Hormone therapy linked to better survival after lung cancer diagnosis in women

Survival among people with lung cancer has been better for women than men, and the findings of a recent study indicate that female hormones may be a factor in this difference. The combination of estrogen plus progesterone and the use of long-term hormone therapy were associated with the most significant improvements in survival.

The study was designed to explore the influence of several reproductive and hormonal factors on overall survival of women with non-small cell lung cancer (NSCLC). After adjusting for stage of disease at diagnosis, treatment type (surgery or radiation), smoking status, age, race, and education level, the only factor studied that predicted survival after a diagnosis of NSCLC was use of hormone therapy.

Among the 485 women, the median survival time was 80 months for women receiving hormone therapy and 37.5 months for women not receiving hormone therapy. Combined estrogen and progesterone was associated with a slightly higher median survival time (87.0 months) than estrogen alone (83.0 months). The findings of the study are published in the March issue of the International Association for the Study of Lung Cancer’s journal, the Journal of Thoracic Oncology (JTO).

The use of hormone therapy for 11 years or more was associated with significantly improved survival, and this finding remained significant among women who took either estrogen alone or estrogen plus progesterone and among women who had never smoked or were smokers.

What has emerged from this study and other published findings is a complex relationship between hormone use and lung cancer outcomes, with variation in results based on years of use,” says lead author Ann G. Schwartz, PhD, MPH, of Karmanos Cancer Institute, Detroit, MI, and an IASLC member.

Studies on the effect of hormone use on lung cancer survival have been limited, and the results have been inconsistent. Because of this, additional research is needed to evaluate the significance of long-term use of hormone therapy on outcomes in lung cancer, with better characterization of tumors in terms of expression of estrogen and progesterone receptors.

Dr. Schwartz adds, “There is more to learn about survival differences between men and women; hormone use may contribute to those differences. The largest impact on lung cancer outcomes will come from successful early detection and treatment.”

Katcoff et al., (2014). Survival in women with NSCLC: The role of reproductive history and hormone use.J.Thorac.Oncol.9:355-361 [Abstract]

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Personalized medicine may be best way to treat cancer

If a driver is travelling to New York City, I-95 might be their route of choice. But they could also take I-78, I-87 or any number of alternate routes. Most cancers begin similarly, with many possible routes to the same disease. A new study found evidence that assessing the route to cancer on a case-by-case basis might make more sense than basing a patient’s cancer treatment on commonly disrupted genes and pathways.

The study found little or no overlap in the most prominent genetic malfunction associated with each individual patient’s disease compared to malfunctions shared among the group of cancer patients as a whole.

This paper argues for the importance of personalized medicine, where we treat each person by looking for the etiology of the disease in patients individually,” said John McDonald, a professor in the School of Biology at the Georgia Institute of Technology in Atlanta. “The findings have ramifications on how we might best optimize cancer treatments as we enter the era of targeted gene therapy.

The research was published February 11 online in the journal PANCREAS and was funded by the Georgia Tech Foundation and the St. Joseph’s Mercy Foundation.

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Venn diagrams show the unique, annotated genes identified as significantly differentially expressed in the group analysis and in the personalized analysis(es) of at least 1 patient (P1: Patient 1, P2: Patient 2, P3: Patient 3, P4: Patient 4). Credit: Lili, et al., 2014

In the study, researchers collected cancer and normal tissue samples from four patients with pancreatic cancer and also analyzed data from eight other pancreatic cancer patients that had been previously reported in the scientific literature by a separate research group.

McDonald’s team compiled a list of the most aberrantly expressed genes in the cancer tissues isolated from these patients relative to adjacent normal pancreatic tissue.

The study found that collectively 287 genes displayed significant differences in expression in the cancers vs normal tissues. Twenty-two cellular pathways were enriched in cancer samples, with more than half related to the body’s immune response. The researchers ran statistical analyses to determine if the genes most significantly abnormally expressed on an individual patient basis were the same as those identified as most abnormally expressed across the entire group of patients.The researchers found that the molecular profile of each individual cancer patient was unique in terms of the most significantly disrupted genes and pathways.

If you’re dealing with a disease like cancer that can be arrived at by multiple pathways, it makes sense that you’re not going to find that each patient has taken the same path,” McDonald said.

Although the researchers found that some genes that were commonly disrupted in all or most of the patients examined, these genes were not among the most significantly disrupted in any individual patient.

By and large, there appears to be a lot of individuality in terms of the molecular basis of pancreatic cancer,” said McDonald, who also serves as the director of the Integrated Cancer Research Center and as the chief scientific officer of the Ovarian Cancer Institute.

