Researchers map paths to cancer drug resistance

A team of researchers have identified key events that prompt certain cancer cells to develop resistance to otherwise lethal therapies.By mapping the specific steps that cells of melanoma, breast cancer and a blood cancer called myelofibrosis use to become resistant to drugs, the researchers now have much better targets for blocking those pathways and keeping current therapies effective. The findings are published in two papers in the journal Science Signaling.

Clinical resistance to anticancer therapies is a major problem,” said lead author Kris Wood, Ph.D., assistant professor of Pharmacology and Cancer Biology at Duke. “The most logical way to solve the problem is to understand why tumor cells become resistant to drugs, and develop strategies to thwart these processes.”

In our studies, we developed a screening technology that allows us to quickly identify the routes cells can use to become resistant, and using that information, we were able to show that these mechanisms seen in the laboratory are actually also occurring in patients’ tumors,” Wood said.

Wood and colleagues conducted a broad survey of the known cell-signaling pathways that, when activated, have the potential to trigger resistance to drugs. Using this screening technology, they were able to corroborate the results of earlier drug-resistance studies, while also finding new pathways that had not previously been described.The new mechanisms they identified in the laboratory were also clinically relevant, appearing in tumor cells from patients who had grown resistant to therapies.

Interestingly, the mechanisms are quite similar among all three of the cancer types,” Wood said. “In breast cancer and melanoma, our findings suggest the same Notch-1 pathway as a potential driver of resistance to a wide array of targeted therapies — a role that has not been widely acknowledged previously.”

Wood said that in myelofibrosis, the researchers tracked a pair of separate signaling pathways downstream of an important signaling molecule called RAS. When activated, these pathways promote resistance to current standard-of-care targeted drugs by suppressing cell death. In the second Science Signaling paper, the researchers suggest that targeting the pathways downstream of RAS may sustain the potency of current therapies.

Together, these findings improve our ability to stratify patients into groups more and less likely to respond to therapy and design drug combinations that work together to block or delay resistance,” Wood said.

Martz et al. Systematic identification of signaling pathways with potential to confer anticancer drug resistance.Sci Signal. 2014;7(357):ra121. doi: 10.1126/scisignal.aaa1877 [Abstract]

Winter et al. RAS signaling promotes resistance to JAK inhibitors by suppressing BAD-mediated apoptosis. Sci Signal. 2014;7(357):ra122. doi: 10.1126/scisignal.2005301 [Abstract]

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Breast reconstruction using patient’s own tissues yield higher satisfaction rates

New insights for patient decision-making, suggests study in plastic and reconstructive surgery

For women who have undergone mastectomy, breast reconstruction using the patient’s own tissues, rather than implants, provides higher satisfaction scores, reports a study in Plastic and Reconstructive Surgery, the official medical journal of the American Society of Plastic Surgeons (ASPS).

But the findings may at least partly reflect differences in the characteristics of women choosing different options for breast reconstruction, according to the study by plastic surgeon Dr. Yassir Eltahir and colleagues of University Medical Center Groningen, the Netherlands.

Higher Satisfaction Score with Autologous Breast Reconstruction

The researchers used the recently developed “BREAST-Q” questionnaire to analyze patient satisfaction and quality of life after breast reconstruction. The BREAST-Q was designed to gauge these important outcomes from the patient’s point of view.

The study included BREAST-Q surveys completed by 92 women who had breast reconstruction between 2006 and 2010. Forty-seven women underwent autologous reconstruction, with the patient’s own tissues–generally “donor” flaps from the abdomen–used to create the new breast. The remaining 45 women underwent alloplastic reconstruction, using implants.

The results suggested that women choosing reconstruction with their own tissues were more satisfied with the results. Scores for satisfaction with the reconstructed breasts averaged about 75 (on a 100-point scale) after autologous reconstruction versus 65.5 for implant-based reconstruction.

Overall patient satisfaction scores were also higher with autologous reconstruction: about 82 versus 74.5. Scores for various aspects of quality of life–including psychosocial, sexual, and physical well-being–were not significantly different between groups.

