Σάββατο, 14 Ιουλίου 2018

RESTRICTIONS FOR XOFIGO

Use of the novel radiopharmaceutical radium-223 dichloride (Xofigo, Bayer) in prostate cancer should be restricted, according to the European Medicines Agency's Pharmacovigilance Risk Assessment Committee (PRAC).
PRAC first noted concerns about this product in December 2017, as reported by Medscape Medical News. At the time, the committee noted that it was investigating reports of an increase in deaths and fractures in an ongoing trial exploring the radiopharmaceutical for an unapproved use.
Now, PRAC has said that it decided, following a review of those data, to recommend restricting the use of radium-223 dichloride to patients who have had two previous treatments for metastatic prostate cancer or who cannot receive other treatments.
PRAC also confirmed its previous interim recommendation that the radium-233 dichloride must not be used with abiraterone acetate (Zytiga, Janssen) and prednisone/prednisolone.

Reports From Clinical Trials 

PRAC gave details of the problem back in December 2017.
The reports of an increase in deaths and fractures came from an ongoing trial (ERA223) that was comparing the radiopharmaceutical with placebo in men with prostate cancer who were already taking abiraterone acetate and a steroid (prednisone or prednisolone).
This trial included patients with prostate cancer who have no symptoms or mild symptoms, such as pain, the committee noted. The investigators were exploring an unapproved use of the radiopharmaceutical, the committee emphasized.
Radium-223 dichloride is currently approved for use in the treatment of castration-resistant prostate cancer in patients who have symptomatic bone metastases.
The product has been on the market for about 5 years. It was  approved in the United States in May 2013 by the Food and Drug Administration and approved in Europe in November 2013.

Favorable Benefit/Risk Ratio When Used as Approved 

Also in December 2017, the manufacturer of the radiopharmaceutical, Bayer, announced in a press statement that the trial had been unblinded on the recommendation of an independent data monitoring committee (IDMC).
"The IDMC recommendation is due to the observation of an imbalance of more fractures and deaths in the treatment arm investigating radium-223 in combination with abiraterone acetate and prednisone/prednisolone," the company said.
"Patient safety is our top priority. We are therefore unblinding the study to thoroughly analyze the data," said Mike Devoy, chief medical officer at Bayer.
"It is important to note that, based on available data from previous trials as well as real-world use, the benefit-risk profile of Xofigo in its approved indication remains favorable," he added.
For more from Medscape Oncology, follow us on Twitter:  @MedscapeOnc

TOO MANY PROPHYLACTIC CONTRALATERAL MASTECTOMIES

Oncologists are often faced with a very difficult decision: whether to follow the science and insist on an evidence-based recommendation for therapy, or acquiesce to a patient's wish to do what they think will make them feel better, even as it contradicts published studies or even guideline-recommended care.
That is the question faced by an increasing number of breast cancer physicians as they treat women with disease in one breast who are convinced that they should have both breasts removed, despite a lack of evidence that it will do anything to improve their survival.
The number of contralateral prophylactic mastectomies performed in North America is increasing by more than 14% a year. 
Whereas prophylactic double mastectomy in women at high risk of developing life-threatening breast cancer at a young age is an accepted procedure, performing contralateral prophylactic mastectomy in lower-risk women who already have the disease is much more controversial, not least because it exposes women to a markedly increased risk for complications compared with breast-conserving approaches.
Yet some estimates have suggested that the number of contralateral prophylactic mastectomies performed in North America is increasing by more than 14% a year.
How is it that the number of contralateral prophylactic mastectomies is rising steadily year by year, despite the best efforts of clinicians to persuade women to opt for less radical treatments?

The Guidelines Are Clear 

When it comes to the settings in which bilateral mastectomy may be appropriate, the guidelines are consistent.
For example, the National Comprehensive Cancer Network guidelines state, in the March 2018 update to the Clinical Practice Guidelines on Oncology,[1] that women with a known or suspected genetic predisposition to breast cancer "may be considered for prophylactic bilateral mastectomy for risk reduction."
Although the panel singles out women with breast cancer aged 35 years or younger and carriers of BRCA1/2 mutations as candidates, it underlines the importance of counseling and multidisciplinary consultations, as well as a discussion of the associated risks.
Moreover, the panel says that contralateral mastectomy in a women already diagnosed with unilateral breast cancer and treated with mastectomy is "discouraged," whereas performing the operation in a similar woman treated with lumpectomy is "strongly discouraged."
The American Society of Breast Surgeons goes further,[2] saying that "with the possible exception of BRCA carriers," contralateral prophylactic mastectomy "does not appear to be associated with a survival benefit." They say that the procedure should be reserved for women at the highest risk for contralateral breast cancer, namely those with BRCA1/2 mutations and those with a lifetime risk for breast cancer of more than 25%, as well as those who have undergone mantle-field radiation.

On the other hand, "average-risk" women, in whom the risk for breast cancer in the healthy breast is 0.1%-0.6% per year, should be "discouraged" from having contralateral prophylactic mastectomy because they "do not derive any oncologic benefit." They emphasize not only that the operation doubles the risk for surgical complications versus treating only the breast cancer, but also that it "may negatively affect oncologic outcomes" by delaying adjuvant therapy or discouraging women from undergoing radiation therapy.
The Society of Surgical Oncology Breast Disease Working Group agrees, pointing out that there is a lack of reliable evidence to support the use of contralateral prophylactic mastectomy.[3] High-risk women should therefore be counseled on alternative management strategies, including chemoprevention and surveillance imaging, it says. Nevertheless, the group acknowledges that the decision "must be individualized," because "there is no formula for predicting whether the patient will achieve peace of mind."

The Evidence Supports the Guidelines 

Of note, the guidelines recommendations are not based simply on expert opinions or consensus discussions, but on large data sets from dozens of studies. For example, prophylactic mastectomy in women with a BRCA1/2 mutation or in those with a family history of breast cancer is backed up by numerous investigations showing that the risk of developing breast cancer is reduced by at least 90% after the procedure.[4,5,6,7]
In contrast, a recent large registry study demonstrated that for women already diagnosed with cancer in one breast, there is no improvement in survival from having both breasts removed.
As reported by Medscape, the analysis of almost 19,000 Californian women diagnosed with stage 0-III unilateral breast cancer showed that bilateral mastectomy was not associated with a mortality difference compared with breast-conserving surgery plus radiation.
Moreover, a Cochrane review of 39 studies involving almost 7400 women,[8]indicated that there was "insufficient evidence" to suggest that contralateral prophylactic mastectomy improved survival, and concluded that bilateral prophylactic mastectomy "should be considered only among those at very high risk."

