Elevated platelets may signal increased cancer risk

Platelets as cancer predictorPlatelets (thrombocytes) are active for more than just adhesion and cohesion in the formation of a ‘hemostatic plug’ (blood clot), along with activation of coagulation mechanisms. Platelets also have important secretory functions that release growth factors and communicate with white blood cells and cells that line blood vessels (endothelial cells). Through this they promote inflammation and tissue proliferation (as in wound healing). Now an important study published in the British Journal of General Practice that an increase in platelet count is clinical risk marker for cancer. The authors note:

“The commonest route to cancer diagnosis follows the development of symptoms, and definitive diagnosis by biopsy and access to specialist care often rely on a primary care physician to recognise the possibility of cancer. It is generally accepted that delay in symptomatic diagnosis is harmful. One feature of possible cancer has only recently been recognised to have diagnostic potential: a raised platelet count, or thrombocytosis.”

Platelets as predictors

Earlier studies have shown the predictive value of thrombocytosis for certain cancers, but none have looked at cancer in general.

“Revised UK national guidance for suspected cancer incorporates thrombocytosis in some of its recommendations for lung, oesophagogastric, and uterine cancers. However, no study has examined thrombocytosis in primary care for all cancers. This study aimed to address that gap.”

The authors examined 1-year data for two groups of subjects: 40,000 patients aged ≥40 years with a platelet count of more than 400 × 109/L (109/L = 10³/uL) and 10,000 matched patients with a normal platelet count. Clinicians, note the reference range: >400 x 10³/uL = thrombocytosisTheir data did show that elevated platelets should be regarded as a cancer risk factor, especially for lung and colorectal cancer.

“A total of 1098 out of 9435 males with thrombocytosis were diagnosed with cancer (11.6%), compared with 106 of 2599 males without thrombocytosis (4.1%). A total of 1355 out of 21 826 females with thrombocytosis developed cancer (6.2%). The risk of cancer increased to 18.1% for males and 10.1% for females, when a second raised platelet count was recorded within 6 months. Lung and colorectal cancer were more commonly diagnosed with thrombocytosis.”

Very importantly:

One-third of patients with thrombocytosis and lung or colorectal cancer had no other symptoms indicative of malignancy.”

The authors summarize their findings:

“This large-scale cohort study is the first from primary care to report the overall risk of cancer in patients with thrombocytosis, compared with those with normal platelet counts. Males with thrombocytosis had an 11.6% incidence of cancer in the following year, and females had an incidence of 6.2%: this compares with 4.1% of males with normal platelet counts. The incidence of cancer rose with age and with a higher platelet count, and at least one-third of patients with lung and colorectal cancer with pre-diagnosis thrombocytosis had no other symptoms indicative of malignancy.”

Commenting in Medscape Family Medicine

“Lead author, Sarah Bailey, MPH, PhD, research fellow at the University of Exeter Medical School, United Kingdom, said in a statement:  “We know that early diagnosis is absolutely key in whether people survive cancer. Our research suggests that substantial numbers of people could have their cancer diagnosed up to three months earlier if thrombocytosis prompted investigation for cancer. This time could make a vital difference in achieving earlier diagnosis.”

Ketone supplementation and the ketogenic diet for cancer

Clinical Cancer ResearchKetone enhancement by diet and supplementation can dramatically improve cancer survival. An easily implemented low carb high fat approach can produce results comparable to a more strict diet and be further enhanced by ketone supplementation.

Glucose consumption at a ravenous rate is characteristic of the peculiar metabolism of cancer cells. Fresh evidence for the ‘Warburg Effect’ the metabolic theory of cancer is eclipsing the earlier ascendant somatic mutation theory. Accordingly, ketogenic LCHF (low carb high fat) diets are gathering momentum in the treatment and prevention of malignancies. A study recently published in Clinical Cancer Research offers evidence that an easily implemented LCHF ketogenic diet supplemented with MCTs (medium chain triglycerides; sHFLC) may render significant benefit in the treatment of glioblastoma, a very malignant and metabolically active brain cancer, while being easier to maintain than a more strict ketogenic diet. The authors state:

“Dysregulated energetics coupled with uncontrolled proliferation has become a hallmark of cancer, leading to increased interest in metabolic therapies. Glioblastoma (GB) is highly malignant, very metabolically active, and typically resistant to current therapies. Dietary treatment options based on glucose deprivation have been explored using a restrictive ketogenic diet (KD), with positive anticancer reports. However, negative side effects and a lack of palatability make the KD difficult to implement in an adult population. Hence, we developed a less stringent, supplemented high-fat low-carbohydrate (sHFLC) diet that mimics the metabolic and antitumor effects of the KD, maintains a stable nutritional profile, and presents an alternative clinical option for diverse patient populations…We report a dietary intervention that produces low circulating glucose while elevating ketones and results in a substantial reduction in GB cellular proliferation.”

Glucose metabolism and the Warburg Effect

The bizarre metabolism of cancer cells has been recognized has an especially promising vulnerable target for treatment.

“Glucose metabolism and the Warburg Effect have gained traction as a potential tumor weakness and exploitable treatment area. Where normal cells utilize glucose for high-yield energy production in the mitochondria (1:36ATP), tumor cells demand higher levels of glucose for diminished energy production, via lactate in the cytosol (1:4ATP) and nucleotide synthesis in the pentose phosphate pathway. This metabolic characteristic, termed the Warburg Effect, is an essential byproduct of rapid cellular proliferation and promoted during tumorigenesis by oncogenic metabolic reprogramming. Hence tumor cells acquire the ability to sustain proliferative signaling mechanisms, which subsequently promotes malignant glycolysis. “

Ketogenic diet

The ketogenic diet has been around has been demonstrated to be safe and effective but in its strict form can be difficult to maintain.

