Tuesday, January 19, 2021

What Triggers Dormant Cancer Cells?

This article first appeared in  StatNews. The Q&A section defines some of the terms used and what some unexpected findings were.

By Shraddha Chakradhar

The recurrence of cancer months or even years after successful treatment is an all too common phenomenon, and scientists have been chipping away at understanding how undetectable cells can once again unleash disease on the body — often more aggressively than the first time around.

In a new study published Wednesday in Science Translational Medicine, one group of researchers describes how a cascade of events set off by high levels of a stress hormone could cause dormant tumor cells to reawaken to once again cause cancer.

The hormone, norepinephrine, is naturally found in the body, but more of this chemical is released into the bloodstream when the body detects higher levels of stress. In some cancer models, scientists found that an elevated level of norepinephrine led to the activation of cells known as neutrophils, which help shield tumor cells from the body’s immune system. Activating neutrophils in turn led to these cells releasing a special type of lipid — which then awakened sleeping cancer cells.

“It’s sort of a triangle,” said Michela Perego, a molecular biologist at the Wistar Institute in Philadelphia and lead author of the study. “And it’s a chain of events that ends up being very powerful in reawakening dormant tumor cells.”

Perego and her colleagues observed this mechanism in mice that were injected with dormant lung cancer cells. The mice were placed in a setup where they had less room than usual to move around, which likely made them feel trapped and spiked their stress levels.

A subset of these mice were also treated with an experimental beta blocker, a class of medications used to treat blood pressure. Dormant tumor cells in mice treated with the drugs remained so, the researchers found.

The team also examined 80 lung cancer patients who had had surgery to treat their disease. In this group, 17 patients saw their tumor return within three years of surgery — a recurrence that’s considered early. Compared to the other 63 patients whose cancer came back later or didn’t return at all, the 17 patients with early recurrence had higher levels of the chemical that indicates activated neutrophils.
If this preliminary finding holds true through more studies, “you could potentially monitor stress hormones in a patient undergoing therapy for cancer,” Perego said, emphasizing that it would be in addition to regular treatment and not in place of it.

STAT spoke with Perego to learn more about the research. The conversation has been lightly edited and condensed for clarity.

What does it mean for a tumor cell to be dormant?
It means there are still cancer cells around, but they are undetectable. They can be in the primary tumor location or somewhere else. If the cells stay that way and don’t start regrowing, it’s fine because you don’t have symptoms and you don’t have growth. But if cells come back, then there’s often resistance to the first therapy or sometimes it’s hard to do surgery.

How can dormant cancer cells be a problem? 
Dormant cells are not a problem until they wake up. There’s big progress that has been made in the last few years in cancer therapy, but we know that some of them only last for some time before the cancer comes back. And we know very little about how cancer comes back, why it comes back, and how we can control cancer for longer before it comes back. We also can’t predict when it is going to come back.

Is this true for all cancers? 
It can happen in all cancers. We know, for instance, that breast cancer patients can experience relapse after 20 years of being in remission. It doesn’t happen at the same rate across cancers, though, or even for all patients with a type of cancer.

How are you defining stress for this study? And is it any stress or certain levels of stress that reactivate sleeping tumors? 
When we say stress, we mean stress hormones, and there are tons of those in the human body. We looked at this specific one, norepinephrine.
We all undergo stress, and some handle it better and some handle it worse. What is very important is that stress alone doesn’t reawaken dormant cells. You need stress hormones, but you also need neutrophils, and you need them to be activated and then for them to produce this specific lipid to turn on tumor cells.

Aren’t neutrophils part of the immune system? How do they help cancer cells?
Neutrophils are important for how organisms fight pathogens. They are good for us, but there is also an evil counterpart to them. Depending on the presence of cancer, neutrophils switch and become bad and support cancer cells. They seem to support tumor growth because they can block the other cells of the immune system that kill tumors. But we don’t fully understand this.