Though the study is small, it raises questions about the validity of pinpointing the most important gene or pathway underlying a disease by pooling data from multiple patients, McDonald said. He favours individual profiling as the preferred method for initiating treatment.

The cost of a molecular profiling analysis to transcribe the DNA sequences of exons — the parts of the genome that carry instructions for proteins — is about $2,000 (exons account for about two percent of a cell’s total DNA). That’s about half the cost of this analysis five years ago, McDonald said, and a $1,000 molecular profiling analysis might not be far off.

As costs continue to come down, personalized molecular profiling will be carried out on more cancer patients,” McDonald said.

Yet cost isn’t the only limiting factor, McDonald said. Scientists and doctors have to shift their paradigm on how they use molecular profiling to treat cancer.

Are you going to believe what you see for one patient or are you going to say, ‘I can’t interpret that data until I group it together with 100 other patients and find what’s in common among them,'” McDonald said. “For any given individual patient there may be mutant genes or aberrant expression patterns that are vitally important for that person’s cancer that aren’t present in other patients’ cancers.

Future work in McDonald’s lab will see if this pattern of individuality is repeated in larger studies and in patients with different cancers. The group is currently working on a genomic profiling analysis of patients with ovarian and lung cancers.

“If there are multiple paths, then maybe individual patients are getting cancer from alternative routes,” McDonald said. “If that’s the case, we should do personalized profiling on each patient before we make judgements on the treatment for that patient.”

Lili et al., (2014). Evidence for the importance of personalized molecular profiling in pancreatic cancer. Pancreas43:198-211 [Abstract]

Metal implants may cut chemotherapy side effects

Cancer patients could one day experience fewer side effects from chemotherapy following a discovery that opens the door for more targeted treatments.

Researchers have identified a possible way of treating tumours that would see doctors place harmless metal implants at the cancer site.The discovery could make treatment more targeted than existing therapies, avoiding unwanted side effects, such as hair loss, tiredness and nausea. These occur when chemotherapy drugs carried in the blood kill healthy cells as well as cancer cells. The scientists found that they could alter the chemical composition of commonly used chemotherapy drugs so that they only become active when they come into contact with a metal called palladium.

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Scientists have developed modified chemotherapy drugs that are designed to remain inactive until they come into contact with a palladium implant located at the tumor site. The hope is that this approach could help reduce side effects associated with treatment by minimizing damage to the rest of the body.
Credit: Asier Unciti-Broceta

Researchers hope that by implanting small devices coated with palladium into patients’ tumours, the drugs would become activated only where they are needed, causing minimal damage to the rest of the body. The scientists reported their discovery today in the journal Nature Communications but the approach will first need to be tested in animals before it can be studied in patients.

The research was led by scientists from the Edinburgh Cancer Research UK Centre at the MRC Institute of Genetics and Molecular Medicine, the University of Edinburgh.

Dr Asier Unciti-Broceta, who led the study, said: “It will be several years before we’re able to start treating patients but we’re hopeful that this approach will lead to better tolerated cancer therapies in the future.”

Weiss et al., (2014). Extracellular palladium-catalysed dealkylation of 5-fluoro-1-propargyl-uracil as a bioorthogonally activated prodrug approach. Nat. Comm., 5:3277 doi:10.1038/ncomms4277 [Article]

Grape seed promise in fight against bowel cancer

University of Adelaide research has shown for the first time that grape seed can aid the effectiveness of chemotherapy in killing colon cancer cells as well as reducing the chemotherapy’s side effects.

Published in the prestigious journal PLOS ONE, the researchers say that combining grape seed extracts with chemotherapy has potential as a new approach for bowel cancer treatment – to both reduce intestinal damage commonly caused by cancer chemotherapy and to enhance its effect.

Lead author Dr Amy Cheah says there is a growing body of evidence about the antioxidant health benefits of grape seed tannins or polyphenols as anti-inflammatory agents and, more recently, for their anti-cancer properties.

This is the first study showing that grape seed can enhance the potency of one of the major chemotherapy drugs in its action against colon cancer cells,” says Dr Cheah, researcher in the School of Agriculture, Food and Wine.

Our research also showed that in laboratory studies grape seed taken orally significantly reduced inflammation and tissue damage caused by chemotherapy in the small intestine, and had no harmful effects on non-cancerous cells. Unlike chemotherapy, grape seed appears to selectively act on cancer cells and leave healthy cells almost unaffected.”

The researchers used commercially available grape seed extract, a by-product of winemaking. Tannins extracted from the grape seed were freeze-dried and powdered. The extract was tested in laboratory studies using colon cancer cells grown in culture.

