Chemotalk Newsletter

Chemotalk Newsletter, Vol. 105 January 1, 2017

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Beginning 2017 with a request.  If you, or anyone you know, has interest in a particular form of cancer, or MS, please let me know so that I can keep an eye out for articles relative to that disease.


By Leah Lawrence

Patients with ACUTE MYELOID LEUKEMIA (AML) or MYELODYSPLASTIC SYNDROME (MDS) with unfavorable risk cytogenetic profiles, TP53 mutations, or both had good clinical response and robust mutation clearance when administrated serial 10-day cycles of decitabine, according to the results of a single-institution study published in the New England Journal of Medicine.

According to John S. Welch, MD, PhD, of Washington University School of Medicine in St. Louis, and colleagues, the trial was designed to identify markers that might help predict response or resistance to single-agent decitabine.

"Decitabine as a single agent is not a cure for anyone with these diseases: the rapid selection of resistant subclones by decitabine and the incomplete clearance of leukemia-specific mutations (even in patients who have a response) explain why remissions are generally short-lived," Welch and colleagues wrote. "However, the use of decitabine may be an important way to induce clinical remissions in patients with AML who have TP53 mutations and who have disease that is notoriously resistant to induction therapy with standard cytotoxic chemotherapy."

The study included 84 patients with AML or MDS. Patients were given decitabine 20 mg/m2 per day for 10 days in monthly cycles. Patients underwent two types of testing: 67 patients had enhanced exome or gene-panel sequencing and 54 patients had serial sequencing at multiple time points to evaluate patterns of mutation clearance. In addition, there was an extension cohort of 32 patients who received decitabine in different protocols.

Of the 116 total patients, a little less than one-half (46%) of patients had bone marrow blast clearance defined as < 5% blasts.

Patients with unfavorable-risk cytogenetic profile had a response rate of 67%. This was significantly higher than that seen in patients with intermediate-risk or favorable risk-cytogenetic profiles (34%; P < .001). Additionally, those patients with TP53 mutations had a response rate of 100% compared with 41% in patients with wild-type TP53 (P < .001).

"TP53 mutations form the nexus of the worst prognostic group in AML and MDS," the researchers wrote. "These data suggest an alternative upfront strategy for the treatment of this group of ultra-high-risk patients that will need to be verified in prospective trials."

Of the 54 patients who had serial sequencing, the researchers found that only two gene mutations (TP53 and SF3B1) had consistent, rapid reduction in variant allele frequency to levels of < 5%. In addition, bone marrow blast clearance often preceded mutation reduction and mutation clearance was never complete, they noted.

The researchers also looked at samples from 20 patients with bone marrow blast clearance after day 28 of cycle 2.

"In these patients, we were able to detect leukemia-specific mutations during morphologic remission. This indicated that decitabine leads only to incomplete clearance of disease," the researchers wrote.

Among the patients who had gene-panel sequencing, 14 had TP53 mutations. Of those, 14 of 14 had blast clearance with decitabine and 17 of 46 with wild-type TP53 had blast clearance (P < .001).

Welch and colleagues noted that previous studies have shown that patients with unfavorable risk profiles and TP53 mutations who are treated with cytotoxic chemotherapy have poor outcomes. However, in this study, neither of these factors was associated with a lower rate of overall survival than the rate seen in patients with intermediate-risk cytogenetic profiles.

In an editorial that accompanied the study, Elihu Estey, MD, from the University of Washington Medical Center in Seattle, wrote that the results of this trial indicate that "patients with AML and TP53 mutations, which are readily detectable with the use of validated commercial platforms, should receive decitabine for 10 days, as might the far larger group of patients with unfavorable-risk cytogenetic profiles."

In addition, Dr. Estey wrote that the trial "points to inevitable, rational replacement of large trials in which homogeneous therapy is administered for a heterogeneous disease by smaller, subgroup-specific trials."

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By Dave Levitan

A retrospective review showed that primary cytoreductive surgery (PCS) was associated with longer survival than neoadjuvant CHEMOTHERAPY (NACT) in women with advanced-stage epithelial OVARIAN CANCER. This could be explained by poorer performance status among those undergoing NACT, however.

