New screening method for prostate cancer recurrence

The American Cancer Society estimated that 220,800 new cases of prostate cancer will be diagnosed in the United States in 2015. Approximately 27,540 men will die of the disease, accounting for 5 percent of all cancer deaths.

A common treatment for prostate cancer is a prostatectomy, in which all or part of the prostate gland is removed. Recent studies have shown that this procedure is often over-prescribed. As early as 2010, the New England Journal of Medicine reported that such a procedure extended the lives of just 1 patient in 48. Side effects from the surgery, including urinary incontinence and impotence, can affect the quality of life of the patient.

For every 20 surgery procedures to take out the prostate, it is estimated that only one life is saved,” said Gabriel Popescu, director of the Quantitative Light Imaging Laboratory (QLI) and senior author on the study. “For the other 19 people, they would be better left alone, because with removing the prostate, the quality of life goes down dramatically. So if you had a tool that could tell which patient will actually be more likely to have a bad outcome, then you could more aggressively treat that case.”

On a study funded by the National Science Foundation and Agilent Technologies, researchers employed spatial light interference microscopy (SLIM), a label-free method, to perform localized measurements of light scattering in prostatectomy tissue microarrays. The quantitative phase imaging (QPI) performed by the SLIM examines the anisotropy, or the difference in a material’s physical properties, as light is scattered through the stroma, the tissue surrounding the prostate glands.

The researchers found that the higher value of anisotropy indicated that the tissue is more organized. A lower value indicated that the various components within the tissue are fragmented and disorganized.

We found that for patients who had bad outcomes, the connective tissue around the glands (stroma) is more disorganized than in the case of patients who have better outcomes,” said Shamira Sridharan, a graduate research assistant in the QLI Lab, and the lead author of the study.

Among individuals who undergo prostatectomy, there are a few statistical tools that take various clinical parameters into consideration and then predict the risk for recurrence,” said Sridharan. “But among people who are in the intermediate risk for recurrence, those methods often fail, so this might lead to under- or overtreatment. Clearly, more accurate tools are necessary for predicting recurrence among that cohort.

Picture

Left: Quantitative phase image of an unstained prostatectomy sample from a patient who had a biochemical recurrence of prostate cancer. Right: A zoomed-in region from the quantitative phase image showing a cancerous gland with debris in the lumen. The stroma, or supportive tissue environment, shows discontinuities in the fiber length and disorganization in the orientation of the fibers.

For example, says Sridharan, after a prostatectomy is performed, the tumor is graded by the pathologist and, in combination with other surgical parameters such as the surgical margin positivity, whether the cancer has invaded into the lymph nodes, extra-prostatic extensions, and PSA levels, a recurrence risk is assigned. However, some of this information is only available post-surgery. By examining the quality of the tissue surrounding the cancerous glands, the researchers believe they can determine progression of the disease at the pre-surgical, or biopsy stage.

The study of 181 tissue samples obtained from the National Cancer Institute-sponsored Cooperative Prostate Tissue Resource (CPCTR) were from individuals who had already undergone a prostatectomy, approximately half who had no recurrence and half who did. SLIM was able to identify those in which the cancer would reappear.

The study is the result of collaborative work between the QLI Lab and three board-certified pathologists: Drs. Andre Balla and Virgilia Macias from the University of Illinois at Chicago, and Dr. Krishnarao Tangella from Presence Covenant Medical Center in Urbana, Illinois.

It is rather remarkable that the difference between cancers with bad outcomes and good outcomes is found not in the malignant cells, but in the tissue adjacent to the cancer. Possibly, this is because the body can recognize which tumors are more aggressive and react to them,” said Balla.

An established method of screening for prostate cancer is the prostate-specific antigen (PSA) test.

PSA is a very good tool in terms of predicting the recurrence of prostate cancer in an individual who’s undergone a prostatectomy,” said Sridharan. “But when PSA screening first started, there was a huge spike in the number of prostate cancer cases diagnosed. So if a screening tool is indeed good, you would see an initial spike, but after that the cases would level off. With PSA that leveling off never happened. The number of cases diagnosed remained high, so now the United States Preventative Task Force no longer recommends routine screening for PSA.”