And the Doctors Agree 

As a result of this overwhelming consensus, clinicians speak with one voice.
Lisa A. Newman, MD, director of the Breast Oncology Program at the Henry Ford Health System in Detroit, Michigan, told Medscape that for women with a BRCAmutation, bilateral prophylactic mastectomy can be a "worthwhile" option, because it can reduce the lifetime risk for breast cancer from 40%-85% to less than 10%.
Steven A. Narod, MD, of the Women's College Research Institute at Women's College Hospital in Toronto, Ontario, Canada, emphasized that the procedure nevertheless needs to be performed early, typically between 25 and 30 years of age. "Once you hit 30 [years of age] with a BRCA mutation, your risk starts to become, on an annual basis, pretty big, so if you're going to do it, there's no scientific rationale to wait beyond 30," he said.
For women already diagnosed with breast cancer, Newman said that contralateral mastectomy can be "very effective as the most aggressive strategy available to prevent breast cancer" in the other breast, reducing the risk by up to 95%. She pointed out that this, however, "does not provide a guarantee against future breast cancer," because women can have microscopic breast tissue in the surrounding areas of the body, such as the chest wall or the underarm region.
Furthermore, the overall lifetime risk of developing breast cancer in an "average-risk" woman is 12%. Prophylactic mastectomy reduces that to 2%, which, Newman said, does not outweigh the risks and psychosocial impact of the procedure.
She also underlined that early, conservative breast cancer treatment is successful in the majority of cases, making it unlikely that having prophylactic mastectomy would result in an additional survival benefit.
In other words, as Ashu Gandhi, MD, PhD, an executive member of the UK's Association of Breast Surgery, summarized, "In the family history/BRCA group, there's a justified reason for removing healthy breasts, but in the [lower-risk] group—the 'woman next door' group—there's no clinically justifiable reason to remove both breasts."

Yet the Numbers Keep Growing 

Despite all the guidelines recommendations and data from large-scale studies, there is "definitely no question" that there has been a "growing trend of having bigger surgery" over the past 15 years, said Nora Jaskowiak, MD, an associate professor of surgery and surgical director of the Breast Center at University of Chicago Medicine, Chicago, Illinois.
"Usually, that bigger surgery is having a bilateral mastectomy," she told Medscape, adding, "Every single week, patients who could save their breast, get radiated, and do very, very well choose instead to have bilateral mastectomy."
This impression is borne out by a recent analysis of data on more than 230,000 US women, which showed that younger women are increasing likely to choose bilateral mastectomy plus immediate breast reconstruction rather than breast-conserving surgery, regardless of how they respond to neoadjuvant chemotherapy.
As reported by Medscape, rates of bilateral mastectomy with immediate reconstruction increased significantly between 2010 and 2014, from 8.0% to 13.2%, even while rates of pathologic complete response to neoadjuvant chemotherapy rose from 33.3% to 46.3% over the same period.
The analysis referred to earlier of 19,000 women with early-stage breast cancer underlined this trend, with the proportion of women undergoing bilateral mastectomy increasing from 2.0% in 1998 to 12.3% in 2011, or an annual increase of 14.3%.
In both studies, the rates of bilateral mastectomy rose fastest in women aged less than 40 years. All of this is despite studies showing that undergoing bilateral mastectomy can have serious consequences for women.
A study in over 18,000 women reported by Medscape showed that compared with unilateral, or single, mastectomy, contralateral prophylactic mastectomy is associated with a significantly increased risk for implant loss, a greater need for transfusion and reoperation, and longer hospital stays.
Another analysis of almost 600 women followed up around 2 years indicated that contralateral mastectomy was also linked to an increased risk for superficial nipple necrosis, wound breakdown, and infections requiring oral antibiotics, as well as an increased risk for implant exposure.[9]
Although women undergoing contralateral prophylactic mastectomy may have increased breast satisfaction from having both reconstructed at the same time, one systematic review of 22 studies suggested that the procedure can affect sexual well-being and somatosensory function.[10] Specifically, Frost and colleagues[11] found in a survey of over 480 women that contralateral prophylactic mastectomy can have adverse effects on body appearance, femininity, and sexual relationships, affecting between one quarter and one fifth of women.
Even women at high risk for breast cancer who under bilateral prophylactic mastectomy can experience psychological issues, with one study suggesting that around one half feel self-conscious, less sexually attractive, and dissatisfied with the scars.[12]

Why Do Women Choose Bilateral Mastectomy? 