"The role of NACT in the treatment of epithelial ovarian cancer remains controversial," wrote study authors led by J. Alejandro Rauh-Hain Fernandez, MD, of Massachusetts General Hospital in Boston. Several retrospective studies have favored PCS over NACT, while two phase III randomized trials demonstrated noninferiority of NACT in women with high disease burden. All the studies have had some methodologic issues, though.

The new analysis included 22,962 women under the age of 70 included in the National Cancer Database who were treated for stage IIIC and IV epithelial ovarian cancer who were diagnosed between 2003 and 2011. Of those, 19,836 (86.4%) were treated with PCS, and 3,126 (13.6%) received NACT; a propensity-matched analysis included 2,935 patients from each treatment group. The results were published online ahead of print in JAMA Oncology.

The median overall survival duration in the propensity-matched analysis was 37.3 months with PCS, and 32.1 months with NACT, for a hazard ratio (HR) of 1.18 (95% CI, 1.11­1.26). Both groups saw improved survival in later years of the study period compared to earlier years of diagnosis, but the association of improved survival with PCS remained as both groups¹ survival lengthened.

The difference was slightly more pronounced in stage IIIC patients, with an HR of 1.24 (95% CI, 1.11­1.37) in favor of PCS. In stage IV patients, the HR was 1.13 (95% CI, 1.04­1.23).

Sensitivity analyses of unobserved variables found that the results would be robust to large differences in prevalence of high disease burden and to BRCA mutation status. However, the improvement in survival could be explained by differences in performance status; if 60% of women receiving NACT had an ECOG performance status of 1 to 2 compared with 50% in the PCS group, that would negate the difference in survival.

"Such information will be important to collect for future observational studies," the authors wrote. "Future research should focus on which patients benefit most from PCS or NACT to tailor the treatment of women with advanced-stage epithelial ovarian cancer."

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by Marie McCullough

An experimental immune therapy temporarily wiped out tumors in the brain and spinal cord of a patient with recurrent GLIOBLASTOMA, one of the most lethal of all cancers.

Suffering from a deadly brain cancer that had spread to his spine, City of Hope patient Richard Grady experienced a novel therapy which helped his immune system attack his disease shrank his tumors

Researchers at the City of Hope in Duarte, Calif., genetically engineered 50-year-old Richard Grady's own T cells to attack his tumors, which shrank and disappeared over 7.5 months. Although the Seattle man's cancer then recurred, he remains alive 15 months after he was told he had only weeks to live.

The case is reported this week in the New England Journal of Medicine. Earlier this month, the journal published another remarkable but solitary case: National Cancer Institute researchers isolated rare, tumor-penetrating T cells from a metastatic COLON CANCER patient, then multiplied and marshaled them to target the gene mutation driving her disease ‹ a formidable mutation previously called "undruggable."

While individual experiences usually do not carry much scientific weight, immunotherapy researchers say these cases bolster hopes that personalized T-cell treatment can work on solid malignancies, including the deadliest types.  Experimental therapies using these immune soldier cells have been highly effective only in BLOOD CANERS and MELANOMA.

"I think there has been a lot of skepticism about using T cells in solid tumors," said City of Hope cancer immunologist Christine E. Brown, lead author of the glioblastoma report. "Even one case is important for the field."

Stephen Gottschalk, a pediatric oncologist involved in T-cell research at Baylor College of Medicine in Houston, agreed. "The overall sentiment is that T cells don't work for solid tumors," he said. "This is one of the first examples where a patient with disseminated glioblastoma responds. I think it's quite dramatic."

Mark Gilbert, chief of the neuro-oncology branch at the National Cancer Institute, reacted more cautiously: "Whether this one case translates into clinical progress or is just an anomaly based on some unique aspect of this patient's cancer, time will tell. It's obviously very interesting."

Many questions remain about the best molecular targets for T cells, how to avoid toxic side effects, and the most effective way to give the therapy.