Based on the PSA levels, many patients underwent a biopsy and prostatectomy,” explained Popescu. “After prostatectomy serum PSA levels go to nearly zero because it is produced almost exclusively in the prostate. So PSA is great tool after prostatectomy in terms of predicting recurrence if the level starts to climb up again, indicating that the cancer has spread to other sites in the body. But in that pre-diagnosis stage, it’s not particularly great because it can lead to over-diagnosis.”

“The idea behind our method is that, if we can predict recurrence after prostatectomy, chances are we can predict recurrence at a biopsy level, before any radical surgery is performed.

What SLIM is very good at is to make invisible objects visible with nanoscale sensitivity,” said Popescu. “So we pick these structural details without the need for staining, which can introduce new variables into the specimen.”

Our dream is for everyone to have SLIM capabilities in their labs,” said Popescu. “One can imagine that a SLIM-based tissue imager will scan biopsies in a clinic and, paired with software that is intelligent enough to look for these specific markers, will provide the pathologist with valuable new information. This additional information will translate into more accurate diagnosis and prognosis.”

SLIM has excellent potential to add value to the existing methods available to pathologists and improve the accuracy of prognosis,” said Tangella.

To further that goal, the QLI is working with students based in the lab of Minh Do, a part-time faculty member in Image Formation and Processing at the Beckman Institute, to build software that will find patterns in the tissue that are relevant for diagnosis and prognosis.

We are currently working diligently to validate these initial results on a variety of patient populations.” said Balla.

The next step is trying to help with patient treatment decisions and translating this to the biopsy, pre-surgery stage,” said Sridharan. “This method is very promising and demonstrates the potential to help with determining who should undergo active surveillance versus surgical treatment.”

Sridharan et al. Prediction of prostate cancer recurrence using quantitative phase imaging. Scientific Reports. 2015; 5: 9976 doi:10.1038/srep09976 [Abstract]

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Cancer survivors have evolving information needs

Cancer patient’s information needs appear to differ depending on the type of cancer they have and where they are in their survivorship. Clinicians caring for cancer survivors may need to understand these needs in order to better address survivor’s concerns about cancer recurrence, late effects, and family member’s risks.

A three-year study of over 2,000 cancer survivors by the University of Pennsylvania’s Annenberg School for Communication discovered that, across survivors, the most frequently sought information was about cancer recurrence. However, interest in other topics varied by cancer type: breast cancer survivors were more likely to seek information about topics related to late effects and family members’ risks than prostate and colon cancer survivors. The patterns of seeking for these topics also changed over time. For instance, breast cancer survivors were less likely to seek information about their risks of cancer recurrence in later years than during the first year after their diagnosis. These findings are reported in the journal Cancer Epidemiology, Biomarkers & Prevention (online first, 2015).

The findings from the study are important because understanding how people seek cancer information during their cancer survivorship is an important component as clinicians help to address the physical and emotional issues their patients may be experiencing. Clinicians may need to intervene at distinct points during the cancer survivorship period with timely information to address their patients’ concerns about cancer recurrence, late effects, and family members’ risks.

Researchers Andy Tan (Dana-Farber Cancer Institute), Rebekah H. Nagler (University of Minnesota), Robert C. Hornik (Annenberg School, University of Pennsylvania), and Angela DeMichele (Abramson Cancer Center, University of Pennsylvania) surveyed over 2,000 cancer survivors three times over a three-year period (2006 to 2008). The participants were survivors of colon cancer (males and females), breast cancer, and prostate cancer. They were, on average, in their early 60s, and the survey population was split evenly between men and women.