So why are women opting to have invasive surgery, such as contralateral prophylactic mastectomy, placing themselves at risk for adverse effects and worse psychological outcomes when the overall benefit could be as much, if not greater, with less invasive treatments?
"People have been looking at this a lot over the past 10 years," Jaskowiak said, "and I think there are a lot of different factors."
One study of almost 3000 women suggested that independent predictors of undergoing contralateral prophylactic mastectomy include white race, being aged less than 50 years, having undergone MRI at diagnosis, the availability of immediate breast reconstruction, and a previous unsuccessful attempt at breast conservation.[13]
Another study, including more than 3600 women, suggested that having contralateral prophylactic mastectomy was linked to a higher educational level, a family history of breast cancer, and the availability of private medical insurance, alongside younger age and white race.[14]
In their study of almost 1500 women, Hawley and colleagues[15] added undergoing genetic testing, regardless of whether the result was positive or negative, to the factors associated with contralateral prophylactic mastectomy, alongside a greater worry about recurrence. This latter finding was supported by a focus group study of women with stage 0-III breast cancer aged less than 40 years, which revealed that women who chose contralateral prophylactic mastectomy were often worried about a future breast event, despite having a low risk.[16]
Narod told Medscape that although genetic testing and the increasing acceptance of bilateral mastectomy as a procedure have both fueled its growth, the reason that has had "the most profound impact is that we've scared women so much."
"There's this high level of baseline anxiety—they're so concerned about daily living under the stress of anxiety that mastectomy is the best way to relieve it," he said. "In other words, there's lots and lots of women out there—and I've seen plenty of them in my clinic—who are being told they have a high risk for cancer, whether it's from a BRCA1 mutation, whether it's from single-nucleotide polymorphisms, whether it's from mammographic density, whether it's from not having kids."
They consequently feel that "it's a matter of time, which translates into this free-floating anxiety, which translates into sleeplessness and some depression, and...other than psychotherapy or drugs, the best cure for that is bilateral mastectomy," Narod added.
Jaskowiak agreed: "Some women are so scared of breast cancer that even if you tell them it's not going to change their survival, they don't want ever to go through what they've just gone through...an abnormal mammogram, additional tests and biopsies, and all that. They want to do anything they can to avoid having to go through all that stuff again."
"I think there's no question that MRI has played a role in this," she said, pointing out that even if the results come back negative, the scrutiny of the other breast and the pain of the procedure is off-putting to women.
Everybody in the chat room says I should just have a bilateral mastectomy.
Jaskowiak believes that social media has also played a role in women choosing contralateral mastectomy. "So many people tell me, 'Oh, well, I went into a breast cancer chat room, and everybody in the chat room says I should just have a bilateral mastectomy.'"
"I don't know how many times I've been told by women about Angelina Jolie, and I have to remind them that they're not Angelina Jolie, that they don't have a mutation, and she never had cancer in the first place," she added.
Yet should anxiety reduction be considered an indication for contralateral prophylactic mastectomy?
Speaking to Medscape, Gandhi said that "the woman might say, 'Well, it doesn't matter to you, but for me it'll make a big difference.'" However, the question of performing mastectomy as a form of anxiety reduction "then becomes not scientific but philosophical," he said.
"If we're reducing the anxiety, then is that not good? On the other hand, we're falsely reducing the anxiety because it has no effect on their prognosis; therefore, it's bad."
Regardless, Gandhi said that "the science is quite secure, but it's very difficult to convince people of that, or it can be, depending on which patient you're dealing with."

Can the Trend Be Reversed? 

For Gandhi, it is clear that the drift toward ever more contralateral mastectomies is something the medical profession "definitely should" be trying to counter.
The medical profession should be trying to do what's scientifically true. 
He said that "scientifically, it's the right thing and the medical profession, at least, should be trying to do what's scientifically true."
However, how that should be achieved is another question.
Jaskowiak said that "this is something that all breast surgeons are struggling with," adding that it will take "a lot of time and a lot of education," involving not just surgeons but also nurses and other staff on the surgical team.
She cited the example of Katharine Yao at NorthShore University HealthSystem in Evanston, Illinois, who has developed a visual decision-making tool to explain risk. "You can tell people that they have a 2.5% chance of getting a breast cancer in their opposite breast in the next 10 years," said Jaskowiak, "but if they see these hundred people and only two of them are lit up, that sometimes ends up helping people."
Gandhi agreed that education is key, saying that more and more people should be told that it makes no difference. However, he feels that "the doctor telling them at the point of diagnosis is probably the least desirable point."
"If they can hear about it before ever having a diagnosis of breast cancer, that would be much better," he said.
One strategy Jaskowiak believes could help reduce the number of bilateral mastectomies is to be more selective about which patients undergo MRI, and another would be if insurance companies reduced the payment for them. "But it doesn't seem very patient-centered to have this figured out by insurance companies," she said. "It seems like doctors should be able to talk to people and educate them."
In the United Kingdom, for example, the rate of increase in contralateral mastectomies has been consistently lower than that in the United States.
Catherine Priestley, a clinical nurse specialist at the charity Breast Cancer Care in London, United Kingdom, said that it may be assumed that "it's got something to do with our healthcare system and the fact that the National Health Service hasn't got the financial resources to do those sorts of things."
"Actually, the decisions are not driven by finance; they're driven by the risk and benefit to somebody as an individual," she said.
"We make a lot of effort in the United Kingdom to dissuade the woman, and one of the reasons for that is, to put it very brutally, we're not paid per case," Gandhi said. "In a healthcare environment where you're paid per case, although ethically you should be giving the correct medical information, there's a part of you that may not do that."
But when it comes down to the decision for an individual patient, Newman stressed that "[i]t is important to address the emotional needs of each breast cancer patient and, as physicians, we should respect a woman's choice for contralateral prophylactic mastectomy."
That is, "as long as the patient is physically fit for the procedure; understands the complications; if she is clear on the fact that her cancer survival rate/treatment needs are driven by the known cancer; and as long as she realizes that she will still require surveillance for developing a new breast cancer or cancer recurrence, despite undergoing the more extensive surgery."
The clinicians who spoke to Medscape for this article have disclosed no relevant financial relationships.

A TELEVISION CANCER DIAGNOSIS

For otolaryngologist Erich Voigt, MD, a lump on the neck is never something to ignore — even if said lump is spotted on the neck of a stranger appearing on a national TV show with unknown whereabouts.
So, when Voigt noticed a woman's lump while casually watching the HGTV program Beachfront Bargain Hunt, he knew he had to act.
"When I noticed the lump, I simply had a feeling that it could be something serious," Voigt, who is director of General and Sleep Otolaryngology at NYU Langone Health in New York City, told Medscape Medical News.
"I paused the TV show, rewound a few times, reviewed the images with a few family members, and then felt obliged to reach out in some way," he said. "I wondered if she knew she had this."
Voigt took to Facebook, sharing a video and voicing his concern: "I am watching a TV show and notice this woman has a left thyroid mass," he posted on his site. "She needs a sonogram and fine needle biopsy. I wonder if she knows and hope it's benign."
It took about 2 weeks, but the posting managed to make its way to the attention of the woman, Nicole McGuinness, 32, who indeed did not know, as her doctors had never noticed the mass. A follow-up biopsy, received in response to Voigt's advice, resulted in a diagnosis of thyroid cancer, and McGuinness was reportedly set to see a surgeon for treatment.
In several subsequent TV appearances related to the story, McGuinness expressed her deep gratitude to Voigt, and the two were brought together in person on an episode of Inside Edition.
"You have no idea how much you've impacted my life," McGuinness told Voigt on the show.
Voigt told Medscape Medical News that in addition to being "very surprised" to learn that his Facebook post successfully made its way to McGuinness' attention, he was alarmed that no one had spotted the lump, even over the passage of time since the show's taping.
"I was surprised that the show she was on was filmed in November 2017 and aired in May 2018 when I saw it, and no one noticed the mass prior to me," he commented.
The case isn't the first time a suspicious mass later determined to be thyroid cancer was brought to an individual's attention thanks to an attentive TV viewer. In an earlier instance in 2013, also involving an appearance on HGTV, a registered nurse spotted a suspicious mass on the neck of Tarek El Moussa, the host of the network's popular program Flip or Flop.
Upon noticing the mass, the nurse, identified in a Today Show report as Ryan Reade, sent an email to the show's producers, alerting them of her suspicions.
As in the subsequent case involving Voigt, the large mass had not been detected by El Moussa's doctors.