“Research into dysregulated cellular metabolism has given rise to the notion that dietary therapies for cancer patients may have significant clinical utility. GB has been proposed to be a promising candidate for dietary intervention due to its substantial reliance and utilization of glucose. At the forefront of dietary anticancer therapy is the ketogenic diet (KD), which is a high-fat, low-carbohydrate, low-protein diet, used for decades to treat refractory epileptic seizures. Extreme carbohydrate restriction mimics a fasting state, resulting in reduction of blood glucose and induction of ketone bodies (e.g., b-hydroxybutyrate/BHB). Ketone bodies are suitable energy replacements for normal cells with functional mitochondria, but have been shown to be unsuitable for tumor cells, as tumor cell mitochondrial functions are dysregulated. Existing preclinical data support the KD and a calorie-restricted KD (RKD) in the treatment of brain cancer by diminishing tumor growth and increasing animal survival. Clinical report, case reports, and pilot trials have demonstrated that the KD is safe, has low toxicity, and is applicable to cancer patients.”

But because of challenges to implementation of the strict ketogenic diet the authors sought to investigate the effect of a more easily maintained less restrictive LCHF diet with supplemented with medium chain triglycerides (MCT).

“…a less restrictive KD-like diet that would exhibit the same physiologic phenotype and antitumor efficacy. By supplementing a high-fat, low-carbohydrate (sHFLC), moderate protein diet with specialized medium-chain triglycerides [MCT; 60%(30%):30%:10%::Fat(MCT): Protein:Carb], we hypothesize that a more balanced diet can be implemented, resulting in diminished tumor progression. MCTs were specifically chosen based on carbon chain lengths (C8: C10::97%:3%), which allow them to rapidly diffuse from the gastrointestinal tract into the hepatic portal system and travel directly to the liver where they are converted into ketone bodies). We believe it is possible to provide a more nutritionally complete, flexible, and palatable anticancer diet with the sHFLC, which could target a diverse patient population and increase patient compliance.”

Tumor cell growth significantly reduced

tumor-volume-with-high-fat-low-carb-low-glucose-ketogenicThey tested glioblastoma cells both in vivo and in vitro resulting in a significant decrease in the proliferation of both the tumor cells, and very importantly the tumor stem cells.

Lowering glucose concentrations resulted in a significant reduction in Ki-67 and MCM2 expression, in both PG and LG as well as a significant increase in active caspase-3 between NG and LG. Therefore, alterations in glucose availability, to levels equivalent to a low glucose state, are sufficient to slow the proliferation of gliomaspheres while concomitantly increasing apoptosis…Quantification of the self-renewing stem cell symmetrical division rate demonstrated a significant decrease in cancer stem cell expansion under reduced glucose conditions. The combination of diminished stem cell division rates, cellular fold expansion, and proliferation markers indicates that lowering glucose affects not only the putative stem cell population, but also the non-stem cell population.”

Low carb high fat benefits comparable to strict ketone diet

This is a very important point for practical implementation of an effective therapeutic diet.

“Animals placed on the sHFLC and KD had a significant reduction in blood glucose, above hypoglycemic levels, compared to controls, with no difference between the sHFLC and KD. Blood ketones were significantly increased in mice maintained on the sHFLC and KD to a safe level, with a statistical difference between the groups.”

The employed a glucose ketone index (GKI) to compare dietary interventions:

“To compare blood glucose and ketone levels among different anticancer dietary therapies, a simple glucose ketone index (GKI) is used. The GKI is a single number, and can be used both clinically and preclinically, to identify a therapeutic zone. On the basis of this formulation, our average calculated GKIs are 24.4 ± 7.14, 3.1 ± 1.07, and 1.94 ± 0.67 for the control, sHFLC and KD, respectively.”

Adding metformin yielded no additional benefit

Those following the topic of metformin as an anticancer therapy should note that it appears to be rendered unnecessary by this dietary approach:

“It has been proposed that a potential combinatorial treatment of metformin with carbohydrate restriction could result in enhanced antitumor efficacy. Mice fed the KD and sHFLC alone demonstrated a significant increase in survival compared with the control-fed mice, statistically equal to metformin alone. In both xenograft models, metformin alone was able to reduce blood glucose, reduce tumor progression, and increase survival, yet the combination sHFLC diet and metformin showed no additive or synergistic effects…These data indicate that the sHFLC diet is capable of increasing animal survival while minimizing tumor burden, is as effective as metformin, and may mechanistically overlap in AMPK-mediated inactivation of the mTOR pathway.”

Most importantly…

“The sHFLC diet slows tumor progression, increases survival, and reduces tumor burden in subcutaneous and orthotopic xenograft models.”

Low carb high fat with MCT oil much easier to maintain than strict ketogenic

Low carb high fat supplemented with MCT oil is as effective as the stricter ketogenic diet and has nutritional advantages.

“Here, we demonstrate that a high-fat, low-carbohydrate diet supplemented with MCT oil (sHFLC) is able to slow tumor progression and increase survival. In vivo, the sHFLC diet was similar to the ketogenic diet (KD) in antitumor efficacy, but showed nutritional advantages in body weight, organ enzyme levels, and lipid profile. Finally, we demonstrate that the sHFLC diet affects the mTOR signaling pathway by reducing expression of upstream regulators and translational downstream effectors…We designed the sHFLC diet for long-term sustainable maintenance of GB and for increased flexibility and palatability.”

Clinical note: Clearly, glucose control is crucial in case management for treatment and prevention of malignancies.

Excess glucose, as seen in GB patients with persistent hyperglycemia, leads to poor patient survival. It has also been suggested that diets with a high glycemic index may increase the risk of tumorigenesis, and low-carbohydrate, high-protein diets that limit circulating glucose can delay cancer development and progression.”

Moreover, regarding the hugely important issue of restricting cancer stem cell expansion:

“Treatment of GB stem cell lines with a constant physiologic concentration of BHB (4 mmol/L), as seen in KD patients, resulted in reduction of clonogenic frequency and symmetrical stem cell divisions, suggesting that elevated ketones affect the putative cancer stem cell population.”

