Colin G. Evans, PhD

Bone metastases appear most commonly in the ribs, the spine (cervical, thoracic, and lumbar vertebrae, and pelvis), and have also been documented in long bones (femur).

Metastatic growth at these sites gives rise to severe bone pain, often requiring powerful analgesia and external beam radiation treatment. Spinal cord or nerve root compression, myelosuppression, and disturbances in calcium metabolism also commonly occur.

A recent review summarized the pathophysiology of bone pain as, &ldquo;components of neuropathic, inflammatory and ischemic pain, arising from ectopic sprouting and sensitization of primary afferent sensory nerve fibers within prostate cancer-invaded bones.&rdquo; It further asserted that metastases arises and is perpetuated by virtue of the cross talk between the osteoclasts and osteoblasts and other factors involved in the bone microenvironment.5 This multifactorial pathophysiology makes it challenging to manage and an imperative to avoid.

The management of bone pain was explored in a study that included 1305 patients with prostate cancer and bone metastases.6 Overall, 76% of the patients had been treated with bone-targeting agents for a variety of causes, including bone pain (34%), high risk of bone complications (33%), number of bone metastases (12%), locations of bone metastases (8%), and prior history of bone complications (6%). Additionally, 27% of the patients with bone metastases needed opioids for the relief of bone pain.

A recent preclinical study has highlighted an unreported mechanism that promotes the growth of bone metastases in prostate cancer.

Using a mouse model they showed that following injection of prostate cancer cells into the intramedullary cavity of the tibia, tumor growth increased pressure within the mouse tibia. In vitro experiments subsequently revealed that pressure applied to osteocytes facilitated prostate cancer growth and invasion, and this was mediated in part by an upregulation of CLL5 and matrix metalloproteinases in osteocytes.

These findings implicate osteocytes, responding to the increased pressure generated by tumor growth, in the orchestration of the metastatic niche within the bone in patients with prostate cancer.

This again emphasizes the clinical imperative to reduce the incidence of bone metastases in prostate cancer.

Impact of Bone Pain on Survival and Quality of Life

Several studies have assessed the impact of bone pain on survival and quality of life. A retrospective analysis examined 599 patients from three randomized controlled trials conducted from 1992 to 1998.

Patients in this analysis had progressive CRPC adenocarcinoma of the prostate and an ECOG performance status of 0 to 2. The Brief Pain Inventory (validated scale) gauged the impact of pain on selected daily activities and quality of life (QOL).

They found a median pain interference score of 17, and a statistically significant association between pain scores and the risk of death. Comparing men with low (<17) and high (&ge;17) pain scores, respectively, the median survival times were 17.6 versus 10.2 months (P <.001). When comparing the same two cohorts, median times to bone progression were 6.7 months and 3.8 months, respectively (P <.001).

Men with pain scores &ge;17 had a 22% greater risk of bone progression than men with pain scores <17. Median times to PSA progression followed a similar pattern, with 4.0 versus 2.9 months for scores of <17 and &ge;17 respectively (P <.001).

Additionally, a study from 2002,9 found that skeletal-related events (SREs) have clinically meaningful and significant impact on health-related QOL, with physical, emotional, and functional wellbeing all declining after pathologic fractures and radiation therapy. Significant declines in preference and utility scores were noted after fractures and radiation. Pain intensity only declined after radiation treatment, but not after other SREs.

Moreover, another study identified an association between skeletal morbidities and patient reported outcomes and survival.

The trial recruited 643 patients, and they received either zoledronic acid or placebo for 15 months. Patients with no SREs at 6 months (landmark) had significantly greater survival at 360 days post landmark (49.7% vs 28.2%; P = .02). Health-related QOL measures in the post landmark period, including pain, were worse in patients who experienced SREs during the landmark period.