After acting on Reade's notification, El Moussa was diagnosed with stage II thyroid cancer, and he went on to undergo surgery and radiation therapy.
In comments to the Today Show, Reade said certain features simply stood out on El Moussa's neck that caught her attention.
"I noticed that at certain angles, at certain times, it just caught my eye that Tarek had a lump on his throat," Reade said, "and I thought it was something that needed to be brought to his attention."

Watchful Eyes Also Spot Potential Skin Cancers 

Thyroid lumps aren't the only suspicious features that attentive viewers have spotted. Television personality Piers Morgan reported being made aware of an alarming "blemish" on his chest by Gillian Nuttall, the founder of Melanoma UK, who noticed it while Morgan was conducting an interview.
Morgan explained in media reports that upon examination, a top dermatologist immediately removed the lesion and informed Morgan that with much further delay it could have turned cancerous. Morgan invited Nuttall to appear on his British TV show Good Morning Britain.  
"Gillian Nuttall, you were my savior," Morgan told Nuttall on the show. "I am living testament to actually getting it checked because you told me to and I'm very grateful to you for that."

"As a Physician, My Role in Life Is to Help Others"

While the cases underscore need for closer checking for lumps or masses during routine exams, they also raise some ethical issues in terms of the clinician's role outside of the clinical setting, particularly considering complicated patient consent and privacy concerns.
Voigt noted that, in compliance with federal laws on health information, he does not discuss his patients' information outside of the clinical setting, but he felt he was not violating any privacy issues in pointing out the lump on Facebook.
"In this unique situation, my conclusion was that this person has already identified herself on television, so I was not revealing anything that was not already in the public eye," he said.
"She is not my patient; however, I chose not to type her name in my post and simply identified the TV show. Additionally, when the media contacted me to discuss the case, I referred them to her and let her make decisions regarding any media participation," he explained.
Voigt meanwhile said that with the media attention regarding his case, he has received "an overwhelming outpouring of kind words to me from people all over the globe about helping a stranger."
He expressed having no reservations about reaching out to offer help even outside of the clinical setting.
"As a physician, my role in life is to help others, not only in my office, but in daily life," Voigt said.
"I am asked very frequently for medical advice when I am not 'working,' and I provide whatever information I can," he said."However, I tell people to see their doctor and get appropriate tests and treatment."
"If I see something that looks dangerous or serious I will reach out to help," he added.

"If You See Something, Say Something"

Approached for comment, Peter Angelos, MD, PhD, chief of Endocrine Surgery and associate director of the MacLean Center for Clinical Medical Ethics at the University of Chicago, agreed that the confines of the clinic should not represent boundaries of offering patients help, when possible.
"I do not see there being a major ethical issue if, for example, I see something concerning and suggest to someone that they should see their physician to have it checked out," he told Medscape Medical News.
"It is much like a good Samaritan telling another driver that they have a flat tire. The driver of the car with the flat tire would never know if someone didn't notify him or her of the problem," Angelos said.
"Certainly, in the era of social media, it may be easier to contact even those that we may not have a relationship with. However, I would still consider this a matter of being a good Samaritan where it is good to help, but not mandatory," he added.
In terms of Voigt's case, while a lack of details on McGuinness' medical background prevents speculation about earlier detection of the lump, Angelos says the case nevertheless serves as a reminder that thyroid nodules may be lurking, unnoticed by the patient.
"The case does certainly emphasize the importance of a thyroid examination in the course of a routine physical examination," he said.
"And if you see something concerning in another person, do them the favor of bringing it to their attention and suggesting that a physician be consulted for an appropriate workup — in other words, 'If you see something, say something,' " he said.
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POSITIVE CHEMOIMMUNOTHERAPY TRIAL OF TRIPLE NEGATIVE BREAST CANCER

Swiss drugmaker Roche said on Monday that a trial showed its immunotherapy Tecentriq (atezolizumab) plus the chemotherapy Abraxane (paclitaxel protein-bound) significantly reduced the risk of disease worsening or death in people with metastatic triple negative breast cancer.
The company, citing its IMpassion130 study, said it also recorded an encouraging overall survival benefit for the PD-L1 positive population, whose tumours express a protein that help them evade immune system detection, at interim analysis.
The Basel-based company called this the first Phase III immunotherapy study in first-line metastatic triple negative breast cancer to demonstrate a statistically significant improvement in progression-free survival in key patient groups, including the conservative intention-to-treat population.
Patients with triple-negative breast cancer test negative for hormone receptors or HER2, meaning their tumours do not respond to hormone therapy or to therapies like Roche's $7 billion-per-year blockbuster Herceptin.
As a result, there is significant interest in finding new, better ways to tackle this form of the disease.
"Highly encouraged by these results, we plan to submit to health authorities globally with the aim of bringing this combination to people with triple negative breast cancer as soon as possible," Roche Chief Medical Officer Sandra Horning said in a statement.
About 12 percent of breast cancers diagnosed in the United States are triple negative, according to the American Cancer Society.