Effective for diverse malignancies

Because a dependence on glycolysis is characteristic of all cancers these principles can be broadly applied.

“The combination of reduced glucose and increased ketone bodies has shown an enhanced anticancer effect…The KD mimics these biologic effects and has been proposed as a treatment for GB and other cancers…numerous groups have investigated the antitumor efficacy of a KD and an RKD in several types of cancer. RKD in experimental mouse models of glioma has been shown to be antitumorigenic, antiangiogenic, and pro survival, while also being anti-invasive, anti-inflammatory, and proapoptic by targeting signaling pathways related to glucose and glutamine metabolism. In animal models, feeding with the KD ad libitum has been reported to increase survival and reduce tumor growth. Other preclinical animal models such as gastric cancer, colon cancer, and metastatic cancer have used the KD, reporting similar antitumorigenic effects.”

Effects on the mTOR pathway is especially important:

“The mTOR pathway is one of the largest and most utilized pathways in cellular signaling, with two complexes (mTORC1/mTORC2) that have demonstrated a role in tumorigenesis. Recently, it’s been shown that inhibition of both mTORC1/mTORC2 signaling results in dramatically reduced cell viability in glioma cell lines, as well as inhibition of tumor growth in vivo. In our assessment of the sHFLC diet’s effects on the mTOR pathway, we found significant reduction in both mTORC1/mTORC2 signaling…Taken together, these findings indicate that inhibition of the mTORC1/2 pathway can be achieved through dietary intervention, resulting in a potent anti-cancer treatment.”

The authors conclusions highlight fundamental concerns in case management:

“Our work demonstrates that there is a distinct relationship between metabolism and proliferation that can be exploited by changing the energy sources in the body. Further research into the biochemical reactions of metabolic intermediates may shed more light on how ketone bodies are differentially utilized by tumor cells, as the role of mitochondria in tumor propagation and carcinogenesis is multifaceted and incompletely understood. Nevertheless, we effectively show that a combination of low glucose and high ketones results in negative proliferative effects on gliomaspheres, which can be translated in vivo with the sHFLC diet. This diet reduces overall tumor burden and increases survival, equivalent to a strict 1:6 KD, and has a complete nutritional profile. Hence we propose that dietary therapy, such as the sHFLC diet, could be utilized in the management of GB.”

The Warburg effect, foundation of the benefits of a low glycemic ketogenic diet

international-journal-of-cancerAn excellent study published in the International Journal of Cancer documenting decreased tumor cell viability and prolonged survival with supplemental ketones includes a fine review of the Warburg effect.

 “A century ago, Otto Warburg discovered that cancer cells display a unique metabolic phenotype of lactate fermentation in the presence of oxygen. This phenotype, known as the Warburg effect, enables tumor visualization using fluorodeoxyglucose positron emission tomography (FDG-PET) scans owing to the elevated rate of glucose consumption in most cancers. Metabolic therapies can exploit this phenotype, offering novel therapeutic directions aside from the classically targeted cytotoxic and gene-based therapies. The Warburg effect exposes a fundamental weakness of cancer cells, reliance on excess glucose for survival and maximal proliferation. Fasting, calorie restriction (CR) and the carbohydrate-restricted ketogenic diet have been successfully used to limit glucose availability and slow cancer progression in a variety of animal models and human studies.”

Importantly, the ketogenic effect is additive to the benefits of low glucose…

“Previously, the anticancer effects of these dietary manipulations have largely been attributed to decreased circulating blood glucose, which limits energy substrates for cancer cells. New evidence suggests, however, that the physiological state of ketosis and elevated circulating ketones also have anticancer effects.”

Ketogenic effect may be primary

For anti-cancer effects elevated ketones may be even more important than low glucose.

“Recently, Fine et al. demonstrated that a carbohydrate-restricted ketogenic diet inhibited disease progression and promoted partial remission in patients with advanced metastatic cancers from various tissue origins. [10] On average, the patients did not exhibit a drop in glucose from baseline, suggesting that decreased glucose availability was not the sole or primary cause of efficacy. Interestingly, the study found that the most important factor dictating the patients’ response to therapy was the degree of elevated ketosis from baseline. Indeed, a prominent metabolic shift to higher levels of ketosis correlated with reduced disease progression, stable disease or partial regression.”

Cancer as a mitochondrial disorder

The metabolic theory of cancer (as opposed to the somatic mutation theory) posits mitochondrial dysfunction as an instigator in the shift of normal to cancer cells.

“Although ketone bodies are efficient energy substrates for healthy extrahepatic tissues, cancer cells cannot effectively use them for energy. Widespread mitochondrial pathology has been observed in most if not all tumors examined, including decreased mitochondrial number, abnormal ultrastructural morphology, mitochondrial swelling, abnormal fusion–fission, partial or total cristolysis, mtDNA mutations, altered mitochondrial membrane potential and abnormal mitochondrial enzyme presence or function, among others.These defects in mitochondrial structure and function impair respiratory capacity and force a reliance on substrate-level phosphorylation for survival. As ketone bodies are metabolized exclusively within the mitochondria, cancer cells with impaired mitochondrial function are unable to efficiently metabolize ketone bodies for energy. Indeed, unlike healthy cells, ketone bodies fail to rescue glioma cells from glucose withdrawal-induced death.”

Ketone bodies oppose cancer in multiple ways

A ketogenic diet does more than just starve cancer cells…

  1. “Ketone bodies inhibit glycolysis, thus decreasing the main pathway of energy production for cancer cells.
  2. Cancer cells thrive in an environment of elevated reactive oxygen species (ROS) production but are very sensitive to even small changes in redox status. Ketones decrease mitochondrial ROS production and enhance endogenous antioxidant defenses in normal cells, but not in cancer cells. Ketone metabolism in healthy cells near the tumor may inhibit cancer cell growth by creating a less favorable redox environment for their survival.
  3. Ketone bodies are transported into the cell through the monocarboxylate transporters (MCTs), which are also responsible for lactate export. It has been shown that inhibiting MCT1 activity or inhibiting lactate export from the cell dramatically decreases cancer cell growth and survival. Ketones may impair cancer cells indirectly by competitive inhibition of the MCTs, decreasing critical lactate export from the cell.
  4. Recently, Verdin and coworkers demonstrated that βHB acts as an endogenous HDAC inhibitor at millimolar concentrations easily achieved through fasting, CR or ketone supplementation such as with a ketone ester (KE). Thus, ketone bodies may elicit their anticancer effects by altering the expression of oncogenes and tumor suppressor genes under control of the cancer epigenome.”