Managing Bone Metastases: Bone-Targeted Agents

There are currently a number of treatments that are approved for the management of patients with mCRPC and bone metastases. They include osteoclasttargeting agents, zoledronic acid and denosumab, and radiopharmaceuticals such as &szlig;-particle emitters, strontium-89 chloride and samarium Sm-153 lexidronam, and the &alpha;-particle emitter radium-223 (Xofigo).

A phase III trial of zoledronic acid (a bisphosphonate) versus placebo in 643 patients with mCRPC and bone metastases, without severe bone pain, showed that fewer patients taking zoledronic acid dosed at 4 mg every 3 weeks for 15 months experienced SREs versus placebo (33% vs 44% P = .021); however, survival was not significantly different between the groups. At 24 months of follow-up, zoledronic acid treatment reduced the risk of SREs by 36% versus placebo. Bone pain was also reduced in patients treated with zoledronic acid compared with placebo.

A phase III trial was conducted on denosumab (a monoclonal antibody against a key activator of osteoclastic resorption, RANKL) versus zoledronic acid (TABLE 1).

The primary endpoint was time to first on-study SRE. Overall survival (OS) and investigator-assessed overall disease progression and PSA levels during the study were among key exploratory endpoints.

The study recruited patients with mCRPC and bone metastases who had no prior treatment with bisphosphonates. A total of 1904 patients were randomized, 950 to denosumab and 951 to zoledronic acid. The median time to the first SRE was 20.7 versus 17.1 months for denosumab and zoledronic acid, respectively (HR, 0.82; 95% CI, 0.71-0.95; P = .008). OS and investigator reported disease progression were not significantly different between the groups. Changes in median PSA concentrations and bone pain were also similar between the groups during the study.

There are a number of toxicity concerns associated with these agents. Nephrotoxicity is a commonly reported adverse event (AE) for bisphosphonates, necessitating monitoring of serum creatinine and appropriate dose adjustment. Denosumab, however, does not cause nephrotoxicity in men with prostate cancer.

An integrated analysis of three randomized phase III trials (5723 patients) confirmed that both drugs are associated with hypocalcemia and osteonecrosis of the jaw (ONJ).13 Hypocalcemia incidence was higher among patients treated with denosumab versus zoledronic acid (3.1% vs 1.3% for grade 3/4). ONJ was found to occur more frequently in patients treated with denosumab than zoledronic acid (1.8% vs 1.3%), but the difference was not statistically significant.

The status of &szlig;-particle emitters strontium-89 chloride and samarium Sm-153 lexidronam has recently been reviewed by Body et al.

Considering the evidence, they conclude that although both agents seem to exert clinically relevant analgesic effects in patients with bone pain in mCRPC, they have not been unequivocally shown to reduce the incidence of SREs or to extend survival.

The toxicities associated with these agents are largely hematological, with marrow toxicity being the major side effect of samarium Sm-153 lexidronam. A temporary increase in bone pain during early treatment occurs in 15% of patients treated with strontium-89 chloride.

The data for the &alpha;-particle emitter radium-223, which selectively binds to areas of increased bone turnover in bone metastases, that secured its approval came from the pivotal phase III ALSYMPCA trial (TABLE 2).

The study randomized 921 patients in a 2:1 fashion to receive six injections of radium-223 or placebo, one injection given every 4 weeks. The primary endpoint was OS. Secondary endpoints included time to first SRE and biochemical endpoints. The efficacy analysis measured radium-223 survival benefit versus placebo seen at an interim analysis.

The final analysis showed median OS of 14.9 versus 11.3 months for radium-223 and placebo respectively, which represented a 30% reduction in the risk of death for patients treated with radium-223 (HR, 0.70; 95% CI, 0.58-0.83; P <.001). Radium-223 treatment significantly prolonged the time to the first SRE (median 15.6 vs 9.8 months; HR 0.66; 95% CI, 0.52-0.83; P <.001). PSA blood levels at week 12 were reduced by &ge;30% in 16% of patients in the radium-223 group and in 6% of patients in the placebo group (P <.001). This was maintained for 4 weeks after the last injection in 14% versus 4% of patients in the radium-223 and placebo arms, respectively (P <.001).