City of Hope has treated 10 patients with repeated injections of the bioengineered T cells through a catheter into a brain tumor cavity, the hole left by surgical removal of a tumor.

That protocol did not stop new tumors from appearing in Grady's brain as well as his spine. (His cancer was originally diagnosed in November 2014 and recurred just six months after surgery, chemotherapy, and radiation.)

So the City of Hope doctors modified their protocol, using an intracranial catheter to inject T cells into the cerebrospinal fluid that bathes the brain and flows down into the spinal cord.

Grady received 16 T-cell infusions. Seven tumors in his brain and eight in his spine ultimately became undetectable on imaging scans. About halfway through the 7.5 months of treatment, he felt so good that he was gradually weaned from a powerful steroid ‹ used to reduce brain swelling as the cancer grows ‹ and  "returned to normal life and work activities," Brown and her co-authors wrote.

To put Grady's case in context, the median survival for recurrent glioblastoma patients is three to six months, Brown said.

The researchers also said it was "particularly noteworthy" that Grady suffered relatively minor side effects ‹ fever, fatigue, body aches ‹ because many T-cell trials have been hampered by severe, even fatal, immune system overstimulation and toxic neurological effects. They now plan to modify their study so more patients can get the dual T-cell infusions.

Despite Grady's manageable side effects, University of Pennsylvania neurosurgeon Donald M. O'Rourke questioned using such an invasive and risky delivery approach.

O'Rourke is leading a study that has treated 10 glioblastoma patients with a single large dose of T cells given through a vein. The cells penetrated the protective barrier of the brain ‹ an insurmountable obstacle for most conventional drugs ‹ and infiltrated tumors without serious side effects. But, as with almost all pilot studies, it is too soon to tell if the treatment is effective or can be enhanced to become so.

"We're hopeful we can build on this," O'Rourke said.

Gottschalk said Baylor researchers also had seen "encouraging" signs in a T-cell trial for glioblastoma.

The trials at City of Hope, Baylor, and Penn are each targeting a different molecular marker, or antigen, on brain tumor cells.

The City of Hope's target antigen is active in about 60 percent of glioblastoma patients, studies suggest. The antigen was not uniformly present, however, and was only moderately abundant on Grady's tumor cells.

"One of our questions," Brown said, "is what level of antigen we need to see responses" to the T cells' attack.

Another question is whether T cells can be programmed to attack multiple antigens at once, because aggressive, fast-mutating cancers like glioblastoma can quickly evolve to make less of the telltale marker. Molecular tests indicated that was what happened to Grady, accounting for his amazing but transient remission.

A T cell, or T lymphocyte, is a type of white blood cell that plays a crucial role in the immune system. T cells scan the intracellular environment, then target and destroy invaders such as viruses by homing in on their distinctive molecules, called antigens. A new way to fight cancer involves heightening T cells' ability to recognize and hunt down the body's own renegade cells. To do this, T cells are separated from the patient's blood, genetically engineered to recognize an antigen found on malignant cells, then returned to the bloodstream to mount an attack.

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The German Institute for Quality and Efficiency in Health Care (IQWiG) investigated the benefit of biomarker tests to support the decision for or against adjuvant systemic chemotherapy in certain BREAST CANCER patients, that is, women with primary hormone receptor-positive, HER2-negative breast cancer and up to 3 affected lymph nodes.

When the Institute presented its preliminary report in November 2015, the evidence was inadequate to prove the benefit or harm of such tests. However, the results of further relevant studies had been announced for the beginning of 2016. Following a request by the Federal Joint Committee (G-BA), IQWiG did not immediately start preparing the final report after the scientific debate on the preliminary report, but waited for these results.

In the summer of 2016 the first results of one of these studies (MINDACT) were published; these results could be considered in the final report and are now the focus of discussion. The new study data provide valuable information on the potential consequences of omitting chemotherapy on the basis of a biomarker test result.