“Clearly, ketone bodies exhibit several unique characteristics that support their use as a metabolic therapy for cancer.”

Ketones oppose metastasis

Effectiveness against metastasis is critical for successful cancer therapy.

The Warburg effect is especially prevalent in aggressive cancers and metastatic cells. Metastasis, the spreading of a primary tumor to distal locations, is the primary cause of cancer morbidity and mortality and is responsible for more than 90% of cancer-related deaths.”

Ketones can be easily increased by diet and supplementation, so authors set out to investigate in vivo effectiveness:

It is possible to raise blood ketone levels without the need for carbohydrate restriction by administering a source of supplemental ketones or ketone precursors. 1,3-Butanediol (BD) is a commercially available food additive and hypoglycemic agent that is converted to βHB by the liver. The KE [ketone ester] elevates both AcAc and βHB in a dose-dependent manner to levels beyond what can be achieved with the KD or therapeutic fasting. Oral administrations of BD and KE have been shown to elevate blood ketones for at least 240 min in rats. As ketone bodies appear to elicit anticancer effects, and metastasis is the most significant obstacle in the successful treatment of neoplasms, we tested the efficacy of ketone supplementation in the VM-M3 cell line and mouse model of metastatic cancer.”

They measured proliferation and viability in highly metastatic cells cultured in the presence and absence of β-hydroxybutyrate (βHB). Also adult male inbred VM mice were implanted subcutaneously with firefly luciferase-tagged syngeneic VM-M3 cells and fed a standard diet supplemented with either 1,3-butanediol (BD) or a ketone ester (KE) which are metabolized into βHB and acetoacetate. They then monitored tumor growth in vivo bioluminescent imaging, and documented Survival time, tumor growth rate, blood glucose, blood βHB and body weight.

Ketone supplementation prolonged survival and reduced tumor burden

Tumor burden with ketone supplementation

Effect of supplemental ketones on tumor bioluminescence. (CR calorie restriction, BD 1,3-butanediol, and KE ketone ester).

The results were amazing, even without reducing glucose and calorie restriction:

Ketone supplementation decreased proliferation and viability of the VM-M3 cells grown in vitro, even in the presence of high glucose. Dietary ketone supplementation with BD and KE prolonged survival in VM-M3 mice with systemic metastatic cancer by 51 and 69%, respectively (p < 0.05). Ketone administration elicited anticancer effects in vitro and in vivo independent of glucose levels or calorie restriction.”

The authors discuss the profound clinical implications:

“The Warburg effect is the most ubiquitous cancer phenotype, exhibited by most if not all cancer types. Exploiting the metabolic deficiencies of cancer cells should be prioritized, because this therapeutic strategy would likely prove effective against most cancers. Mitochondrial dysfunction underlies many aspects of cancer metabolic deficiency and prevents cancer cells from effectively using ketone bodies for energy. In our study, ketone supplementation decreased VM-M3 cell proliferation and viability, confirming similar results demonstrated in other cancer types in vitro. Therefore, we hypothesized that dietary administration of ketone body precursors would inhibit disease progression in vivo. Indeed, dietary administration of ketone precursors, BD and KE, increased mean survival time by 51 and 69%, respectively, in VM-M3 mice with metastatic cancer. These data support the use of supplemental ketone administration as a feasible and efficacious cancer therapy, which should be further investigated…”

Although carbohydrate restriction has other important metabolic benefits, ketone supplementation was effective in prolonging survival even without it.

“Ketone supplementation decreased blood glucose after acute administration, decreased body weight with chronic administration and sustained ketosis in vivo, even when administered with a high-carbohydrate rodent chow in both healthy (VM/Dk) and cancer (VM-M3) mice. Our study demonstrates the ability of dietary administration of BD and KE to significantly elevate ketone bodiesin vivo for at least 12 hr in healthy VM/Dk mice and 7 days in VM-M3 cancer mice.”

Moreover, ketone supplementation on its own reduces weight, diminishes appetite and improves insulin sensitivity.

“It is important to note that the metabolic changes associated with acute and chronic ketosis are vast and can dramatically affect blood metabolite concentrations. In previous studies, chronic BD and βHB administration has been shown to decrease food intake in the rat and pigmy goat. Similarly, Veech and coworkers demonstrated that feeding a KE-supplemented diet increased malonyl-CoA, an anorexigenic metabolite known to decrease food intake. Ketone-induced appetite suppression may account for the decreased blood glucose and body weight seen in treated VM-M3 cancer mice. Additionally, prior studies suggest that ketones increase insulin sensitivity, which may be contributing to the decreased circulating blood glucose in KE-fed mice…Furthermore, chronic ketosis enhances ketone utilization by tissues, known as keto-adaptation, resulting in lower blood ketone concentrations.”

A ketogenic high fat diet with ketone supplementation may be more effective than calorie restriction

In the past, dietary treatment in cancer has emphasized carbohydrate or calorie restriction to exploit the Warburg effect, but this may not be the best approach.

“Interestingly, although CR [calorie restriction] decreased blood glucose and elevated blood ketones, CR mice exhibited a trend of increased latency to disease progression and increased survival that was not statistically significant from controls in our study. As described, some data suggest that elevated ketones are responsible for much of the anticancer efficacy of the ketogenic diet.Perhaps elevating ketones with exogenous sources such as ketone supplementation or a ketogenic diet, rather than elevating ketones endogenously through lipolysis such as occurs with CR, provides a more effective anticancer strategy. Additionally, ketone supplementation may preserve lean muscle mass to a greater degree than CR, and may therefore support overall health of the organism in this way…These data support the in vitro and in vivo conclusions of Fine et al. suggesting that ketone bodies can inhibit cancer progression independently of other factors such as carbohydrate restriction or CR.

