbbVie’s growth, which is considerable, has been driven by Humira, it’s mega-blockbuster drug for a variety of autoimmune diseases such as arthritis, psoriasis, Crohn’s disease and ulcerative colitis. It has about 25 percent market share for its approved indications. The company has projected Humira sales to hit $21 billion by 2020.
But the company also has a strong pipeline. It expects to get approval for elagolix for endometriosis-associated pain in this year’s third quarter. It has submitted an application for risankizumab for plaque psoriasis, and has upadacitinib, another autoimmune disease drug, that might be approved in 2019.
It should be noted that there’s quite a bit of competition coming down the road for AbbVie in the JAK inhibitor market. Physicians are increasingly prescribing JAKi after Humira.
Dividend Sensei appropriately notes, “Many investors have worried that Humira is AbbVie’s Achilles heel because it lost patent protection in 2017 in the EU and a key U.S. patent expired in 2016. Fortunately, the company has been able to strike deals with Amgen and Samsung Bioepisin recent months that means it won’t face any biosimilar competition until 2023.”
Looking a bit further down the road to 2025, Dividend Sensei notes that the company is expecting its neurological drugs for Alzheimer’s disease, Parkinson’s disease and multiple sclerosis to begin launching. That might be wildly optimistic. Alzheimer’s is where drugs go to die; it’s a desert wasteland of failed Phase III clinical trials with well over 127 drugs having failed in that arena in the last decade or so.
One negative for AbbVie is its debt, which is $37.3 billion, almost double the industry average. Dividend Sensei doesn’t seem particularly concerned about that because of a very strong investment grade credit rating, and an extremely low corporate tax rate—9 percent this year, increasing to 13 percent over the next couple years—and a high free cash flow minus dividend cost.
So Dividend Sensei is definitely a fan of AbbVie. Pfizer is less flashy, but more stable and reliable. While Humira makes up almost 60 percent of AbbVie’s total revenue, Pfizer had eight blockbuster drugs in 2017. It has a deep pipeline with 28 late-stage programs and an exceptionally strong vaccine program.
And in a January 2018 comparison of Johnson & Johnson to AbbVie, The Motley Fool’s Brian Stoffel, likes J&J a little bit better. He noted, “On the surface, these two are pretty evenly matched. Their price-to-earnings and free cash flow ratios are virtually identical. And both have very solid dividends, with only half of their free cash flow being eaten up to make the quarterly payments to shareholders. But when growth is taken into consideration via the PEG Ratio, AbbVie trades at a significant discount to Johnson & Johnson. That’s enough for me to give AbbVie the nod here…. Perhaps I’m being a bit more conservative by siding with the slower growth company, but I believe Johnson & Johnson’s moat and financial fortitude are enough to give it an edge over AbbVie’s drug portfolio and attractive price tag.”
AbbVie looks very strong for the short-term and probably strong for the long-term. What could go wrong? Humira sales could fall apart more quickly than expected. Biosimilar competition will begin later this year in Europe and in early 2023 in the U.S.
There is always the possibility of pipeline failures. The company already had disappointing Phase II results for Rova-T for small cell lung cancer, and betting on any company’s prospects in Alzheimer’s and Parkinson’s disease seems like a longshot. However, Keith Speights, writing for The Motley Fool, says, “While there’s always a chance that AbbVie will underperform the S&P 500 in the coming years, I think the odds are definitely in favor of AbbVie beating the market.”
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Janssen taking Legend CAR T therapy to clinic

Janssen Biotech Inc. said FDA cleared an IND for CAR T therapy JNJ-68284528 (LCAR-B38M) to treat multiple myeloma. The unit of Johnson & Johnson (NYSE:JNJ) expects to start a Phase Ib/II study next half of the therapy targeting BCMA (TNF receptor superfamily member 17; TNFRSF17; CD269).
At last year's American Society of Clinical Oncology (ASCO) meeting, Legend reported JNJ-68284528 led to a 100% objective response rate among 19 MM patients in the first phase of the Chinese Phase I/II LEGEND-2 study. No neurotoxicities, which can plague anti-CD19 CAR T therapies, were observed.
In December 2017, Janssen obtained a global license to the therapy from the Legend Biotech USA Inc. and Legend Biotech Ireland Ltd. subsidiaries of Genscript Biotech Corp. (HKSE:1548). The partners are developing JNJ-68284528 jointly worldwide.
The therapy is Janssen's first in the CAR T space. At the time of the deal, Janssen's Global Therapeutic Area Head of Oncology Peter Lebowitz told BioCentury BCMA was the first target to meet the company's safety and efficacy standards for the CAR T modality (see BioCentury, Jan. 5).
Janssen said the primary efficacy endpoint in the Phase II portion of its planned trial to treat relapsed or refractory MM will be overall response rate (ORR) as defined by the International Myeloma Working Group response criteria.
Several companies are evaluating BCMA-targeted therapies in the clinic for MM. The most advanced is bb2121 from bluebird bio Inc. (NASDAQ:BLUE) and partner Celgene Corp. (NASDAQ:CELG). It is in the pivotal Phase II KarMMa trial in relapsed and refractory MM, and could launch as early as 2020 (see BioCentury, Jan. 26).
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