ADJUVANT CHEMOTHERAPY FOR ER+ BREAST CANCER

Adjuvant breast cancer treatments—chemotherapy, human epidermal growth factor receptor 2 (HER2)–targeted therapies, and endocrine therapy—prevent recurrence and extend survival. Unfortunately, because risk assessment is imprecise and treatments are not uniformly effective, many women are treated to benefit a small number. If these therapies were entirely harmless, we would have few qualms about overtreatment. Chemotherapy has the most onerous short-term side effects and is the treatment that patients most wish to avoid. Moreover, long-term toxicities include secondary leukemia, heart failure, neuropathy, premature menopause, and infertility. Some women who receive adjuvant chemotherapy do not return to work or face difficulty in role functioning.[1,2] The recognition that benefits are limited and that toxicity can be formidable has led to gradual adjustments in most oncologists' approach. There has also been a steady improvement in prognosis over the past decades, partially attributed to better outcomes associated with screen-detected cancers.[3,4]
Over the past 15 years, multiple genomic assays have been developed that more precisely characterize the risk of developing recurrent breast cancer.[5] The 70-gene assay (Mammaprint) was evaluated in a complex randomized trial, which demonstrated that women with clinically high-risk but genomically low-risk cancers derive little benefit from adjuvant chemotherapy.[6] In the United States, the most widely used genomic assay for estrogen receptor–positive (ER+) breast cancer is the 21-gene recurrence score (RS). In 2004, Paik et al. demonstrated that the RS was prognostic in a group of node-negative patients.[7] Subsequently, these investigators found that the RS was predictive of chemotherapy benefit and that patients with low and intermediate scores do not appear to achieve substantial risk reduction.[7,8] The results of randomized trials are pending, but US oncologists have embraced the RS in decision-making. Its use, initially in node-negative patients, has expanded to include many women with node-positive disease, particularly those with limited lymph node involvement.[9]
Kurian and colleagues demonstrate that use of adjuvant chemotherapy for patients with stage I–II ER+/HER2- disease declined from 26.6% to 14.1% and 81.1% to 64.2% among node-negative and node-positive patients, respectively, between 2013 and 2015.[10] The frequency of RS use remained unchanged among node-negative patients. RS use increased among node-positive patients from 26.1% to 42.7%, but the authors determined that the test accounted for only one-third of the decline in chemotherapy administration. The increased use of RS among node-negative patients extended for years beyond the initial publications.[11] Similarly, uptake in node-positive patients appears to be evolving gradually since the 2010 publication.[9]Data from the prospective randomized trials with RS will likely lead to increased and more informed use in the future, particularly if the trials substantiate the retrospective studies.[12]
There is little doubt that genomic assays that predict risk and possible chemotherapy benefit have played a major role in reduction of chemotherapy utilization. But genomic assays are only part of the story. With the advent of targeted therapy for breast cancer, both oncologists and their patients appear less willing than in the past to take a toxic treatment for a very small benefit. In the 1990s, the assumption that guided oncologists was that a benefit as small as 1% would be sufficient for patients to accept adjuvant chemotherapy.[13–15] While there is a high degree of variability in patient preferences, our strong sense is that such small benefits are no longer acceptable. Oncologists have also found that they can identify patients at very low risk of recurrence based on clinical characteristics (tumor size, nodal status, hormone receptors, grade). Some oncologists may even skip ordering a genomic assay if they believe the score is likely to be favorable, particularly if other patient characteristics suggest that risks of treatment are likely to outweigh benefit.
The decline in chemotherapy use from 2013 to 2015 also coincided with changes in Medicare Part B reimbursement mandated by budget sequestration, which went into effect in March of 2013. This legislation cut payments by 2%, yielding a reduction in the margins that oncology practices generate from the "buy and bill" model of chemotherapy delivery. Whether this change in reimbursement directly altered provider behavior is not clear, but there has been a shift in chemotherapy administration from smaller practices to hospitals, where physicians may derive less financial incentive to prescribe chemotherapy.[16]
Although there were no major changes in adjuvant chemotherapy guidelines during the study period, a National Comprehensive Care Network database study demonstrated excellent outcomes for patients with small ER+/HER2- tumors not treated with chemotherapy with distant recurrence-free survival rates of 98% (T1a) and 96% (T1b).[17] These data suggest that most patients with small ER+ tumors should not receive chemotherapy and may have also led to a decline in chemotherapy use.
Genomic expression assays may ultimately have an even greater impact on the management of young women with ER+ breast cancer, a population that faces the long-term consequences of treatment toxicities. Due to the small proportion of young women in NSABP B14 and B20 and the increased risk of recurrence in very young women,[18] many oncologists have been uneasy trusting a favorable genomic assay in a young patient with node-negative disease. Predictive evidence of the RS in node-positive patients remains limited to postmenopausal women.[9] Nonetheless, it is likely that the RS assay and other genomics predictors reflect disease biology that is independent of age. It is known that young women with ER+ disease do indeed have outcomes inferior to their older counterparts,[19] but there is reason to believe that this disparity may relate to the adequacy of endocrine therapy in young women. Recent data from the SOFT trial clearly indicate that many young women can be effectively managed with endocrine therapy alone.[20–22]
In spite of our increasing ability to identify patients with more indolent tumors and excellent outcomes, de-escalation of treatment remains a challenge. While the Kurian study[10] demonstrated that the proportion of oncologists who recommended chemotherapy in the "less favorable" scenario dropped from 91.3% to 56.4% after the low RS was revealed, limiting chemotherapy use in real time is far more vexing than when one sits in front of the computer monitor. It is both understandable and easier for most oncologists to err on the side of overtreatment than undertreatment. As clinicians, we fear omitting a therapy that could be life saving, but benefits and toxicities must be balanced. Clinical trials such as TAILORx and RxPONDER will likely identify patient populations that can safely forego chemotherapy. For those who do still receive chemotherapy, recent data support limiting anthracyclines to women with higher-risk features, thus reducing long-term complications.[23]
De-escalation of therapy is not a concept that is confined to ER-positive and HER2-negative disease. In the setting of HER2-positive and triple-negative disease, several agents—capecitabine, platinum, pertuzumab, and neratinib—have been used to escalate the intensity of treatment.[24–27] Although these approaches represent advances, the benefits for an individual are often marginal. Whether we are focusing on traditional chemotherapy or targeted approaches, we must strive to integrate prognostic biomarkers such as pathologic complete response and develop new prognostic and predictive biomarkers. Our goal is to provide the adjuvant treatment that allows each patient to remain cancer free and, at the same time, avoid unnecessary toxicity. Kurian and colleagues[10] demonstrate substantial progress in the de-escalation of treatment for patients with stage I–II ER+ disease over a span of only two years. We hope and anticipate that such trends will continue and expand to other subgroups of patients.