Enhancement of radiation and chemotherapy

Ketogenic diet and ketone supplementation can enhance the cytotoxic effects of the increase in ROS (reactive oxygen species) by radiation and chemotherapy.

“The ketogenic diet has been shown to enhance the efficacy of both radiation and chemotherapy in vivo. As supplemental ketones mimic the physiological ketosis induced by the ketogenic diet, combining supplemental ketone therapy with standard of care could produce similar effects, even if administered with a SD [standard diet]. Furthermore, the neuroprotective effects of ketone metabolism have been widely documented. Ketone metabolism protects normal cells from oxidative damage by decreasing mitochondrial ROS production and enhancing endogenous antioxidant defenses. Radiation and chemotherapy work in large part by inducing ROS production in the tumor, but simultaneously incur damage to normal tissue. Ketone metabolism by healthy tissue would likely mitigate some of the adverse side effects of standard of care as ketones have been shown to protect against oxidative stress.”

The authors’ conclusion needs to be appreciated by any practitioner involvement in cancer case management:

Our data strongly suggest that supplemental ketone administration could provide a safe, feasible and cost-effective adjuvant to standard care that should be further investigated in preclinical and clinical settings.”

Exploiting Cancer Metabolism with Ketosis—Dr. Angela Poff

Chemotherapy: how much does it actually improve survival?

BMJ chemotherapy and survivalChemotherapy drugs have had little effect on cancer survival in adults according to an analysis just published in BMJ (British Journal of Medicine).

The author notes that although there have been advances in chemotherapy in recent years, a thorough examination of the data reveals that…

“Despite considerable investment and innovation, chemotherapy drugs have had little effect on survival in adults with metastatic cancer.”

In fact, the data on the survival benefits of chemotherapy are so disturbing that they raise questions about ethics, drug trials and approval, and patient consent.

The approval of drugs with such small survival benefits raises ethical questions, including whether recipients are aware of the drugs’ limited benefits, whether the high cost:benefit ratios are justified, and whether trials are providing the right information.”

Key messages include:

  • “Advances in chemotherapy have contributed little to population cancer survival

  • Responses in clinical trials may not apply to patients treated in the community

  • Evaluation outside trial centres is essential to ensure that scarce resources are not squandered

  • Stricter approval criteria are needed to achieve ethical treatment and reduce cancer costs

  • Ethical informed consent and empowerment of patients must be promoted”

The author strongly advises a more clinically sound and ethical way forward:
Many irregularities and competing interests—in pharma, in trials, in government approval, and in the clinical use of cancer drugs—impact ethically on the care and costs of patients with cancer. Non-representative clinical trials with imprecise endpoints and misinformed patients with unrealistic expectations compel interventions that are mostly not in their best interests. Spending a six figure sum to prolong life by a few weeks or months is already unaffordable, and inappropriate for many of the 20% of the (Western) population who will almost inevitably die from solid tumour metastases.”

 

Patients deserve better information and more supportive treatment….

Ethical cancer care demands empowerment of patients with accurate, impartial information followed by genuinely informed consent in both the clinical trial and therapeutic settings. Intensified prevention, earlier detection, more prompt and radical treatment of localised and regional disease, together with highly skilled, earlier, supportive care are the important yet underfinanced priorities in cancer control. Ethical impediments to sound practice need to be addressed and corrected. Above all, the efficacy bar for approval needs to be raised for both new and existing cancer drugs—by using more meaningful statistical and disease specific criteria of risk-benefit and cost-benefit. Finally, aggressively targeting the less than ethical actions of stakeholders in the heavily veiled medical-industrial complex may be the only way forward: current market driven rather than health driven priorities and practices do not benefit cancer patients.”

The entire paper can be downloaded here, and an illuminating, brief interview with the author can heard by clicking on the arrow in the upper left corner of the image below:

 

the-bmjThe editor-in-chief of BMJ in an accompanying editorial states:

“People with cancer are living longer now than 40 years ago. This is clearly good news. But how much of this improvement can we attribute to drug treatment? Not much, concludes Peter Wise this week in an article I humbly suggest all oncologists should read. The nearly 20% improvement in five year survival over the past four decades is probably mainly due to improved early diagnosis and treatment rather than developments in cytotoxic chemotherapy, he says. And patients are being badly misled by over-enthusiastic accounts of what chemotherapy can achieve. Many expect a cure. In reality they will gain on average only a few months of extra life.”

Moreover…

Unjustified enthusiasm for cancer drug treatments comes at huge cost, financial and personal (including treatment related deaths and reduced quality of life), and increased risk of dying in hospital rather than at home. Many patients don’t realise that opting for supportive rather than active treatment—often called “refusal”—is an option and may give them longer as well as better quality life than chemotherapy. Conflicts of interest among clinicians compound their reluctance to have tricky conversations.”

The editor summarizes the author’s recommendations in light of this data:

“Wise concludes with a call for higher bars for drug approval for new and existing drugs. Ethical cancer care demands empowerment of patients, he says, with accurate, impartial information followed by genuinely informed consent. And funds and attention should shift to prevention, early detection, prompt and radical treatment of localised and regional disease, and early provision of supportive care. Only then will cancer care serve patients rather than governments and industry.”

ONCOblot cancer test, sensitive and specific, explained in brief video

This brief video of less than 3 minutes offers a quick explanation of the valuable ONCOblot test for cancer detection.

The ONCOblot test has demonstrated extraordinary accuracy down to as little as 2 million cells or less, with identification of tissue of origin.

BioMed Central paper on ONCOblot test for early cancer detectionA recent study published in Clinical Proteomics illustrates how this test can detect cancer years in advance of a clinical diagnosis.