Significant Differences in Patient Characteristics

The researchers also noted some important differences between the two groups of patients. Women choosing autologous reconstruction were older: 51 versus 44 years. Autologous reconstruction was performed on a delayed basis, an average of 21 months after mastectomy; whereas implant-based reconstruction was usually performed immediately.

Women receiving implant reconstruction were also more likely to undergo reconstruction of both breasts. Many of these women underwent preventive double mastectomy because of high genetic risk of breast cancer.

Women undergoing autologous reconstruction were more likely to receive radiation therapy, had a higher average body weight, and were less educated. Complication rates were similar between groups, although the autologous reconstruction group had a higher rate of secondary corrective surgeries.

Women have several options for breast reconstruction after mastectomy, in terms of the type of reconstruction and immediate versus delayed reconstruction. Studies comparing the outcomes of autologous versus implant-based reconstruction have reported conflicting results. The new study, using the validated BREAST-Q questionnaire, suggests higher patient satisfaction rates for women undergoing reconstruction using their own tissues.

But the findings may reflect differences in patient characteristics between groups. For example, younger women undergoing immediate implant reconstruction may have higher expectations, compared to women who have waited several months for delayed autologous reconstruction. The researchers plan further studies to evaluate some of the questions raised by their preliminary results.

Meanwhile, Dr. Eltahir and coauthors emphasize that both methods of breast reconstruction provided good outcomes, with similar scores for quality of life. “The study found no ideal breast reconstruction suitable for all patients,” the researchers write. “However, it may inform patients and medical teams in making decisions about breast reconstruction.

Eltahir et al. Which breast is the best? Successful autologous or alloplastic breast reconstruction: Patient-reported quality-of-life outcome. Plast Reconstr Surg. 2015;135(1):43-50. doi: 10.1097/PRS.0000000000000804 [Article]

Risk for leukemia after treatment for early-stage breast cancer higher than reported

The risk of developing leukemia after radiation therapy or chemotherapy for early stage breast cancer remains very small, but it is twice as high as previously reported, according to results of a new study led by researchers at the Johns Hopkins Kimmel Cancer Center.

The study team reviewed data on 20,063 breast cancer patients treated at eight U.S. cancer centers between 1998 and 2007 whose cancer recurrence and secondary cancer rates were recorded in a database kept by the National Comprehensive Cancer Network. In that group, 50 patients had developed some form of leukemia within 10 years after radiation therapy, chemotherapy or a combination of the two. That translates to roughly a cumulative risk of 0.5 percent.

Data from earlier randomized clinical trials, which typically include just a few hundred patients, found that about 0.25 percent of breast cancer patients develop leukemia as a late effect of chemotherapy, says Judith Karp, M.D., professor emerita of oncology at the Johns Hopkins University School of Medicine, who retired in 2013 as director of the Kimmel Cancer Center’s Leukemia Program. Results  were published online in the Journal of Clinical Oncology.

The frequency of bone marrow cancers such as leukemia is small, there’s no question about it,” Karp says. “However, the cumulative risk over a decade is now shown to be twice as high as we thought it was, and that risk doesn’t seem to slow down five years after treatment.”

Most medical oncologists have come to think that the risk is early and short-lived,” says Karp. “So this was a little bit of a wake-up call that we are not seeing any plateau of that risk, and it is higher.”

Antonio Wolff, M.D., a professor of oncology at the Johns Hopkins University School of Medicine, says the study could help early-stage breast cancer patients and their physicians think more carefully about the use of chemotherapy for “just-in-case” reasons, especially when patients have a low risk of cancer recurrence.

Our study provides useful information for physicians and patients to consider a potential downside of preventive or adjuvant chemotherapy in patients with very low risk of breast cancer recurrence,” says Wolff. “It could be a false and dangerous security blanket to some patients by exposing them to a small risk of serious late effects with little or no real benefit from the treatment.”