Safety profiles were similar between the treatment arms. One patient experienced grade 3 febrile neutropenia in each group. There was one grade 5 hematological event (thrombocytopenia) in the radium-223 group considered possibly related to the study drug.

The incidence of bone pain was reduced in patients treated with radium-223 versus placebo (10% vs 16%). Significantly more patients in the radium-223 group versus placebo experienced a meaningful improvement in QOL as determined by the Functional Assessment of Cancer Therapy-Prostate score (25 % vs 16%; P = .02).

Newly approved therapies appear to provide the greatest benefits to patients with asymptomatic metastatic prostate cancer, suggesting that earlier detection of metastases is essential to improving care.

A leading question facing the early detection of bone metastases is whether scans should be triggered by a biochemical event or conducted at a fixed interval.

In a study published in 2014, using the SEARCH database, PSA levels, PSA doubling time, and PSA velocity were predictors of metastases in patients with increasing PSA levels after radical prostatectomy.

In the study, data were analyzed from 401 patients undergoing a bone scan for suspected metastatic disease from 1995 to 2012 at six Veteran Affairs Medical Centers. All patients had bone scans, and their PSA levels and PSA kinetics at the time of scan were available. The secondary objective of the study was to use PSA and PSA doubling time (PSA-DT) to rank bone scans according to positivity.

In the study, in patients who were hormone therapy naive, screening for bone metastases should be initiated for a PSA-DT of <9 months. In contrast, there was only a 2% risk of a positive bone scan if the PSA-DT was &ge;9 months. A longer PSA-DT was still associated with a very low risk of a positive scan, even in men with high PSA values.

In men after androgen deprivation therapy (ADT), they could not identify a subgroup where the risk of a positive bone scan was low. Even among patients with very low PSA and PSA-DT, the risk of a positive bone scan was &ge;10%, and the authors recommended that bone scans should begin early in patients after ADT, even before a PSA level of 5 ng/mL was reached.

In a more recent analysis, again using the SEARCH database, they devised a tool to assist physicians in the selection of patients with CRPC who may be in need of bone scans. The table combines PSA and PSA-DT, and stratifies patients according to the risk of having a bone scan. They also point out that the table could be used for the identification of particular populations of patients for specific clinical trials (TABLE 3).

This analysis found that men with a PSA of <5, 5 to 14.9, 15 to 49.9, and &ge;50 ng/mL had scan positivity of 6%, 14%, 29%, and 57%, respectively (P trend <.001). Scan positivity was 11%, 22%, 34%, and 47% for men with PSADT &ge;15, 9 to 14.9, 3 to 8.9, and >3 months, respectively (P trend <.001).

Considering prostate cancer in general, the extent of the disease dictates the best timing and sequencing of treatments in addition to patient-specific factors. These include the site and extent of disease, speed of progression, symptoms experienced, comorbidities, availability of particular treatments, and contraindications of therapeutic agents/procedures.

With novel bone-directed therapies available, trials are currently assessing the best use of these therapies in combination.

Body JJ, Casimiro S, Costa L. Targeting bone metastases in prostate cancer:Improving clinical outcome.

Wang CY, Wu GY, Shen MJ, et al. Comparison of distribution characteristics of metastatic bone lesions between breast and prostate carcinomas.

Sartor O, Coleman R, Nilsson S, et al. Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: results from a phase 3, double-blind, randomised trial.

Smith MR, Coleman RE, Klotz L, et al. Denosumab for the prevention of skeletal complications in metastatic castration-resistant prostate cancer: comparison of skeletal-related events and symptomatic skeletal events.

Muralidharan A, Smith MT. Pathobiology and management of prostate cancer-induced bone pain: recent insights and future treatments.

Body JJ, Henry D, Von Moos R et al. (a) Bone targeting agent (BTA) treatment patterns and the impact of bone metastases (BM) on prostate cancer patients in a real world setting. European Cancer Congress 2015 Vienna abstract # 1527.