The research showed grape seed extract:

    • showed no side effects on the healthy intestine at concentrations of up to 1000mg/kg;
    • significantly decreased intestinal damage compared to the chemotherapy control;
    • decreased chemotherapy-induced inflammation by up to 55%
    • increased growth-inhibitory effects of chemotherapy on colon cancer cells in culture by 26%

Our experimental studies have shown that grape seed extract reduced chemotherapy-induced inflammation and damage and helped protect healthy cells in the gastrointestinal tract,” says Dr Cheah. “While this effect is very promising, we were initially concerned that grape seed could reduce the effectiveness of the chemotherapy.”

In contrast, we found that grape seed extract not only aided the ability of chemotherapy to kill cancer cells, but was also more potent than the chemotherapy we tested at one concentration.”

Co-author and project leader Professor Gordon Howarth says: “Grape seed is showing great potential as an anti-inflammatory treatment for a range of bowel diseases and now as a possible anti-cancer treatment. These first anti-cancer results are from cell culture and the next step will be to investigate more widely.”

Fellow co-author and joint lead researcher Dr Sue Bastian, Senior Lecturer in Oenology, says: “These findings could be a boost to the wine grape industry as it value adds to what is essentially a by-product of the winemaking process.

Cheah et al., (2014). Grape seed extract dose-responsively decreases disease severity in a rat model of mucositis; Concomitantly enhancing chemotherapeutic effectiveness in colon cancer cells. PLOS One, DOI: 10.1371/journal.pone.0085184 [Article]

Rare bacteria outbreak in cancer clinic tied to lapse in infection control procedure

Improper handling of intravenous saline at a West Virginia outpatient oncology clinic was linked with the first reported outbreak of Tsukamurella spp., gram-positive bacteria that rarely cause disease in humans, in a new report from the Centers for Disease Control and Prevention (CDC). The report was published in the March issue of Infection Control and Hospital Epidemiology, the journal of the Society for Healthcare Epidemiology of America.

“This outbreak illustrates the need for outpatient clinics to follow proper infection control guidelines and medication preparation practices to minimize the risk of infection for patients with weakened immune systems,” said Isaac See, MD, lead author of the study. “A combination of careful descriptive epidemiology with attention to outlier cases, direct observations, and analytic studies were needed to support this investigation, which pointed to deficiencies in medication preparation practices as the cause of these unusual infections.”

From September 2011-May 2012, 15 immunocompromised patients developed Tsukamurella bloodstream infections. All patients had received a diagnosis of malignancy, and had an indwelling central line, although central line types varied. A case-control study determined that the only risk factor for developing Tsukamurella infection was the receipt of saline flush, prepared by the clinic staff from large preservative-free bags of saline, from the clinic during September-October 2011.

Investigations by the West Virginia Bureau of Public Health (WVBPH) and the CDC found several lapses in infection control procedures relating to the care of long-term intravenous catheters and preparation of chemotherapy for patients at the clinic. These investigations also suggested that saline flush syringes were the likely source of infection.

Following the recommendations of WVBPH and CDC, the clinic instituted several changes to its infection prevention and control practices; including using pre-packaged manufactured saline flushes. After the clinic changed this practice, Tsukamurella
bloodstream infections stopped occurring, further supporting the saline flush as the source of infection.

To help outpatient oncology facilities establish appropriate infection control strategies, the CDC developed a basic infection control plan tailored to these settings outlining key policies and procedures needed to meet minimal requirements for patient safety. These include the proper use and handling of injectable medications and correct procedures for assessing central lines. Outpatient oncology facilities without an existing plan are encouraged to use this document as a starting point.

See et al., (2014). Outbreak of Tsukamurella spp. bloodstream infections among patients of an oncology clinic—West Virginia, 2011-2012. Infect. Cont. Hosp. Ep.35:3 [Article]

Contradiction in the management of breast biopsy abnormalities

Contrary to existing understanding, long-term follow-up of patients with two types of breast tissue abnormalities suggests that both types of abnormalities have the same potential to progress to breast cancer, according to a study published in Cancer Prevention Research, a journal of the American Association for Cancer Research. Findings from this study could improve clinical management of patients with breast tissue abnormalities.

This study challenges current understanding that atypical ductal hyperplasia (ADH), a type of breast tissue abnormality, leads to breast cancer in the same breast while atypical lobular hyperplasia (ALH), another type of breast tissue abnormality, may not be a direct precursor of breast cancer, but may indicate equal risk of breast cancer across both breasts.

“Ours is the first report with sufficient numbers of both types of atypia and long-term follow-up for breast cancers that compared the side of breast that had atypia with the side of breast in which cancer arose and the timeframe when the cancers developed,” said Lynn C. Hartmann, M.D., professor of oncology at the Mayo Clinic in Rochester, Minn. “We showed that even though the two types of atypia look different histologically, they behave quite similarly in terms of what happens to patients.