In this series of three surveys administered over three years, the researchers asked what type of information participants sought, including:

  • How to reduce the chance of their cancer coming back
  • How to reduce their chance of getting another cancer
  • How to reduce the risk of their children or family members getting breast/prostate/colon cancer or a different type of cancer
  • Whether they are at risk of having other health problems as a result of their cancer or treatment

Across all participants, reducing the chance of cancer coming back was the number one researched subject in all three surveys. Over 28 percent of cancer survivors expressed looking for information about their risk of cancer recurrence, compared with only 12 percent who said they had looked for information about the risks of their family members getting a different cancer from their diagnosis.

Cancer type was related to survivor’s information seeking patterns over time. Although breast cancer survivors were more likely to seek information about survivorship topics earlier in their trajectory, their seeking declined over time. In comparison, female colon cancer survivors were more likely to seek information about certain topics than female breast cancer survivors in later years. The researchers surmised this may be due to the ample amount of breast cancer information readily available and the existence of robust survivorship organizations to support breast cancer survivors.

Not surprisingly, information about reducing risks of recurrence was the most frequently sought after topic among cancer survivors and over all three years of the study,” says Dr. Tan, lead author of the study. He noted that the study points to several “teachable moments” for clinicians, as well as avenues for additional study.

Additionally, Dr. Tan said, “clinicians should consider the early survivorship timeframe as an opportunity to counsel patients on other positive health behaviors, from diet to smoking cessation, to help manage risks of cancer recurrence, since this window of opportunity may be when a patient is most open to receiving such information.

Tan et al. Evolving information needs among colon, breast, and prostate cancer survivors: Results from a longitudinal mixed-effects analysis. Cancer Epidemiol Biomarkers Prev. 2015; doi: 10.1158/1055-9965.EPI-15-0041 [Abstract]

Body’s ‘serial killers’ captured on film destroying cancer cells

A dramatic video has captured the behaviour of cytotoxic T cells – the body’s ‘serial killers’ – as they hunt down and eliminate cancer cells before moving on to their next target.

In a study published today in the journal Immunity, a collaboration of researchers from the UK and the USA, led by Professor Gillian Griffiths at the University of Cambridge, describe how specialised members of our white blood cells known as cytotoxic T cells destroy tumour cells and virally-infected cells. Using state-of-the-art imaging techniques, the research team, with funding from the Wellcome Trust, has captured the process on film.

Inside all of us lurks an army of serial killers whose primary function is to kill again and again,” explains Professor Griffiths, Director of the Cambridge Institute for Medical Research. “These cells patrol our bodies, identifying and destroying virally infected and cancer cells and they do so with remarkable precision and efficiency.”

There are billions of T cells within our blood – one teaspoon full of blood alone is believed to have around 5 million T cells, each measuring around 10 micrometres in length, about a tenth the width of a human hair. Each cell is engaged in the ferocious and unrelenting battle to keep us healthy. The cells, seen in the video as orange or green amorphous ‘blobs’ move around rapidly, investigating their environment as they travel.

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This is a cytotoxic T cell, the body’s ‘serial killers’, as it hunts down and eliminates cancer cells. CREDIT Gillian Griffiths/Jonny Settl

When a cytotoxic T cell finds an infected cell or, in the case of the film, a cancer cell (blue), membrane protrusions rapidly explore the surface of the cell, checking for tell-tale signs that this is an uninvited guest. The T cell binds to the cancer cell and injects poisonous proteins known as cytotoxins (red) down special pathways called microtubules to the interface between the T cell and the cancer cell, before puncturing the surface of the cancer cell and delivering its deadly cargo.

In our bodies, where cells are packed together, it’s essential that the T cell focuses the lethal hit on its target, otherwise it will cause collateral damage to neighbouring, healthy cells,” says Professor Griffiths. “Once the cytotoxins are injected into the cancer cells, its fate is sealed and we can watch as it withers and dies. The T cell then moves on, hungry to find another victim.”

The researchers captured the footage through high-resolution 3D time-lapse multi-colour imaging, making use of both spinning disk confocal microscopy and lattice light sheet microscopy. These techniques involves capturing slices through an object and ‘stitching’ them together to provide the final 3D images across the whole cell. Using these approaches the researchers have managed to elucidate the order the events leading to delivery of the lethal hit from these serial killers.