In recent years, oncologists have learned that postsurgical chemotherapy for breast cancer mostly benefits a small and select group of patients. The National Comprehensive Cancer Network clinical guidelines no longer recommend it for all patients with stage 1 breast cancers, the term for invasive breast cancers no larger than 2 centimeters that have not spread to nearby lymph nodes.

Wolff says that each patient’s treatment plan for early-stage cancer could differ depending on a variety of factors, including the size of the tumors; whether the cancer has spread to the lymph nodes; and whether the tumor tests positive for certain breast cancer-related hormone and growth receptors, such as estrogen receptors (ER) and human epidermal growth factor receptor 2 (HER2).

The study team, led by Johns Hopkins researchers, also included a hypothetical case to put the risks of early-stage breast cancer and chemotherapy treatment in perspective. She was a 60-year-old woman in average health, diagnosed with stage 1 breast cancer that was rapidly growing and ER-positive, and who is calculated to have a 12.3 percent risk of dying of breast cancer after 10 years. She could improve her 10-year survival rate by 1.8 percent with four cycles of chemotherapy, but she would also increase her risk of leukemia over that same time by 0.5 percent.

The good news is that the majority of patients with stage 1 breast cancer will survive their breast cancer diagnosis,” he adds, “and of all the solid tumors, breast cancer is among the most curable of them.”

Wolff says it isn’t yet clear whether the increased risk of leukemia after post surgical chemotherapy applies to patients with other kinds of solid tumors, especially since the drug regimens used in breast cancer differ from those used for other cancers.

Boileau et al. Sentinel node biopsy after neoadjuvant chemotherapy in biopsy-proven node-positive breast cancer: The SN FNAC study. J Clin Oncol. 2014; Epub ahead of print. doi:10.1200/JCO.2014.55.7827 [Abstract]

Youngest bone marrow transplant patients at higher risk of cognitive decline

St. Jude Children’s Research Hospital study identifies small group of patients at risk for intellectual decline after bone marrow transplantation; results set stage for new strategies to preserve IQ and fight cancer.

Toddlers who undergo total body irradiation in preparation for bone marrow transplantation are at higher risk for a decline in IQ and may be candidates for stepped up interventions to preserve intellectual functioning, St. Jude Children’s Research Hospital investigators reported. The findings appear in the current issue of the Journal of Clinical Oncology.

The results clarify the risk of intellectual decline faced by children, teenagers and young adults following bone marrow transplantation. The procedure is used for treatment of cancer and other diseases. It involves replacing the patient’s own blood-producing stem cells with those from a healthy donor.

Researchers tracked IQ scores of 170 St. Jude patients before and for five years after transplantation, making this the most comprehensive effort yet to determine how the procedure affects intelligence. The patients ranged in age from 4 months to 23 years when their transplants occurred. The procedure had little lasting impact on the IQ scores of most patients.

For the great majority of patients, these findings provide reassurance that transplantation will not have a significant negative impact on cognitive development,” said corresponding author Sean Phipps, Ph.D., chair of the St. Jude Department of Psychology. “We have also identified a high-risk group of younger patients who may benefit from more intensive interventions, including developmental stimulation and other rehabilitative therapies designed to prevent a decline in intellectual functioning and aid in recovery.

The high-risk group includes patients whose transplants occurred when they were aged 3 years or younger and involved total body irradiation (TBI). TBI is used to prepare patients for transplantation by killing remaining cancer cells and protecting the transplanted cells from their immune systems. TBI is associated with a range of short-term and long-term side effects. At St. Jude, therapeutic advances have significantly reduced the use of TBI in bone marrow transplantations.

Previous studies of bone marrow transplantation survivors reported conflicting results about the long-term impact of age and TBI on cognitive abilities.

Before transplantation, the average IQ scores of all patients in this study were in the normal range. One year after transplantation, average IQ scores of patients aged 5 and younger had declined sharply. But scores of most patients rebounded in subsequent years. Five years after the procedure, IQ scores for most patients, even the youngest survivors, had largely recovered and fell within the range of normal intelligence.