Sottnik JL, Dai J, Zhang H, et al. Tumor-induced pressure in the bone microenvironment causes osteocytes to promote the growth of prostate cancer bone metastases.

Halabi S, Vogelzang NJ, Kornblith AB, et al. Pain predicts overall survival in men with metastatic castration-refractory prostate cancer.

Weinfurt KP, Li Y, Castel LD, et al. The significance of skeletalrelated events for the health-related quality of life of patients with metastatic prostate cancer.

Saad F, Gleason DM, Murray R, et al. A randomized, placebocontrolled trial of zoledronic acid in patients with hormonerefractory metastatic prostate carcinoma.

DePuy V, Anstrom KJ, Castel LD, et al. Effects of skeletal morbidities on longitudinal patient-reported outcomes and survival in patients with metastatic prostate cancer.

Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, doubleblind study.

Lipton A, Fizazi K, Stopeck AT, et al. Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomised, phase 3 trials.

Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer.

Moreira DM, Cooperberg MR, Howard LE, et al. Predicting bone scan positivity after biochemical recurrence following radical prostatectomy in both hormone-naive men and patients receiving androgen-deprivation therapy: results from the SEARCH database.

Moreira DM, Howard LE, Sourbeer KN, et al. Predicting bone scan positivity in non-metastatic castration-resistant prostate cancer.

Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-422.

Basch E, Autio K, Ryan CJ, et al. Abiraterone acetate plus prednisone versus prednisone alone in chemotherapy-naive men with metastatic castration-resistant prostate cancer: patientreported outcome results of a randomised phase 3 trial.

Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy.

Ryan CJ, Saylor PJ, Everly JJ, et al. Bone-targeting radiopharmaceuticals for the treatment of bone-metastatic castrationresistant prostate cancer: exploring the implications of new data.

Articles

Bone metastases in metastatic castration-resistant prostate cancer (mCRPC) can invade a range of sites in the skeleton where they precipitate a spectrum of pathological processes that increase morbidity, negatively affect quality of life, and decrease survival.

Preventing and Treating Bone Metastases in mCRPC

concluded that docetaxel should be considered the new standard of care for men with hormone-sensitive metastatic prostate cancer.

One of the studies included in this meta-analysis was recently published in the

, and its conclusions are echoed in the meta - analysis.

The primary objective of this study was to determine whether overall survival would be longer for patients receiving docetaxel therapy at the commencement of androgen deprivation therapy versus patients receiving ADT alone (NCT00309985). The study was designed to ensure it had 80% power to detect a 33% difference in overall survival (OS) between the two groups. Secondary objectives included PSA levels, median time to disease progression, median time to development of castration-resistant prostate cancer, and safety. The study enrolled and randomized patients from July 2006 through December 2012. The cut - off date for survival in the publication was December 23, 2013. All other data were from the database as of December 23, 2014.

Inclusion criteria mandated all eligible patients had a pathological diagnosis of prostate cancer or a clinical presentation of prostate cancer with an elevated prostate-specific antigen (PSA) level. Presence of disease had to be confirmed radiologically, and ECOG performance status of 0, 1, or 2. Prior adjuvant therapy was allowed, subject to timing of duration (&le;24 months) and of progression following cessation of therapy (>12 months). Patients were enrolled if they were already taking docetaxel provided they did not experience progression and the treatment had begun within 120 days before randomization. Indices of organ function had to prove adequate for treatment with docetaxel.

Patients randomized to ADT alone were seen every 3 months. For those randomized to the combination, patients were seen every 3 weeks during the course of docetaxel, and once every 3 months thereafter. PSA was measured at every visit. A PSA level of <0.2 ng/mL on two consecutive measurements &ge;4 weeks apart was taken to indicate a complete serologic response. An increase in PSA >50% more than the nadir attained following the start of ADT (2 consecutive increases &ge;2 weeks apart) was taken to indicate serologic progression. Imaging was conducted at baseline and at the time of documented castration resistance or as medically indicated.