The video is available at https://www.youtube.com/watch?v=ntk8XsxVDi0.

Ritter et al. Actin depletion initiates events leading to granule secretion at the immunological synapse. Immunity. 2015;42, 864–876 [Article]

Nuclear medicine scan could identify who might benefit from aromatase inhibitor treatment

A new, noninvasive nuclear medicine test can be used to determine whether aromatase inhibitor treatment will be effective for specific cancer patients, according to a recent study reported in The Journal of Nuclear Medicine. The research shows that a PET scan with the ligand C-11-vorozole reliably detects aromatase in all body organs – demonstrating the value of its future use to pre-determine the effectiveness of the treatment for breast, ovarian, endometrial and lung cancer patients, potentially reducing unnecessary treatment costs and adverse effects.

Aromatase inhibitors are drugs that work by blocking the aromatase enzyme, which turns the androgen hormone into cancer-stimulating estrogen. They are widely used in the adjuvant treatment of breast cancer and other endocrine conditions. However, no quantitative, noninvasive studies had been done of the distribution and regulation of aromatase in living humans.

Anat Biegon, PhD, corresponding author of the study, explains, “This is the first study conducted in living human subjects that surveys the whole body, comparing healthy young and old men and women.”

For the study, 13 men and 20 women were injected intravenously with C-11-vorozole (111-296 MBq/subject), with PET data acquired over a 90-minute period. Each subject had four scans, two per day separated by two to six weeks. Brain and torso or pelvic scans were included. Young women were scanned at two discrete phases of the menstrual cycle (midcycle and late luteal). Men and postmenopausal women were also scanned after pretreatment with a clinical dose of the aromatase inhibitor letrozole. Time-activity curves were obtained, and standardized uptake values (SUV) were calculated for major organs, including brain, heart, lungs, liver, kidneys, spleen, muscle, bone, and male and female reproductive organs. Organ and whole-body radiation exposures were calculated using OLINDA software.

The study shows for the first time that the body organ with the largest stable capacity for estrogen biosynthesis is the male brain, closely followed by the female brain. Aromatase availability is slightly but consistently higher in all organs in men relative to women, with the exception of the ovary. In addition, aromatase availability in the ovary is tightly linked to the ovulatory phase of the menstrual cycle in young women, with increased levels evident in one ovary/cycle around the time of ovulation. Also of interest is the finding that aging and cigarette smoke reduce aromatase availability in the brains of healthy men and women.

Dr. Biegon points out the significance of the study: “Research using in vitro methods indicates aromatase over expression is not limited to breast cancer and is evident in a considerable proportion of ovarian, endometrial, and lung tumors. This study provides methodological, baseline and dosimetry information supporting the use of PET and C-11 vorozole in the non-invasive identification of individuals with disparate disorders who may benefit from treatment with aromatase inhibitors.” She notes, “It also offers the ability to distinguish breast cancer patients who are not likely to benefit from this treatment, reducing unnecessary treatment costs and adverse effects. Finally, aromatase imaging can be used in monitoring efficacy of treatment with aromatase inhibitors and aid in the development of new drugs in this class.”

Another key finding relates to the differences between men and women. Dr. Biegon states, “Radiotracer uptake and the resultant radiation exposure can be sex-dependent and strongly modulated by hormonal status. Nuclear medicine procedures need to be adjusted for these factors when applied in women.”

Biegon et al. Aromatase Imaging with [N-Methyl-11C] Vorozole PET in Healthy Men and Women. J Nucl Med. 2015;56:580-585 EPub ahead of print. doi: 10.2967/jnumed.114.150383 [Abstract]

Potential for a more personalized approach to womb cancer

Traditionally, patients with endometrial cancer, cancer of the womb lining,  have their disease risk classified using a combination of clinical and tissue characteristics, including their age and the growth and invasion of their tumour.