Patients in the high-risk group were the lone exception. IQ scores of patients who were both aged 3 or younger when their transplants occurred and who received TBI failed to recover from the first-year decline. Five years after transplantation, these survivors had average IQ scores in the low-normal range of intelligence. Their scores were more than 16 points lower than the scores of patients who were just as young when their transplants occurred but did not receive TBI.

Of the 72 patients in this study whose transplants included TBI, researchers found there was a long-term impact on intellectual functioning only of patients who were aged 3 or younger at transplantation.

The significant first-year decline reflects the intensity of transplantation, which our results suggest leads to greater disruption in development in the youngest children than was previously recognized,” said the study’s first author Victoria Willard, Ph.D., a St. Jude psychology department research associate.

“These findings are good news for most parents whose children must undergo transplantation and provide another reason for hope of good long-term outcomes. For those whose children are in the newly recognized high-risk group, increased attention and activities designed to stimulate cognitive development may help to prevent reduced IQ following transplantation,” Phipps said.

Willard et al. Cognitive outcome after pediatric stem-cell transplantation: Impact of age and total-body Irradiation. J. Clin. Oncol. 2014;32(35): 3982-3988 [Abstract]

New drug combination for advanced breast cancer delays disease progression

A new combination of cancer drugs delayed disease progression for patients with hormone-receptor-positive metastatic breast cancer, according to a multi-center phase II trial. 

The findings of the randomized study were presented at the 2014 San Antonio Breast Cancer Symposium, by Kerin Adelson, M.D., assistant professor of medical oncology at Yale Cancer Center and chief quality officer at Smilow Cancer Hospital at Yale-New Haven.

The trial enrolled 118 post-menopausal women with metastatic hormone-receptor-positive breast cancer whose cancer continued to progress after being treated with an aromatase inhibitor. The study, based on work done by Doris Germain of Mt. Sinai Hospital, found that the combination of the drugs bortezomib and fulvestrant, versus fulvestrant alone, doubled the rate of survival at 12 months and reduced the chance of cancer progression overall.

Bortezomib, used most commonly in treating multiple myeloma, is a proteasome inhibitor that prevents cancer cells from clearing toxic material. Fulvestrant causes clumping of the estrogen-receptor protein. When bortezomib blocks the ability of the cell to clear these protein clumps, they grow larger and become toxic to the cancer cells. This, in turn, amplifies the effectiveness of fulvestrant, a drug commonly used in this subset of patients.

The drug combination doubled the number of patients whose cancer had not progressed after one year from 14% to 28%, according to Adelson.

This provides the foundation for future studies combining selective estrogen-receptor destroyers with proteasome inhibitors,” Adelson said. “Because the study showed a statistically significant benefit among patients whose disease progressed on an aromatase inhibitor, a larger phase III study comparing this combination to other approved therapies used after initial therapies fail, like exemestane and everolimus, should be done.”

The study results also suggest that the drug combination can delay or overcome resistance to fulvestrant. The combination should be studied in other populations of patients, Adelson added, including those who are newly diagnosed with metastatic breast cancer and those who have already progressed on fulvestrant.

San Antonio Breast Cancer Symposium 2014

HIV drug blocks bone metastases in prostate cancer

The receptor CCR5, targeted by HIV drugs, is also key in driving prostate cancer metastases, suggesting that blocking this molecule could slow prostate cancer spread.

Although prostate cancer can be successfully treated in many men, when the disease metastasizes to the bone, it is eventually lethal. In a study published online in the journal Cancer Research, researchers show that the receptor CCR5 best known for its role in HIV therapy, may also be involved in driving the spread of prostate cancer to the bone.

Because this work shows we can dramatically reduce metastasis in pre-clinical models, and because the drug is already FDA approved for HIV treatment- we may be able to test soon whether this drug can block metastasis in patients with prostate cancer,” says Richard Pestell, M.D., Ph.D., MBA, Director of the Sidney Kimmel Cancer Center at Thomas Jefferson University and senior author on the study.