The study randomized 790 patients, 397 to receive ADT alone or to ADT with docetaxel (75 mg/m

) every 3 weeks for 6 cycles and premedicated with dexamethasone (8 mg oral). Dose modification for ADT was not allowed, and no more than two were allowed for docetaxel (down to 65 mg/m

). Administration of growth factors was left to the discretion of the investigators. Patient characteristics were evenly distributed between the two groups. Approximately 70% of patients had an ECOG performance score of 0, about 65% presented with high-volume disease, and about 60% had a Gleason score of &ge;8.

The median age of the patients in the ADT group was 63 years (39-91) and 64 years (36-88) in the docetaxel and ADT group. The majority of patients (73%) had received no prior curative local therapy. For the patients who had begun ADT therapy before randomization, the median time interval between the start of therapy to randomization was similar between the study arms at 1.2 months and 1.3 months for the combination arm and the ADT monotherapy arm, respectively.

About 86% of patients in the combination group completed the 6 cycles of therapy, and 74% did not require dose modification. The median follow-up was 28.9 months. Median OS was 57.6 months versus 44.0 months for patients receiving ADT and docetaxel or ADT alone, respectively (HR for death in combination group, 0.61; 95% CI 0.47-0.80;

<.001), a difference of 13.6 months. When analyzing data for the subgroup of patients with high-volume disease, at the final analysis, median OS was again superior in the combination therapy group versus the ADT-alone group at 49.2 months and 32.2 months respectively (HR for death, 0.60; 95% CI, 0,45-0.81;

<.001). Median survival for patients with low-volume disease had not been reached in either study arm; however, all subgroups analyzed showed benefit with docetaxel treatment. A total of 85 patients died in the combination group versus 114 in the ADT-alone group, all designated as prostate cancer deaths.

Secondary efficacy endpoints also showed a benefit in the combination arm. The percentage of patients receiving combination therapy who achieved a decrease in PSA to less than 0.2 ng/mL was significantly greater than those receiving ADT alone.

Another advantage for the combination arm became apparent for the median time to development of castration-resistant prostate cancer. Median time to development was 20.2 months versus 11.7 months for the combination and ADT-alone groups, respectively, (HR combination group, 0.61; 95% CI, 0.51-0.72;

<.001), and similarly for median time to clinical progression at 33.0 months versus 19.8 months for the combination and ADT-alone groups respectively (HR, 0.61; 95% CI, 0.50-0.75;

The study reported treatment-related grade 3 or 4 allergic reactions in the combination therapy group along with grade 3 fatigue in 4%. Occurring at rates of 1% or less were grade 3 diarrhea, stomatitis, motor neuropathy, and sensory neuropathy. Neutropenic fever occurred in 6% of patients in the combination group, and 2% had grade 3 or 4 infection with neutropenia.

The authors concluded that docetaxel with ADT, prescribed as per the study protocol, led to significantly longer OS than in men treated with only ADT in men with metastatic hormone-sensitive prostate cancer. These data and others included in the recent meta-analysis support combination therapy of docetaxel with ADT for men with metastatic, hormone-sensitive prostate cancer.

Vale CI, Burdett S, Rydzewska LHM, et al.

. 2015; pii: S1470-2045(15)00489-1. doi: 10.1016/S1470-2045(15)00489-1.

TargetedOnc.com. Metastatic hormone-sensitive prostate cancer should include docetaxel alongside ADT.

http://www.targetedonc.com/news/metastatic-hormone-sensitive-prostate-cancer-docetaxel-adt

Sweeney CJ, Chen YH, Carducci M, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer.

A recent paper concluded that docetaxel added to standard of care should be considered the new standard of care for men with hormone-sensitive metastatic prostate cancer.

Metastatic Hormone-Sensitive Prostate Cancer Sees Treatment Paradigm Shift

The latest results from an open-label, phase Ib study of the STAT3 inhibitor BBI-608 (napabucasin) with a standard chemotherapy (FOLFIRI with or without bevacizumab) in the treatment of advanced colorectal cancer, have been presented at the ASCO 2016 Gastrointestinal Symposium. Evidence of antitumor activity and a favorable safety profile were seen in phase I studies.