However, one cannot speak of a clear benefit of the test investigated in the MINDACT study. This is because, on the one hand, the follow-up period of 5 years is too short; many cases of distant metastasis, that is, metastasis not in the vicinity of the affected breast, occur only after several years. On the other, it is questionable whether 1 to 2% more deaths caused by the recurrence and spreading of the cancer due to the omission of chemotherapy are really negligible.

IQWiG investigated the benefit of the use of biomarkers to support the treatment decision of women for whom it is so far unclear whether they would experience a recurrence of disease at all or whether their cancer would respond to chemotherapy. If this were not the case, chemotherapy would be an unnecessary burden. This question is open in patients with primary hormone receptor-positive, HER2-negative breast cancer with at most 3 affected lymph nodes. Chemotherapy after successful tumour surgery aims to eliminate potential micrometastisis and thus prevent disease recurrence. However, even without chemotherapy, most women affected do not experience a recurrence. The group of patients who actually benefit from chemotherapy cannot be reliably determined solely on the basis of established factors such as age, lymph node status, and grading. The hope is that so-called biomarkers can provide reliable conclusions on the benefit of such adjunctive therapy.

The literature analysis identified 8 studies that were relevant for the research question of the benefit assessment. In 6 of these studies, the data of many patients were missing, for example, because samples had already been used for other analyses, were not suitable for the test or no consent had been given for the renewed use of the sample. If the evidence base is so incomplete, in particular for the important long-term analyses, then this can lead to biased conclusions. The results of these studies could therefore not be used for the benefit assessment.

A further study investigated the decision on the choice between 2 chemotherapies, but not the potential omission of chemotherapy. The following text therefore refers solely to the 8th study, MINDACT.

Almost every second woman with a high clinical risk score has a favourable biomarker test result

The MINDACT study, a randomized controlled trial, included nearly 7000 women with early-stage breast cancer who had undergone surgery. Most study participants fulfilled the inclusion criteria for the present assessment.

The participants underwent both a conventional clinical risk assessment and a genomic risk assessment to estimate the risk of distant metastasis (classified as "low" or "high" in both assessments); if distant metastasis occurs, 2 out of 3 women affected die of cancer within 10 years. The clinical risk assessment yielded a low score in half of the women analysed; the score was high in the other half. In the genomic risk assessment, the tumour samples were tested with a biomarker (MammaPrint), which determines the expression of 70 genes (gene expression profile). In 46% of the women with a high clinical risk score, the additional application of this test yielded a low genomic risk score. Half of these women received chemotherapy to determine whether women with such a discordant risk assessment would benefit from chemotherapy.

In the commenting procedure on IQWiG's preliminary report, the participating experts agreed that distant metastasis and other complications of breast cancer could occur many years after the primary tumour, so a follow-up period of at least 10 years needs to be considered. However, the recently published first results of the MINDACT study cover only a 5-year period. For this reason, no reliable assessment is so far possible of the advantages or disadvantages of omitting chemotherapy on the basis of low biomarker risk scores. IQWiG could only roughly estimate the results to be expected after 10 years.

Stefan Lange, IQWiG's Deputy Director notes: "No one knows exactly whether the differences between the groups with and without chemotherapy will increase or decrease in the next years or whether the rate of distant metastasis will be similar. But the results now available are the best we can currently work with. It is a good thing that this large and carefully planned study was conducted. Of the approximately 70,000 women diagnosed with breast cancer in Germany every year, it is unclear for a roughly estimated number of 20,000 whether they will benefit from chemotherapy. The MINDACT study provides important data for these women and their physicians in order to be able to discuss in detail the advantages and disadvantages of chemotherapy and the limited informative value of biomarker tests."

The study authors sought primarily to evaluate whether a treatment decision based on the biomarker test result is inferior to a treatment decision based on the clinical risk score. For this purpose, they defined (in advance and with statistical specifications) that in women with a high clinical and low genomic risk score who omitted chemotherapy, the 5-year survival rate without distant metastasis ("distant metastasis-free survival") would have to be at least 92%. This was actually the case in 94.7% of the women; the corresponding 95% confidence interval was 92.5% to 96.2%. The crucial lower boundary of this interval is just above the defined threshold of 92%; according to the study authors, this demonstrates non-inferiority.