What was surprising about what you found? 
That these hormones were so powerful in influencing the immune system was such a surprise. The whole idea that these stress hormones could show a physical effect, and take a physical toll, on cells was unexpected.

You tested beta blockers in mice as a way to stop this “triangle” of activity — why? 
Beta blockers are already used in clinics to block norepinephrine, for people with heart failure and other stress-sensitive conditions. It’s nice because it’s not a new drug that has to be developed. And it could be something to add in to existing cancer therapy to help with patients’ stress hormones.

What’s next? 
Every time you find a mechanism, you open up another 10 questions. There are a lot of other hormones that we don’t know about and how they interact with the mechanism we described. There’s also a lot to learn about the tumor environment, and how that might influence [dormancy].
The final goal of this research is to get it to the clinic, so I would be very happy to see some of this translate that way. For example, we could develop techniques to detect lipids or stress hormones to indicate when a relapse may be occurring.

This article was published by STAT News.

Friday, January 15, 2021

NCCN Guidelines on Treatment of OC


This is a great panel discussion about the current treatment guidelines for treating OC that was updated in 2020.

Tuesday, January 12, 2021

This article first appeared in AJMC and is reprinted here.

One patient had a complete response and the majority of patients achieved disease control at 12 weeks.

A phase 1 trial of an anti-folate receptor alpha (FolRα) human immunoglobulin G1 (IgG1) antibody for women with advanced ovarian cancer showed responses in 32% of evaluable patients, including 1 complete response (CR).

The results were announced by Sutro Biopharma, which is developing its candidate STRO-002; the FolRα targeting antibody-drug conjugate (ADC) uses non-natural amino acids to target FolRα, which is overexpressed in some cancers, including ovarian cancer.

The ongoing dose-escalation phase 1 study, STRO-002-GM1, is a single-arm monotherapy trial for patients with ovarian cancer not selected based on their FolRα-expression levels. The dose-escalation portion of the study was fully enrolled with 39 patients in August 2020. Patients were heavily pre-treated and had a median of 6 prior lines of therapy, platinum-based regimens, bevacizumab, poly-ADP-ribose polymerase inhibitors, and checkpoint inhibitors.

Results included those from 34 patients treated with clinically active dose levels, 2.9 mg/kg or higher, of which 31 patients had post-baseline scans and were evaluable for RECIST responses. At the data cutoff of October 30, 2020, median time on treatment was 19 weeks and 10 patients remained on treatment. Results out of 31 evaluable patients included:

  • 10 patients met RECIST criteria for response, with 1 achieving a CR and 9 patients achieving a partial response (PR)
  • Of the PRs, 3 were confirmed PRs and 6 unconfirmed PRs
  • 23 patients (74%) achieved disease control at 12 weeks
  • 18 patients (58%) achieved disease control at 16 weeks
  • 4 patients (13%) were on treatment for 52 weeks
  • 3 patients remained on treatment beyond 64 weeks

The drug was well-tolerated; 86% of all treatment-emergent adverse events (AEs) were grade 1 or 2. The most common grade 3 and 4 AEs were reversible neutropenia. Grade 3 arthralgia (15.4%) and neuropathy (7.7%) were observed and managed with standard medical treatment.

“We are encouraged to see meaningful clinical benefit from STRO-002 for patients with advanced platinum-resistant and refractory ovarian cancer. The women on the study are heavily pretreated and have limited treatment options as many have received experimental agents and participated in other clinical trials,” said Lainie P. Martin, MD, who heads the Gynecology/Oncology Program at Hospital of the University of Pennsylvania and an investigator on the STRO-002 study. “The deepening of responses in patients as well as disease control over time demonstrates STRO-002 to be an important potential treatment option for patients with ovarian cancer.”

The company said that although a maximum tolerated dose was not reached, it plans to randomize dose levels of 4.3 and 5.2 mg/kg in the dose-expansion trial with less heavily pre-treated patients. The candidate is also being studied in endometrial cancer.