“In a population of asbestos-exposed subjects who eventually developed malignant mesothelioma, ENOX2 protein transcript variants characteristic of malignant mesothelioma were present in serum 4–10 years in advance of clinical symptoms.”

For further information see ONCOblot® Labs. Practitioner colleagues who would like to discuss our use of this test are welcome to contact.

Breast cancer recurrence reduced by prolonged nightly fasting

JAMA Oncology breast cancer and prolonged nightly fastingBreast cancer risk and prognosis is affected by glucose and insulin regulation. The authors of a study recently published in JAMA Oncology demonstrate that fasting intermittently by extending the overnight fast between dinner the night before and eating the next day reduces the risk of cancer recurrence. They state:

“To our knowledge, no studies in humans have examined nightly fasting duration and cancer outcomes.”

So they set out to…

“…investigate whether duration of nightly fasting predicted recurrence and mortality among women with early-stage breast cancer and, if so, whether it was associated with risk factors for poor outcomes, including glucoregulation (hemoglobin A1c), chronic inflammation (C-reactive protein), obesity, and sleep.”

Breast cancer and HgbA1c reduced by prolonged nightly fasting; sleep improved

They analyzed data collected over 12 years for 2413 women with breast cancer but without diabetes aged 27 to 70 years at diagnosis who were participants in the Women’s Healthy Eating and Living study. Their main outcomes were recurrence, new primary tumors, mortality, assess concentrations of hemoglobin A1c and C-reactive protein. Happily their data show significant improvements in recurrence, HgbA1c and sleep duration:

“The cohort of 2413 women reported a mean (SD) fasting duration of 12.5 (1.7) hours per night. In repeated-measures Cox proportional hazards regression models, fasting less than 13 hours per night (lower 2 tertiles of nightly fasting distribution) was associated with an increase in the risk of breast cancer recurrence compared with fasting 13 or more hours per night (hazard ratio, 1.36). Nightly fasting less than 13 hours was not associated with a statistically significant higher risk of breast cancer mortality or a statistically significant higher risk of all-cause mortality. In multivariable linear regression models, each 2-hour increase in the nightly fasting duration was associated with significantly lower hemoglobin A1c levels and a longer duration of nighttime sleep.”

Intermittent fasting

The two most main methods of intermittent fasting are 5:2 and 16:8. 5:2 is 5 days of normal eating alternating with two very low calorie days (500 cal for females and 600 cal for males). 16:8, which I prefer, delays eating and drinking anything other than water, coffee or tea (black) until 16 hours after dinner the night before. This has numerous metabolic and immune benefits, and should be a mainstay in the ‘oncology toolbox.’ The authors conclude:

Prolonging the length of the nightly fasting interval may be a simple, nonpharmacologic strategy for reducing the risk of breast cancer recurrence. Improvements in glucoregulation and sleep may be mechanisms linking nightly fasting with breast cancer prognosis.”

Silicone breast implants and risk of lymphoma

Journal of AutoimmunitySilicone and possibly other substances used in the manufacture of breast implants can stimulate a chronic inflammatory reaction by the immune system. A paper just published in the Journal of Autoimmunity reviews evidence that the immune reaction to silicone in breast implants can promote the development of lymphoma. The authors note:

“The risk of hematological malignancies is mainly determined by genetic background, age, sex, race and ethnicity, geographic location, exposure to certain chemicals and radiation; along with the more recently proposed immune factors such as chronic inflammation, immunodeficiencies, autoimmunity, and infections. Paradigmatic examples include the development of lymphoma in Sjögren’s syndrome and Hashimoto thyroiditis, gastric MALT lymphoma in Helicobacter pylori infection, or lymphomas associated with infections by Epstein–Barr virus, human herpes virus 8 (HHV 8) and leukemia/lymphoma virus 1 (HTLV-1).”

Silicone implants stimulate an immune reaction

“A growing number of reports indicates an increased risk of lymphoma, particularly of the anaplastic large cell (ALCL) type. The implants, specifically those used in the past, elicit chronic stimulation of the immune system against the prosthetic material. This is particularly the case in genetically susceptible hosts. We suggest that polyclonal activation may result in monoclonality in those at risk hosts, ultimately leading to lymphoma.”

These key points emerge:

  • Chronic infection and inflammation have been implicated as the causative mechanisms in the development of lymphomas.
  • The connection between ALCL and breast implants has been hypothesized for several years. Since the earliest report in 1997, numerous cases were described, with 173 cases of breast-implant associated ALCL being recently reported.
  • An immune reaction to silicone or other substances used in manufacturing process of breast implants, might cause T cell infiltration with later clonal expansion of T lymphocytes. The T-cell response may be as well reaction to biofilms.
  • Skin injuries and Sjögren’s syndrome are two conceptual models providing intriguing insight to the connection between silicone implants and ALCL.

Patients with silicone breast implants should be monitored

Practitioners should keep in mind the authors’ conclusion and evaluate patients with silicone implants for chronic inflammation:

“We suggest that patients with an inflammatory response against silicone implants be monitored carefully.”

Breast cancer, autoantibodies and autoimmune inflammation

BMC CancerChronic inflammation is a contributing cause for many cancers, and research recently published in BMC Cancer presents evidence that autoimmune inflammation may contribute to breast cancer by demonstrating the presence of autoantibodies directly involved in breast cancer development.

Similarities between breast cancer and autoimmune diseases

The authors state:

“Our studies on autoantibodies in malignancies strongly suggested that cancer sera exhibit immunologic features that are common in the rheumatic autoimmune diseases [ADs]. We have shown that anti-collagen antibodies and antinuclear antibodies [ANA] are found in the sera from lung cancer and head and neck cancer patients as frequently as in the systemic ADs such as rheumatoid arthritis [RA] and systemic lupus erythematosus [SLE]. With the use of molecular techniques and high throughput analyses, we and others have clearly shown that autoantibody classifiers have been constructed with high sensitivity and specificity for the diagnosis of breast and other cancers.”