“More than a million American women have a breast biopsy with benign findings every year, and about 10 percent of these biopsies reveal atypical hyperplasia, a premalignant finding with a proliferation of abnormal cells, which have some but not all the features of a breast cancer,” she added. “There are two types of atypical hyperplasia based on their microscopic appearance—ADH and ALH—and it has been thought that they behave differently.

“Most have considered ADH a direct precursor to breast cancer, arguing that it requires complete surgical excision while others have maintained that ALH serves as an indicator of heightened and equal risk of breast cancer across both breasts and does not need complete surgical removal,” explained Hartmann. “Moreover, some experts have argued that women with atypia develop ‘better risk’ breast cancers, meaning low-grade cancers with a good prognosis.”

Hartmann and colleagues identified 698 women from the Mayo Benign Breast Disease Cohort who had biopsy-confirmed atypia; 330 of them had ADH, 327 had ALH, and 32 had both. The investigators followed these women for an average of 12.5 years, and 143 of them developed breast cancer.

The investigators found that the ratio of breast cancer in the same breast in which the atypia was detected versus in the opposite breast was the same, 2:1, for both ADH and ALH.

A similar number of women with either ADH or ALH developed breast cancer in the same breast within five years of diagnosis, which led the authors to suggest that, like ADH, ALH may also be a precursor in addition to being a risk indicator.

Contrary to current understanding that ALH might mostly lead to the development of lobular cancer, this study found that ALH predominantly resulted in ductal cancer of the breast, which is a similar outcome as with ADH. Both ADH and ALH resulted in invasive ductal cancers, of which 69 percent were of intermediate or high grade. About 25 percent of them had spread to the lymph nodes. The pattern of cancers in these patients resembled those seen in the general population.

“If a woman has a breast biopsy and if it shows atypia, it might be wise for her to be seen at a breast center for recommendations about surveillance and preventive therapy options,” said Hartmann. “We hope these data will further help clinicians make informed decisions for breast atypia management strategies.”

Hartmann et al., (2014). Understanding the premalignant potential of atypical hyperplasia through its natural history: A longitudinal cohort study. Cancer Prev. Res., EPub Ahead of Print, doi:10.1158/1940-6207.CAPR-13-0222 [Article]

Dormant prostate cancer cells may be reawakened by factors produced in inflammatory cells

Researchers in the Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute discovered in pre-clinical models that dormant prostate cancer cells found in bone tissue can be reawakened, causing metastasis to other parts of the body. Understanding this mechanism of action may allow researchers to intervene prior to disease progression.

“Understanding how and why dormant cells in bone tissue metastasize will aid us in preventing the spread of disease, prolonging survival and improving overall quality of life,” said Chia-Yi “Gina” Chu, PhD, a researcher and postdoctoral fellow in the Uro-Oncology Research Program and lead author of the study published in the journal Endocrine-Related Cancer.

In the study, investigators found that cancerous cells in the bone were reawakened after exposure to RANKL, a signaling molecule commonly produced by inflammatory cells. Researchers then genetically engineered cells to overproduce RANKL and found that these cells could significantly alter the gene expression of surrounding dormant cells in lab studies and in laboratory mice, causing them to transform into aggressive cancer cells.

Researchers then injected these engineered RANKL cells directly into the blood circulation of laboratory mice, which caused dormant cells within the skeleton to reawaken, creating tumors within the bone. When the RANKL receptor or its downstream targets were blocked, tumors did not form.

“After examination, these engineered tumors were found to contain both RANKL-producing prostate cancer cells and dormant cells, which had been transformed to become cancerous,” said Chu. “However, the transformed cells displayed aggressive traits that would metastasize to bone and become resistant to standard hormone therapies used to treat the disease.”

Though findings are preliminary, researchers plan to identify other cells known to produce RANKL that may also recruit and reprogram dormant cells to colonize bone tissue. Investigators plan to embark into clinical research with human patients in collaboration with leading Cedars-Sinai researchers, including Edwin Posadas, MD, medical director of the Urologic Oncology Program.

“Though more work must be done to understand how RANKL reprograms dormant cells to become cancerous, we look forward to examining its influence on promoting metastasis and secondary tumors, as well as the possibility of ‘deprogramming’ metastatic cancer cells,” said Leland Chung, PhD, director of the Uro-Oncology Research Program.

Chu et al., (2014). RANK- and c-Met-mediated signal network promotes prostate cancer metastatic colonization. Endocr. Relat. Cancer, EPub Ahead of Print, doi: 10.1530/ERC-13-0548 [Article]