"BBI-608 is a cancer stem cell inhibitor targeting the 'stemness' of the cancer cell, meaning it [the drug] aims to target processes that the cancer cell uses to resist cancer treatments. This particular drug targets the STAT3 and beta-catenin pathways, felt to play a critical role in malignant growth and development of metastases," explained Joleen M. Hubbard, MD, assistant professor of oncology at the Mayo Clinic in Minnesota who presented the data.

Cancer stem cells are hypermalignant and consequently highly tumorigenic and metastatic. They have been isolated from many different cancer types and are found to be resistant to conventional chemotherapy and radiation. Stemness genes have been shown to be induced by such treatments and consequently stemness-high cancer cells remain after the completion of therapies and are considered to be responsible for relapse.

Using gene-silencing techniques, STAT3 was found to be important for cancer stemness, and the molecule BBI-608 was found to block transcription of genes driven by STAT3. Subsequent in vitro and in vivo work confirmed BBI-608 can block development of or kill stemness-high cancer cells, making it a promising candidate for clinical development.

Relevant to this study, it demonstrated strong synergy with 5 fluorouracil and irinotecan in experimental mouse models of colon cancer.

The trial, sponsored by Boston Biomedical Inc, recruited patients with advanced unresectable, metastatic or recurrent colorectal carcinoma for whom a number of standard chemotherapies would be acceptable as determined by the investigator. The study was conducted at multiple sites in the US and one in Canada (NCT02024607).

The primary objective of the study was to evaluate the safety, tolerability, and antitumor activity of BBI-608 in combination with FOLFIRI, with and without bevacizumab, in patients with advanced colorectal cancer. Secondary objectives included the pharmacokinetics and pharmacodynamics of BBI-608 and assess the antitumor activity of BBI-608 and FOLFIRI, with and without bevacizumab.

The study enrolled 18 patients who were heavily pretreated. Of these, 10 had received and progressed on FOLFIRI and all patients had received an average of more than three previous courses of therapy. The patients had a Karnofsky performance status &ge;70% and adequate bone marrow, hepatic, and renal function. Seventeen patients were evaluable for response, 9 of them received BBI-608 in combination with FOLFIRI and bevacizumab and 8 received BBI-608 with FOLFIRI alone. Objective tumor responses were assessed every 8 weeks. The doses are shown in

, and the regimens were administered biweekly until progression of disease, unacceptable toxicity, or other specified discontinuation criterion was met.

"It is felt that by targeting the STAT3 and beta-catenin pathway, BBI-608 may help prevent the resistance that develops with FOLFIRI +/- bevacizumab treatment. Synergy has also been seen with other chemotherapy regimens, supporting this theory," said Hubbard. The study was conducted to confirm the recommended phase II dose for BBI-608.

Doses and Regimens in BBI-608 Phase 1B Study in Advanced Colorectal Cancer

Data were available for 17 of the patients. The most common AEs are shown in

and investigators encountered no new AEs, no dose limiting toxicities, and noted that the safety profile was similar to that experienced when each regimen was used as monotherapy.

Most Common Adverse Effects in Phase IB Study of BBI-608 in Advanced Colorectal Cancer

There were several grade 3 AEs related to protocol therapy namely diarrhea (3 patients), fatigue (2 patients) and dehydration (1 patient). Dose reduction and/or antidiarrheal medications ensured resolution of all AEs.

Prolonged disease control for more than 24 weeks was achieved in &ge;50% of patients, (59%, 10/17 evaluable patients) or (56%, 10/18 intent-to-treat patients) Partial response (PR) or stable disease (SD) was achieved by 94% (16/17 of evaluable patients). The PRs (2) were 44% and 33% regression by Response Evaluation Criteria in Solid Tumors (RECIST 1.1 criteria). The majority (13/14) of patients with SD had tumor regression <25%. For the 17 evaluable patients, the median progression-free survival was 5.56 months. No significant pharmacokinetic interactions were noted.