Predictive antibodies

Autoantibodies can appear years before the condition evolves to an easily recognized clinical entity.

“It is well known that autoantibodies (such ANAs in SLE and rheumatoid factors and anti-cyclic citrullinated peptides antibodies in RA) can be detected many years before the onset of these ADs. We and others have also found autoantibodies in the sera of patients with cancer before clinical diagnosis, notably suggesting that the breakdown of tolerance to tumor antigens is an early event in carcinogenesis. The diagnostic value of autoantibodies as immune biomarkers in the systemic and organ-specific ADs such as SLE, RA, scleroderma, and primary biliary cirrhosis [PBC] is well established.”

Although anti-nuclear antibodies (ANAs) have been recognized in breast cancer sera for many years there has been no comprehensive study of autoantibodies in the sera of a large cohort of patients with pathology-proven breast cancer. So…

“The objective of this work was to demonstrate that the autoantibodies detected in BC sera have unique immunological features, resembling the model epitomized by the rheumatic and organ-specific ADs.”

Autoantibodies clearly apparent in breast cancer

They used immunofluorescence on HEp-2 cells to survey autoantibodies in sera from women undergoing annual screening mammography with suspicious assessment and immunoblots of breast cancer proteins, crithidia luciliae assay for anti-dsDNA antibodies, and multiple ELISAs for extractable nuclear antigens [ENAs], anti-centromere antibodies [CENPs], and NSP1 antibodies and for the M2 component of pyruvate dehydrogenase. These included sera from 100 cases each of ductal carcinoma in situ [DCIS], invasive ductal carcinoma [IDC] of the breast and controls of benign breast disease [BBD]. The pathologic diagnoses of cases were made by breast biopsy. Autoantibodies were clearly present in the subjects with breast cancer:

“The combined use of IFA [immunofluorescence] on HEp-2 cells and IBs [immunoblots] of BC [breast cancer] proteins detected autoantibodies in virtually all sera from patients with breast cancer. IFA of BC and control sera revealed a spectrum of autoantibodies with maximal reactivity in sera from patients with IDC and decreasing reactivity in DCIS and BBD sera; minimal nuclear or cytoplasmic reactivity was shown in the sera from patients with OA and from healthy hospital nurses.”

Moreover, they showed that autoantibodies in breast cancer sera have unique immunological features comparable to those found in rheumatic and organ-specific autoimmune diseases.

“We show here that autoantibodies reacting with antigens located in several important cell organelles (including mitochondria, centromeres, nucleoli, centrosomes, and the mitotic spindle) are consistently found in sera from women with suspicious mammography findings. The level of these autoantibodies was highest in women with IDC, lesser in women with DCIS, and still lower but above background levels in healthy women with BBD. Moreover, AMAs, anti-centromere, and anti-centrosome antibodies are not components of the autoantibody repertoire of normal healthy women.”

Clincial implications for diagnosis and prevention of breast cancer

The authors note the diagnostic utility of breast cancer antibody profiles:

“These findings suggest that, in the future, the combination of suspicious mammography and autoantibody signatures could potentially identify a group of women in the early stages of breast carcinogenesis. Here we provide evidence that most of the antigens targeted by autoantibodies in BC sera differ from those involved in the rheumatic and organ-specific ADs.”

Although autoantibodies and other screening methods are superseded by the ONCOblot test, this report is a valuable reminder for clinicians to thoroughly attend to low grade chronic inflammation and early stages of autoimmunity as a fundamental tactic in breast cancer prevention.

Moreover, considering the current controversy regarding justification and potential harm associated with radical treatment of DCIS, investigating and treatment underlying autoimmune inflammatory factors presents a middle option between invasive therapy and doing nothing.

The authors conclude:

“In this study, detection of autoantibodies in the sera from practically all women with breast cancer provides compelling evidence that an antigen-driven autoantibody response takes place in BC. Moreover, we report here that the autoantibody profile detected in BC sera has distinctive features, probably reflecting unique BC-associated antibody specificities targeting antigens in the mitochondria, the centrosomes, the spindle apparatus, the nucleoli, and the cytoskeleton.”

Furthermore…

“The consistent finding of anti-centrosome antibodies in breast cancer sera is novel and supports the possibility that centrosome autoimmunity might be involved in cancer pathogenesis. Detection of AMAs, anti-centromere, anti-centrosome antibodies, and MNDs in a fraction of women with suspicious mammography findings and BBD indicates that the process triggering autoantibody formation starts in the pre-malignant phase. Our findings suggest the hypothesis that autoimmunity triggered by TAAs may inflict epithelial damage to the breast, promoting chronic inflammation and cancer progression; i.e., that BC may behave as an organ-specific AD triggered by multiple epithelial and other breast antigens.”

Allergic inflammation may promote breast cancer metastasis

Journal of Leukocyte BiologyIt’s well known that inflammation contributes to ‘flipping the molecular switches’ that turn on breast cancer and other malignancies. A study entitled Allergen induced pulmonary inflammation enhances mammary tumor growth and metastasis: Role of CHI3L1 recently published in the Journal of Leukocyte Biology reveals a mechanism by which allergic inflammation can promote breast cancer metastasis. The authors state:

“Metastasis is the primary cause of mortality in women with breast cancer. Metastasis to the lungs is greater in patients with pulmonary inflammatory illnesses. It is unknown how pre-existing pulmonary inflammation affects mammary tumor progression. We developed a novel breast cancer model in which pulmonary inflammation is induced in mice prior to tumor cell implantation.”

CHI3L1 associated with allergic inflammation promotes breast cancer metastasis

They had earlier shown that a glycoprotein known as CHI3L1 associated with lung inflammation induces the production of proinflammatory and protumorigenic molecules. Here they show how allergic inflammation alters the lung environment to promote breast cancer metastasis.