The work builds on previous research from Dr. Pestell’s lab that showed in 2012 that CCR5 signaling was key in the spread of aggressive forms of breast cancer to the lungs. Their prior paper demonstrated that breast cancer cells that carried the CCR5 receptor on their surface were drawn to the lung. Given that prostate cancer cells were attracted to the bone and brain, Pestell’s team investigated whether CCR5 could play a role in prostate cancer metastases as well.

The research was complicated by the fact that there was no immune competent mouse model of prostate cancer that reliably developed bone and brain metastases. So the researchers developed a prostate cancer cell line, driven by an upregulated Src gene, that regularly caused bone metastases in immune-competent mouse models. Because the immune system is so important in human prostate cancer it was important to develop a model that reflected human disease.

The researchers analyzed the genes of the metastasized bone and brain tumors and found genes driving the cancer were also involved in the CCR5 signaling pathway. To investigate further, the researchers administered the CCR5-blocking drug maraviroc to the new prostate cancer mouse model. In comparison to control animals, maraviroc dramatically reduced the overall metastatic load by 60 percent in the bone, brain and other organs.

Finally, in order to determine whether a similar mechanism might be at play in human prostate cancer, the researchers mined the genomic data of patients with prostate cancer and found that CCR5 was more highly expressed in prostate cancer tissue compared with normal tissue, and even more highly expressed in metastases compared with primary tumors. “In fact, we noticed that patients who had a lower expression of the CCR5-pathway genes had a longer survival times, whereas high expression of these CCR5 genes was associated with a shorter overall survival,” said co-first author Xuanmao Jiao, Ph.D., and an instructor in the department of Cancer Biology at Jefferson.

Sicoli D et al. CCR5 receptor antagonists block metastasis to bone of v-Src oncogene-transformed metastatic prostate cancer cell lines. Cancer Res. 2014;EPub Ahead of Print, doi: 10.1158/0008-5472.CAN-14-0612 [Abstract]

Survival differences seen for advanced-stage laryngeal cancer

The five-year survival rate for advanced-stage laryngeal cancer was higher than national levels in a small study at a single academic center performing a high rate of surgical therapy, including a total laryngectomy (removal of the voice box), to treat the disease, despite a national trend toward organ preservation, according to a report published online by JAMA Otolaryngology-Head & Neck Surgery.

The larynx is a common site of head and neck cancer with more than 10,000 cases annually. Over the past two decades, treatment for advanced-stage laryngeal cancer has shifted from primary surgical therapy to organ preservation treatments with chemotherapy and radiation, according to study background.

Blake Joseph LeBlanc, M.D., of Louisiana State University Health-Shreveport (LSU Health), and co-authors examined survival rates at their institution for primary surgical treatment of advanced-stage tumor with outcomes in the National Cancer Database (NCDB).

In an analysis of 165 patients (majority male, average age 55 years) with laryngeal cancer in the LSU Health tumor registry from 1998 to 2007, 48 (29.09 percent) had clinically early-stage (I/II) disease and 117 (70.91 percent) had advanced-stage (III/IV) disease. Of the 117 patients with advanced-stage disease, 64 (54.70 percent) underwent primary surgical therapy to include total laryngectomy or pharyngolaryngectomy (removal of the voice box and area at the back of the mouth and throat). Data from the NCDB shows the national rate of laryngectomy declined from 60 percent in the 1980s to 32 percent in 2007. At LSU Health, five-year survival for stage IV was 55.54 percent compared with 31.60 percent nationally. LSU Health’s overall survival at all stages rate was 59.14 percent and similar to the nationwide rate, according to the study results.

This study shows that LSU Health treats a high percentage of patients with advanced-stage laryngeal carcinoma who have lower socioeconomic status, yet still has improved survival rates compared with the NCDB over the study time period. This contributes to a growing body of literature that suggests that initial surgical therapy for advanced-stage disease may result in increased survival compared with organ preservation,” authors note.

LeBlanc et al. Improvements in survival and disparities for advanced-stage laryngeal cancer. JAMA Otolaryngol Head Neck Surg. EPub Ahead of Print, 2014. doi:10.1001/jamaoto.2014.2998 [Abstract]