PREDICTIVE SCORE FOR MALIGNANT PLEURAL EFFUSION

The PROMISE score accurately predicts three-month mortality in patients with malignant pleural effusion, according to a new report.
Treatments for malignant pleural effusion have expanded during the past decade, but the factors that drive malignant progression, resistance to therapy and mortality are poorly understood.
Dr. Ioannis Psallidas from Oxford University Hospitals NHS Foundation Trust, in Oxford, UK, and colleagues used data from five different clinical groups to develop and validate PROMISE, the first score dedicated to the prospective assessment of survival in patients with malignant pleural effusion.
The final PROMISE score assigned points for seven clinical elements (chemotherapy, radiotherapy, blood test results, cancer type and performance status) and added points for tissue inhibitor of metalloproteinases 1 (TIMP1) concentration as the biological element.
The overall PROMISE score (clinical plus biological) showed good discrimination between patients in the external validation dataset who died within three months and those who survived (C statistic, 0.90), the team reported in The Lancet Oncology, online June 13.
PROMISE scores were used to classify patients into four categories of risk for three-month mortality: A, less than 25% (0-20 points); B, 25% to less than 50% (21-27 points clinical, 21-28 points biological, i.e., including TIMP1); C, 50% to less than 75% (28-35 points clinical, 29-35 points biological); and D, 75% or more (>35 points clinical, >37 points biological).
In terms of survival discrimination, PROMISE outperformed the LENT score, which predicts patient survival on the basis of tumor type, pleural fluid lactate dehydrogenase (LDH), performance status and blood neutrophil-to-lymphocyte ratio.
"Although future confirmatory studies are required, the PROMISE score (either clinical or biological) could potentially be used in everyday clinical practice as a method to improve patient management and reduce associated health-care costs, and as an enrichment strategy for future clinical trials," the researchers conclude.
"Individuals with a PROMISE score category A (with <25 a="" absolute="" aggressive="" and="" be="" category="" correlates="" could="" d="" death="" for="" good="" management="" more="" n="" of="" oncological="" or="" particularly="" patients="" pleural="" potential="" prognosis="" promise="" risk="" score="" selected="" surgical="" these="" they="" with="" write.="">=75% absolute risk of death), it is reasonable to offer minimally invasive procedures aimed at symptom control (e.g., therapeutic aspiration or indwelling pleural catheter insertion), best supportive care, and a strategy to spend as few days as possible in hospital."
"Although clear recommendations cannot be given for patients with scores in categories B and C, the PROMISE study score provides a personalized absolute risk of death that can be openly discussed during clinical consultation and can be used as a basis for rational patient choices of further treatments offered," they note.
"The effect of adding TIMP1 to the standard prognostic factors is very modest," write Dr. Paul Baas and Dr. Sajak Burgers from the Netherlands Cancer Institute, in Amsterdam, in a related editorial. "Inclusion of TIMP1 only contributed 2 of the maximum of 43 points (C-reactive protein contributed ten points), which underlines its limited value. The proposed new prognostic score might not be practice changing."
"Effective antitumor treatment remains one of the best therapies for malignant pleural effusions," they note. "A multitude of therapies have evolved over the past decade. Targeted treatment and immunotherapy are the best examples. The optimal approach of patients with symptomatic pleural effusions will be a balance between an optimal systemic antitumor treatment and local pleural fluid control."
Dr. Psallidas did not respond to a request for comments.
SOURCE: https://bit.ly/2lKBp3A and https://bit.ly/2tEiFXM
Lancet Oncol 2018.

YOUNG PATIENTS WITH RECTAL CANCER-A SPECIAL CATEGORY?

Patients younger than 50 years with stage II or III rectal cancer do not appear to benefit from guideline-driven treatment recommendations in terms of overall survival compared with older patients who do benefit from those recommendations, a retrospective view of the National Cancer Data Base (NCDB) indicates.
Lead author Atif Iqbal, MD, University of Florida College of Medicine, Gainesville, and colleagues explain that the "National Comprehensive Cancer Network (NCCN) guidelines define the current standard of care for the intended cure of rectal cancer as surgical resection alone for stage I disease and as neoadjuvant chemoradiation therapy with subsequent surgical resection and systemic chemotherapy for stage II and III disease."
"For stage II and III disease, younger patients are more likely to receive NCCN guideline-driven care...but this does not seem to affect their survival," the researchers add.
"In contrast, older patients show a large and significant survival benefit from it," they add.
The study was published online July 9 in Cancer.
This is a finding that should "open the eyes" of all involved in the treatment of rectal cancer, in view of the "alarming trend" of an increase in diagnoses of colorectal cancer in younger patients, comments the author of an accompanying editorial.

Study Details

Data analyzed for the study included all patients diagnosed with rectal cancer from 2004 through 2014. The final analysis included 5591 rectal cancer patients younger than 50 years and 19,348 rectal cancer patients aged 50 to 75 years.
"The younger cohort had better short-term mortality and long-term survival rates than their older counterparts," the investigators note. The 30-day mortality rate was 2% for older patients vs 0.2% for younger patients; the 90-day mortality rate was 3.7% for older patients vs 0.5% for younger patients (< .001 for both endpoints).
"This difference became more pronounced with 3-, 5-, and 10-year survival rates...and it persisted independently for stage I, II, and II disease," the investigators add.
Among older patients with stage II or III disease, the survival benefit for those who received stage-appropriate treatment was 14% at 5 years; that survival benefit persisted to 10 years.
Younger patients with stage I disease gained a survival benefit when treated according to guideline-driven care.
In contrast, guideline-driven care did not confer a survival benefit among younger patients with stage II or III disease, the investigators emphasize.
"Our data suggest that patients younger than 50 years with rectal cancer differ at presentation in comparison with the more aged cohort," the team states.
For example, such patients are more likely to be female, belong to a minority group, and lack insurance.
They are also more likely to present with a higher stage of disease and have worse tumor characteristics compared with older patients.
"This study uses a large national cancer database to demonstrate that patients younger than 50 years diagnosed with rectal cancer represent a unique demographic group in which the survival advantage of receiving NCCN guideline-driven therapy for stage II and III disease does not materialize," the investigators state.
"This analysis supports the notion that early-onset rectal cancer may differ in its biology and response to therapy, as has been previously shown in colon cancer," they suggest.