However, this is an unconventional understanding of non-inferiority: Instead of evaluating only one study arm, the risk of distant metastasis of women in the groups with and without chemotherapy should have been compared. In addition, the 5-year threshold of 92% was not explained, in contrast to the one specified by IQWiG, namely, a 10-year rate of distant metastasis-free survival of 95%. This threshold has already been undercut. Other experts define a more liberal threshold of 90%. This criterion will probably not be fulfilled either: As, according to experts, many recurrences occur only years later, the lower boundary of the confidence interval will probably drop under 90% in the next 5 years.

Besides, for the commission awarded to IQWiG by the G-BA, other results of this study are more important. If women with a high clinical and low genomic risk score receive or omit chemotherapy, how large is the 5-year difference between groups with regard to the rates of local or distant recurrence, and, in particular, deaths? The study authors determined that, after 5 years, 95.9% of women who had undergone chemotherapy were free of distant metastasis; in women who had not, this rate was 94.4%, a statistically non-significant difference of 1.5%. However, because of the uncertainty caused by the limited number of participants, this difference could also amount to nearly 4%.

But for women affected, disease-free (i.e. recurrence-free) survival and overall survival are at least as important as distant metastasis-free survival. In the study, the treatment effects were in the same direction for all 3 outcomes.

If 1000 women omit chemotherapy on the basis of a low biomarker score, then 32 additional recurrences of any type (including deaths) can be expected; but due to uncertainty, this number could increase to 61. Regarding mortality alone, 11 additional deaths can be expected; this number could increase to 26.

Stefan Lange notes: "According to the study authors, the difference between groups is so small that many women with breast cancer might not require chemotherapy. I would like to discuss that in more detail with the women affected and with experts. In other discussions, for example, on the introduction of colorectal or prostate cancer screening, alleged increases in survival rates of a fraction of a percent have been propagated as essential goals to be aspired. But in the case of the decision on chemotherapy, it is supposed to be negligible that of the approximately 10,000 women per year who, according to the manufacturer information, could omit chemotherapy thanks to the new test, up to 260 more could die?"

This would be comprehensible if the higher risk were accompanied by very clear advantages. A breast cancer patient with a high risk of distant metastasis according to the clinical assessment but a low risk according to the genomic assessment must on the one hand consider the potential side effects and late complications of chemotherapy and on the other, the higher risk of future distant metastasis or cancer-related death.

Daniel Fleer, the responsible project manager from IQWiG's department of Non-Drug Interventions, explains: "Unfortunately, most statements on the disadvantages of chemotherapy are rather vague. It is repeatedly stated that an estimated 2 to 3% of patients undergoing chemotherapy suffer serious harm, for instance, permanent damage to internal organs such as the heart of kidney, or even die. However, these are only very rough estimates that are simply cited, often without any supporting evidence. Thanks to the MINDACT study, women affected now have substantially more information on the extent of the risk of omitting chemotherapy. However, no information has been provided so far on side effects that are important for decision-making. For the time being, 1 of the 2 components required to make an informed decision thus remains unclear. Overall, IQWIG concludes that the data on the currently available biomarkers provide no hint of a benefit or harm of a biomarker-based strategy to support the decision for or against adjuvant chemotherapy in primary breast cancer. At the moment one cannot in good faith advise a woman with a high clinical risk and low genomic risk to omit chemotherapy. The actual "added value" of the biomarker test for women affected can only be judged when further results of ongoing studies become available.

IQWiG published the preliminary results in the form of the preliminary report in November 2015 and interested parties were invited to submit comments. At the end of the commenting procedure, the preliminary report was revised and sent as a final report to the commissioning agency in October 2016. The written comments submitted were published in a separate document together with the final report. The report was produced in collaboration with external experts.

Until next month....


And if you have any thoughts of how this newsletter could be improved, please email me directly, at

Elaine Jesmer

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