The study authors conclude that BBI-608 at 240 mg bid combined with FOLFIRI with or without bevacizumab is safe and shows anticancer activity even in patients who previously failed on FOLFIRI therapy. The dose of 240 mg BID is now considered to be the recommended dose of BBI-608 when used with FOLFIRI, with or without bevacizumab, in further studies.

Commenting on future data and development for BBI-608, Hubbard stated, "In other arms of this phase Ib study, BBI-608 is being studied with other combinations of gastrointestinal cancer treatment including FOLFOX, FOLFOX + bevacizumab, CAPOX, and regorafenib. It's also being studied in combination with chemotherapy for pancreatic cancer, as well as chemotherapy for gastric cancer."

Reflecting further on the potential of BBI-608, Axel Grothey, MD, professor of oncology at the Mayo Clinic and coauthor of the abstract and poster, said in a press release, "These clinical studies of napabucasin in advanced gastroenterological cancers, including the presentation of data in refractory colorectal cancer specifically, show encouraging clinical activity by targeting cancer stem cell pathways that contribute to cancer recurrence, metastases, and resistance to therapies. I look forward to the further investigation of this innovative approach to cancer treatment in additional clinical studies."

Hubbard JM, O&rsquo;Neil BH, Jonker DJ et al. Phase 1b study of cancer stem cell (CSC) pathway inhibitor BBI-608 administered in combination with FOLFIRI with and without bevacizumab (Bev) in patients (pts) with advanced colorectal cancer.

http://bostonbiomedical.com/boston-biomedicals-investigational-cancer-stem-cell-pathway-inhibitor-napabucasin-bbi608-featured-at-the-asco-2016-gastrointestinal-cancers-symposium/ Accessed January 25, 2016.

http://bostonbiomedical.com/wp-content/uploads/Abst569-BBI608-246-ASCOGI2016.pdf Accessed January 25, 2016.

Li Y, Rogoff HA, Keates S, et al. Suppression of cancer relapse and metastasis by inhibiting cancer stemness.

First-in-Class Cancer Stemness Inhibitor Shows Promising Results in Advanced Colorectal Cancer

These two subtypes have different distribution patterns on the body and L597 mutation melanomas having more favorable prognostic characteristics than those with the K601E mutation.&nbsp;Preliminary reports show these mutations may respond to targeted therapies, and the authors urge that prospective studies be conducted to clarify the responses of these mutations to BRAF and MEK inhibition.

The researchers employed data from the Melbourne Melanoma Project database to arrive at their conclusions. The data included patients recruited between 2009 and May 2013 and contained molecular analysis data for primary melanomas in 1159 patients (99.7% of the total database). After excluding data on

melanomas, cutaneous metastases, benign nevi, and spitzoid tumors of unknown malignant potential, the final total of 1119 examples of invasive melanomas remained.

mutations were found in melanomas in 435 patients. The majority of these were V600 mutations (n = 406) the most common being the V600E mutation (n=310). BRAF wild type (BRAF wt), were encountered in 684 patients, and among these, 37 had

The team also found less common V600 mutations, such as V600D (n=4), V600M (n=1), V600K (n=86), and V600R (n=5). Sunburn history was reported by similar proportions of patients (V600E, 60.5%; K601E, 66.7%; L597, 66.7%;

were the most commonly found non-V600 mutations, comprising 3.3% and 3.1% of all

mutations. The patients were predominantly male, (K601E:71.4%; L597: 73.3%) and this gender difference was statistically significant (

These patients were significantly older versus patients with the V600E mutation (median 66 years range 58-71; median 50 years, range 40-61;

= .001). Using the presence or absence of solar keratoses as a measure of prior sun exposure, it was found that a history of solar keratosis was more common in patients with the L597 mutation (58.3%) than in patients with V600E mutations (

= .04). L597 melanomas were most often located on the extremities in 40% of patients, and on the head and neck in a further 33% of patients.