"Time to Take Notice"

In an accompanying editorial, Matthew Kalady, MD, Cleveland Clinic, Ohio, suggests that this study should "open the eyes" of all involved in the treatment of rectal cancer as well as those who make recommendations to help guide therapy and formulate screening policies.
"The alarming trend of increased CRC [colorectal cancer] in the young population should make us stand up and take notice," Kalady writes.
"We need to evaluate why this is happening and explore the unique characteristics that define this population and potential differences in comparison with older age rectal cancers," he adds.
The fact that most recommendations for the management of rectal cancer are based on studies of older patients may explain at least part of treatment response observed among younger patients in the current study, Kalady suggests.
But the lack of survival benefit seen in younger patients treated according to NCCN guidelines may also have something to do with limitations inherent in the database that was used in the analysis.
As Kalady points out, "half of all patients with rectal cancer in the NCDB were excluded from the analysis because of missing data; including one-third of the patients without clinical stage information, which is the key determinant in treatment planning," he points out.
Information such as the location of the tumor within the rectum, circumferential margins, lymph node involvement, and the quality of the surgical specimen was also not available, "all of which influence cancer outcomes," Kalady also notes.
The current analysis also does not examine either the risk for local recurrence or disease-free recurrence, both of which are important endpoints in rectal cancer outcomes in addition to overall survival.
"[I]t is our responsibility to continually evaluate our approach to CRC prevention, screening, and treatment," Kalady writes.
"Furthermore, there needs to be a concerted effort not just for the care of patients with rectal cancer (young and old) but also toward understanding the differences in the biology of these tumors, if there are any," he suggests.
"It is time to take notice," Kalady concludes.
The study was supported in part by funds from the National Institutes of Health, the American Cancer Society, the National Cancer Institute, Elekta AB, the National Center for Research Resources, and the National Center for Advancing Translational Sciences. Dr Iqbal has disclosed no relevant financial relationships. Coauthor Thomas J. George Jr, MD, has acted as a consultant for Merck and Bayer for work performed outside of the current study. His institutional research has been supported by Incyte, Bristol-Myers Squibb, Bayer, Merck, NewLink, AstraZeneca/Med-Immune, and Tesaro. Dr Kalady has disclosed no relevant financial relationships.
Cancer. Published online July 9, 2018. AbstractEditorial

GENETIC RISK FACTORS FOR LEUKEMIA

Early genetic changes may be key to identifying seemingly healthy individuals who face an increased risk of developing acute myeloid leukemia (AML), according to new findings.
These findings illuminate the "black box of leukemia" and answer the question of where, when, and how the disease begins, said study coauthor John Dick, PhD, senior scientist at Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario,  Canada
"We have been able to identify people in the general population who have traces of mutations in their blood that represent the first steps in how normal blood cells begin on a pathway of becoming increasingly abnormal and puts them at risk of progressing to AML," he said in a press release.
"We can find these traces up to 10 years before AML actually develops, and this long time window gives us the first opportunity to think about how to prevent AML," he added.
The study was published June 9 in Nature.
The incidence of AML increases with age, and mortality exceeds 90% when it is diagnosed after age 65 years, note the authors. However, most patients remain initially asymptomatic and generally present with acute complications of bone marrow failure.
The current study builds on research from 2014, when Dick and colleagues identified a preleukemic stem cell in blood samples obtained at the initial diagnosis of AML. The preleukemic stem cell, they noted, continues to maintain normal function but has begun the process of generating a pathway of cells that become increasingly abnormal and culminate in  AML.
"Our 2014 study predicted that people with early mutations in their blood stem cells, long before the disease appears and makes them sick, should be able to be detected within the general population by testing a blood sample for the presence of the mutation," Dick explained in the press statement.

Identifying AML vs ARCH

For their study, Dick and colleagues collaborated with the European Prospective Investigation Into Cancer and Nutrition (EPIC) study, which tracked 521,000 participants recruited across 10 European countries and followed them for almost 15 years. Stored blood samples from this trial were used to determine the genetic changes were already present years before AML actually developed.
The onset of AML is generally preceded by the accumulation of somatic mutations in preleukemic hematopoietic stem and progenitor cells (HSPCs) that undergo clonal expansion, but recurrent AML mutations also accumulate in HSPCs of healthy individuals who do not develop AML. This benign process is known as age-related clonal hematopoiesis (ARCH). The authors first conducted deep sequencing to differentiate between individuals who have a high risk of developing AML and those with benign ARCH.

The team identified 95 individuals who had participated in the EPIC trial and then went on to develop AML, and they found blood samples that were obtained an average of 6.3 years before diagnosis.
They also identified 414 unselected age- and sex-matched controls.
When they compared peripheral blood cells between the cases and controls, they found distinct genetic differences, with cases showing more mutations per sample, higher variant allele frequencies, and enrichment of mutations in specific genes.
Genetic parameters were used to develop a model that accurately predicted AML-free survival, which was validated in an independent cohort of 29 pre-AML cases and 262 controls.
In the combined initial and validation cohorts, the authors observed that ARCH, defined on the basis of putative driver mutations (ARCH-PD), appeared in 73.4% of the pre-AML cases at a median of 7.6 years before diagnosis but was detected in only 36.7% of controls (P < 2.2 × 10−16, two-sided Fisher exact test). In addition, 39% of pre-AML cases who were older than age 50 years had a driver mutation with a variant allele frequency of more than 10% vs 4% of controls.
DNMT3A and TET2 were the most commonly mutated genes in both groups, and canonical NPM2 mutations or FLT3-internal tandem duplication mutations were not observed, which is consistent with previous findings that these mutations occur late in leukemogenesis.
Another observation was that recurrent CEBPA mutations, which have been implicated in about 10% of de novo AML cases, were also not observed, suggesting that driver events in this gene may also occur late in the disease process.
"Overall, these findings demonstrate notable differences in the mutational landscape of ARCH and pre-AML," they note. "Moreover, this work, in conjunction with recent insights into the origins of AML relapse, suggests that AML progression typically occurs over many years through clonal evolution of pre-leukaemic HSPCs before acquisition of late mutations leads to overt malignant transformation."
Coauthor George Vassiliou, FRCPath, MRCP(UK), PhD, from the Wellcome Sanger Institute and the Wellcome-MRC Cambridge Stem Cell Institute, and consultant hematologist at Cambridge University Hospitals NHS Trust, outlined plans for future research in a press statement.
"We hope to build on these findings to develop robust screening tests for identifying those at risk and drive research into how to prevent or stall progression towards AML," he said. "Our aspiration is that one day AML prevention would provide a compelling alternative to treatment."
The UHN research team was funded by the Leukemia and Lymphoma Society, Ontario Institute for Cancer Research, Canadian Cancer Society, Canadian Institutes for Health Research, International Development Research Centre, Terry Fox Research Institute, Medicine by Design– Canada First Research Excellence Fund, the Benjamin Pearl Fellowship from the McEwen Centre for Regenerative Medicine, the Ontario Ministry of Health and Long-term Care, and The Princess Margaret Cancer Foundation; also funded by the Wellcome Trust, UK Medical Research Council, Cancer Research UK. The authors have disclosed no relevant financial relationships. 
Nature. Published online June 9, 2018. Abstract
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NO INCREASED CANCER RISK FOR WOMEN UNDERGOING IVF