Around 15-20% of patients have high-risk disease, but it is unclear what the best treatment approach is for these patients. Now Manchester researchers have investigated genetic alterations in high-risk endometrial cancer, to see if they could be used to create tumour subtypes.

Professor Richard Edmondson, Professor of Gynaecological Oncology at The University of Manchester and Saint Mary’s Hospital, said: “Previous work, using comprehensive genetic profiling, has suggested that endometrial cancer can be classified into four subtypes. Our study has explored whether it is possible to use a simpler approach to detect subgroups in high risk patients.

Using routinely available technology, the international TransPORTEC research consortium analysed samples from 116 patients with endometrial cancer to look for genetic variations.

The team, which also included Dr Emma Crosbie and Professor Henry Kitchener from Manchester, found that genetic subtypes existed in their group of patients, and that they could use their classification to predict which patients were more likely to relapse.

In addition, the analysis allowed them to identify distinctive genetic mutations that can be targeted with specific anti-cancer drugs.

It looks like these cancers classed as ‘high-risk’ in fact vary significantly in outcome. Our results could be used to refine risk assessment for endometrial cancer patients and allow doctors to choose either a less aggressive approach or more targeted treatment for individual patients,” added Professor Edmondson.

Stelloo et al. Refining prognosis and identifying targetable pathways for high-risk endometrial cancer; a TransPORTEC initiative. Mod Pathol. 2015; doi: 10.1038/modpathol.2015.43 EPub ahead of print [Abstract]

Statin drugs can delay prostate cancer progression in patients

Men who went on cholesterol-lowering statin drugs when they began androgen deprivation therapy for prostate cancer had a longer time in which their disease was under control than did men who didn’t take statins, a clinical trial led by Dana-Farber Cancer Institute investigators shows.

In a study published online today by JAMA Oncology, the researchers report that men who had been taking statins since the start of androgen deprivation therapy (ADT) went a median of 27.5 months before their disease began to worsen, compared to 17.4 months for men who didn’t take statins. The trial involved 926 patients, 70 percent of whom had their disease progress during a six-year period.

This median 10-month benefit in delaying disease progression suggests that statins could be a valuable addition to our current therapies for prostate cancer,” says the study’s first author, Lauren Harshman, MD, medical oncologist at the Lank Center for Genitourinary Oncology at Dana-Farber. “These results are supported by multiple prior epidemiologic studies demonstrating that statin use may be associated with improved outcomes in prostate cancer, but require validation.

The trial grew out of laboratory studies that suggested statins could delay prostate cancer growth in patients receiving ADT. (ADT reduces the amount of androgen in the body, preventing prostate cancer cells from using it to fuel their growth. For many years, it has been the frontline treatment for patients with hormone-sensitive prostate cancer that has spread beyond the prostate gland.)

The laboratory phase of the research focused on a protein called SLCO2B1, which helps a variety of drugs and hormones enter cells. One of these immigrants to the cell is dehydroepiandrosterone sulfate (DHEAS), a precursor of testosterone, the hormone that spurs prostate cancer cell growth. Statin drugs, too, rely on SLCO2B1 to gain entry to cells.

In a series of experiments, the researchers showed that statins could interfere with DHEAS uptake in lab-grown prostate cancer cell lines. By monopolizing the available pool of SLCO2B1 within a prostate tumor, statins essentially deny DHEAS a passkey to the cancer cells. The clinical study results suggest this approach could be effective in patients.

We present a plausible mechanism by which statins may work in prostate cancer by decreasing the tumor’s available androgen pool and thus improving patient outcomes,” says the study’s senior author, Philip Kantoff, MD, leader of the Lank Center for Genitourinary Oncology and chief of solid tumor oncology at Dana-Farber. “Further study is required to validate our findings.”

Harshman et al. Statin use at the time of initiation of androgen deprivation therapy and time to progression in patients with hormone-sensitive prostate cancer. JAMA Oncol.2015;doi:10.1001/jamaoncol.2015.0829 EPub ahead of print [Article]