When assessed by Breslow thickness, it was found that 35.5% of V600E, 42.9% of L597, and 27.9% of BRAF wt melanomas were <1.0 mm. Examination of histological subtypes revealed that 66.7% of L597 melanomas were of the superficial spreading subtype (SSM), and this association was statistically significant. However, they were more likely to be of the lentigo maligna subtype (LMM) than SMM when compared with V600E- mutant melanomas (P = .02). Ulceration, a poor prognostic feature, was seen in 33.3% of L597 cases, and 85.7% had &ge;1 mitoses/mm

In contrast to patients with L597 mutations, these individuals were younger, had a median age of 58 years (31-86) and this was not significantly different from patients with the V600E mutation (

= .2). Thirty six percent of patients with the K601E mutation and 50.6% of patients with V600E were under 50 years of age. With respect to a history of solar keratoses, patients with the K601E mutation had an incidence of only 16.7% (similar to V600E patients). Given this finding, the authors reiterated that the K601E and V600E-mutant primary lesions were more often found on the trunk, areas with less sun exposure, versus BRAF wt lesions, which are more common on sun-exposed sites (K601E, 64.3%,

Regarding Breslow thickness, a smaller percentage of K601E melanomas (21.4%) had a median thickness of <1mm with 35.7% having a thickness >4.0 mm. There was a difference in melanoma histology between K601E and L597 mutations. A greater proportion of K601E melanomas were nodal melanomas, with fewer SMM versus the other mutations, but this was not statistically significant. However, 43% of patients with the K601E mutation had nodal disease on diagnosis versus only 14% of patient with BRAF wt tumors (

- harboring melanomas differ in terms of mutation load. The finding that BRAF

melanomas lacked an association with chronic sun damage suggests the mutation is more likely to occur in low mutation load melanomas. This melanoma is more likely to occur in patients with &ldquo;nevus prone&rdquo; skin, who develop melanomas at an earlier age with less prior sun damage.

The scenario is different for melanomas with the L597 mutation. These are considered to be more likely to arise in high mutation load tumors, and high mutation load may be a predictor of response to therapy with immune checkpoint inhibitors.

The L597 mutation melanomas generally had more favorable prognostic features than those harboring the K601E mutation because they were thinner and nodal involvement was less common.

The paper calculates that the incidence rate of the mutations L597 and K601E is 2.6%, and that in 2012 the absolute number of these patients would be 1976 in the United States alone. There is clearly a precedent for investigating the clinical impact of these mutations particularly since major clinical trials only recruit V600E or V600K mutations. In-vitro sensitivity of these mutations to MEK and BRAF inhibition has been demonstrated, and a small number of patients with these mutations have shown responses to therapy with a MEK inhibitor.

A phase II clinical trial that recruited patients with recurrent or stage III/IV melanoma with BRAF non-V600 mutations is currently evaluating the MEK inhibitor, trametinib (NCT02296112). The estimated primary completion date is January 2018. The authors conclude these mutations are a significant minority of melanomas and a prospective evaluation of possible therapeutic approaches is warranted.

Voskoboynik M, Mar V, Mailer S, et al. Clinico-pathological characteristics associated with BRAF(K) (601E) and BRAF(L) (597) mutations in melanoma.

Dahlman KB, Xia J, Hutchinson K, et al. BRAF(L597) mutations in melanoma are associated with sensitivity to MEK inhibitors.

Bowyer SE, Rao AD, Lyle M, et al. Activity of trametinib in K601E and L597Q BRAF mutation-positive metastatic melanoma.

Snyder A, Makarov V, Merghoub T, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma.

A team in Australia have revealed the clinicopathological phenotypes and clinical activities of rarer BRAF mutations, namely BRAFK601E (K601E) and BRAFL597 (L597).

Colin G. Evans, PhD | Authors

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