Women who receive assisted reproductive technology, such as in vitro fertilization (IVF), have no increased risk of invasive breast or uterine cancer, according to a new population-based study of more than 250,000 British women.
The study, published online July 11 in BMJ by Carrie L. Williams of UCL Great Ormond Street Institute of Child Health, in London, UK, and colleagues, did show increases in all types of ovarian cancer; however, those increases were limited to women with other known risk factors.
"The women showed an increased risk of ovarian cancer, but only a few extra cancers per year and only when they had known risk factors, suggesting this was not due to the IVF," senior investigator Alastair G. Sutcliffe, MD, also of UCL Great Ormond Street Institute of Child Health, told Medscape Medical News.
There was also an unexpected small increased risk of in situ breast cancer, most notably in those who had the greatest number of assisted-reproduction treatment cycles.
"The only surprise was the increase in in situ breast cancer, however it was very slight — just 1 in 50,000 women who have had an IVF cycle would have that extra risk," Sutcliffe commented.

Carcinogenicity Concerns of High Hormone Levels

The repeated exposures to high levels of hormones including estradiol, exogenous gonadotropins, and numerous punctures to the ovaries that occur with assisted reproduction have raised concerns about possible carcinogenic effects. However, findings from previous studies looking at rates of breast, endometrial, and ovarian cancers in women receiving the treatments have been inconsistent, and most studies have been relatively small.
To evaluate the risk in a larger population, Sutcliffe and colleagues studied records from 255,768 women who received assisted-reproduction treatment in Great Britain between 1991 and 2010, as documented by the Human Fertilization and Embryology Authority, and linked the information with data from national cancer records. They then compared cancer rates in those who had received IVF or other assisted-reproduction treatments with expected rates in the general population.
The average age of first assisted-reproduction treatment was 34.5 years, and the women had an average of 1.8 treatment cycles, with only 20% (50,485) having more than two stimulated cycles.
With an average follow-up of 8.8 years and a maximum follow-up of 19 years, there were no significant increases in the risk of uterine (corpus uteri) cancer (164 cancers observed vs 146.9 cancers expected in the general population; standardized incidence ratio [SIR], 1.12; 95% CI, 0.95 - 1.30).
The overall incidence of breast cancer was also not increased (2578 vs 2641.2 cases; SIR, 0.98; 95% CI, 0.94 - 1.01), nor was the incidence of invasive breast cancer (2272 vs 2371.4 cases; SIR, 0.96; 95% CI, 0.92 - 1.00).
The relatively small increased risk of in situ breast cancer (291 vs 253.5 cases; SIR, 1.15; 95% CI, 1.02 - 1.29) was primarily associated with having five or more treatment cycles (P = .03), which was uncommon, the researchers note.
The overall incidence of ovarian cancer was increased relative to the general population (SIR, 1.39; 95% CI, 1.26 - 1.53), but this higher risk was only seen in women with known risk factors for endometriosis, low parity, or both.
There were no increases in ovarian cancer rates among women who received fertility treatment only because of male factors or unexplained infertility.
Overall, the causes of infertility included having at least one female-related factor in 44% of women, only male-related factors in 33%, and in 19% of cases, the cause of infertility was unexplained.
Approximately half the study population had at least one live birth following completion of treatment.

Perplexing Findings on In Situ Breast Cancers; More Work Needed 

The authors noted that the link between in situ breast cancers and treatment cycles was somewhat perplexing.
"Interpretation of these findings is challenging: the significant association with increasing number of cycles suggests a causal association, yet there was no overall increased risk of breast cancer," the authors write.
"To our knowledge, this study is the first to analyze risks of in situ and invasive breast cancers after assisted reproduction separately, so there are no previous data with which to compare."
The findings on the ovarian cancer risk meanwhile are consistent with previous studies, which have generally also shown an increased risk that lost significance after adjusting for the confounding effects of infertility.
Although this study had relatively long follow-up, the authors acknowledge they may have missed some cancers that take many years to develop.
"Our study comprised over 250,000 treated women, including almost 65,000 person-years of follow-up for at least 15 years beyond last treatment, with an average follow-up of 8.8 years and a maximum follow-up of 19 years," they explain.
"However, we cannot exclude the possibility of different risk profiles for any studied cancer on longer follow-up, at ages when most reproductive-related cancers occur."
Importantly, the wide array of factors that could play a role in infertility and important differences compared with the general population following assisted-reproduction technology require continued investigation as possible factors in the risk of cancer, the authors underscore.
"Women treated with assisted reproduction are likely to differ from the general population in their parity, age at first birth, age at menopause, and endometriosis," they stress.
"More information on these and other factors [including] socioeconomic status, oral contraceptive use, body mass index, and breastfeeding would be useful."
The study was funded by Cancer Research UK, National Institute for Health Research, Great Ormond Street Hospital for Children NHS Foundation Trust, and University College London. Sutcliffe's research was partly funded the Medical Research Council. Coauthor Ian Jacobs received funding from Breast Cancer Now. 
BMJ. Published online July 11, 2018. Abstract
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