This article was published by AJMC.


Thursday, January 7, 2021

PARPi Appear Linked to Blood Cancers

 This article first appeared on Medpage Today.

By: Leah Lawrence

Although rare, poly-ADP ribose polymerase (PARP) inhibitors were associated with an increased risk for myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), and occurred even after brief drug exposure, researchers reported.

A systematic review and meta-analysis of 18 randomized clinical trials comparing PARP inhibitors to placebo control in adults revealed more than double the risk for MDS and AML (Peto odds ratio [OR] 2.63, 95% CI 1.13-6.14, P=0.026) with PARP inhibitors, reported Joachim Alexandre, MD, of Caen University Hospital, France, and colleagues.

All cases were reported in ovarian cancer trials. Writing in the Lancet Haematology, the researchers said this could be explained by these trials having the longest follow-up compared with other tumor types.

Incidence of MDS and AML across PARP inhibitor groups was 0.73% compared with 0.47% for placebo groups. When studies that included other control treatments were included in the analysis, PARP inhibitor treatment still significantly increased the risk for MDS and AML (Peto OR 2.25, 95% CI 1.07-4.75, P=0.033).

An additional analysis of real-world data from VigiBase focused on clinical features on 99 cases of MDS and 79 cases of AML related to PARP inhibitor treatment. Among these cases, the median duration of PARP inhibitor exposure was 9.8 months, but ranged from 0.2 to 66.8 months. The median latency period for MDS and AML from first PARP inhibitor exposure was 17.8 months, ranging from 0.6 months to 66.8 months. Specifically, MDS occurred after a median of 17.8 months from first exposure; AML, 20.6 months.

“These delays to onset of myelodysplastic syndrome and acute myeloid leukemia are shorter than typically described with conventional chemotherapeutic drugs,” the researchers noted.

Outcomes were available for 104 cases of MDS/AML: 9% reported recovery, 46% of cases were ongoing, and 45% of cases resulted in death.

Alexandre and colleagues noted that the significant risk for MDS and AML related to PARP inhibitor treatment in first-line maintenance trials “suggest that these events might be a toxicity specific to PARP inhibitors.” However, in the SOLO2 trial of women with platinum-sensitive, relapsed, BRCA1/2-mutated ovarian cancer, PARP inhibition was associated with improved median overall survival; long-term follow-up showed 16 cases of MDS or AML in the PARP inhibitor group and four cases in the placebo group.

“We cannot exclude a competitive bias between death and myelodysplastic syndrome or acute myeloid leukemia occurrence, and therefore we cannot exclude that these adverse events could have a stronger association with previous lines of chemotherapy than with PARP inhibition,” Alexandre and colleagues wrote.

In an editorial that accompanied the study, Anna Tinker, MD, of the University of British Columbia in Vancouver, Canada, noted that maturing data from randomized clinical trials of PARP inhibitors in a growing number of tumor types might further refine the low overall incidence of MDS and AML found in this study and could reveal if “risk might differ in a drug-specific manner.”

Subgroup analyses by Alexandre and colleagues showed no significant differences in risk for MDS or AML by previous systemic therapy, PARP inhibitor used, biomarker specificity, PARP inhibitor treatment setting, PARP inhibition assignation, follow-up duration, or PARP inhibitor treatment duration.

“Given the common use of PARP inhibitors in BRCA1/2 mutation carriers, the finding that these patients do not appear to have elevated risk is reassuring,” Tinker wrote. “Commonly labeled as a late toxicity, clinicians need to remain aware that the onset of myelodysplastic syndrome and acute myeloid leukemia can occur soon after PARP inhibitor initiation even after brief drug exposure.”

Patients should be counseled “on the rare but life-threatening toxicities of PARP inhibitors,” she wrote, and offered “appropriate monitoring and investigations of hematological changes.”

This article was published by Medpage Today