“In the present study, we determined how pre-existing allergen-induced inflammation changes the pulmonary microenvironment to exacerbate tumor metastasis. We showed that pre-existing pulmonary inflammation in mammary tumor bearers is associated with: 1) an increase in growth of the primary tumor and metastasis; 2) an increase in the expression of a glycoprotein known as CHI3L1; and 3) increase in the levels of myeloid populations in their lungs. We also showed that myeloid derived cells from the lungs of allergic tumor bearers produce higher amounts of CHI3L1 than the saline controls.”

They further demonstrated the key role of CHI3L1 by removing the glycoprotein from the picture:

“In this study, we show that CHI3L1 knockout tumor bearers with pre-existing allergic pulmonary inflammation had decreased levels of myeloid-derived cells, decreased levels of proinflammatory mediators, and a significant reduction in tumor volume and metastasis compared with the wild-type controls.”

Targeting allergic inflammation in breast cancer

The authors conclude with a comment on the clinical importance of targeting allergen-induced inflammation in breast cancer management:

Pre-existing inflammation and CHI3L1 might be driving the establishment of a premetastatic milieu in the lungs and aiding in the support of metastatic foci. Understanding the role of allergen-induced CHI3L1 and inflammation in tumor bearers and its effects on the pulmonary microenvironment could result in targeted therapies for breast cancer.”

Breast cancer, oxidative stress and NF-κB

Breast Cancer Research and TreatmentA paper just published in the journal Breast Cancer Research and Treatment highlights how reactive oxygen species (ROS) activate pro-inflammatory NF-κB (nuclear factor kappa beta, also an oncogenic transcription factor) to promote more aggressive breast cancer, and that this can be ameliorated by N-acetyl-cysteine. The authors state:

Reactive oxygen species (ROS) are thought to be among the initiating insults that drive carcinogenesis; however, beyond the mutagenic properties of ROS, it is unclear how reactive oxygen species and response to redox imbalance may shape cancer phenotype.”

DNA damage-responsive kinase ATM turns on NF-κB

They demonstrate that oxidative damage to DNA activates the kinase ATM which in turn revs up the tumor-promoting and inflammatory NF-κB:

“We have previously observed that basal activity of the powerfully oncogenic transcription factor NF-κB in cultured breast cancer and other tumor cell lines is dependent upon the DNA damage-responsive kinase ATM. Here we show that, in MDA-MB-231 and HeLa cells, basal ATM-dependent NF-κB activation occurs through a canonical DNA damage-responsive signaling pathway as knockdown of two proteins involved in this signaling pathway, ERC1 and TAB1, results in loss of NF-κB basal activity. We further show that knockdown of ATM in MDA-MB-231, a breast cancer line with a pronounced mesenchymal phenotype, results in the reversion of these cells to an epithelial morphology and gene expression pattern.”

In other words, by removing ATM from the chain prevents NF-κB from converting cells to the worse breast cancer phenotype.

N-acetyl cysteine (NAC) to the rescue

Clinicians involved in case management of autoimmune disorders are aware that N-acetyl cysteine (NAC) is one of the beneficent agents that help wind down NF-κB activity (a major player also in autoimmune inflammation). Here the authors show that NAC prevents NF-κB from turning on more harmful breast cancer genes:

“Culture of MDA-MB-231 and HeLa cells on the antioxidant N-acetyl cysteine (NAC) blunted NF-κB transcriptional activity, and long-term culture on low doses of NAC resulted in coordinate reductions in steady-state ROS levels, acquisition of an epithelial morphology, as well as upregulation of epithelial and downregulation of mesenchymal marker gene expression. Moreover, these reversible effects are attributable, at least in part, to downregulation of ATM-dependent NF-κB signaling in MDA-MB-231 cells as RNAi-mediated knockdown of the NF-κB subunit RelA or its upstream activator TG2 produced similar alterations in phenotype.”

Clinical note

Practitioners involved in breast cancer prevention and treatment should be attentive to patients’ oxidative status which can be quantified with biomarkers such as the DNA oxidation product 8-Hydroxy-2-deoxyguanosine, and have practical familiarity with NAC and other agents that reduce ROS to acceptable levels and rein in NF-κB. The authors summarize:

“We conclude that chronic activation of ATM in response to persistent ROS insult triggers continual activation of the oncogenic NF-κB transcriptional complex that, in turn, promotes aggressive breast cancer phenotype.”

Cancer survival enhanced by complementary therapies

Current Oncology ReportsEvidence reported in a study just published in Current Oncology Reports demonstrates that appropriate complementary therapies, beyond improving symptoms and quality of life, prolong cancer survival. The authors note:

Cancer survivorship has become a topic of great interest in the past few years. Unfortunately, even with successful treatment as well as good follow-up care, many patients continue to experience unmet physical, emotional, and spiritual needs as well as having an unsettling fear, fear of recurrence, a fear which most survivors share, even many years after their treatment ended. As a result, patients are continually looking for additional ways to address these needs and fears. Among the most popular approach is the use of complementary and integrative medicine (CIM). Most studies on CIM use among cancer patients and survivors concentrate on symptom improvement and improvement of quality of life and do not touch a crucial question if these therapies can affect patients’ survival in terms of prolongation of life.”

They compiled data from a collection of studies that assessed the use of nutrition and nutritional supplements, mind–body interventions, physical activity, and combined CAM approaches in cancer patients to assess the cancer survival benefit and found:

“Interestingly, in recent years, there are a growing number of studies that suggest that approaches such as mind-body interventions, enhanced general nutrition, nutritional supplements, physical activity, and other CIM approaches may have a positive effect on survival of cancer patients. Although additional studies are needed to confirm these findings, given the low cost of these CIM interventions, their minimal risk, and the potential magnitude of their effects, these approaches might be considered as additional important tools to integrate into cancer survivorship care plans.”

More than reducing symptoms and improving quality of life

Lead author Moshe Frenkel, MD, chair of the Israeli Society of Complementary Medicine and founder of the Integrative Oncology Clinic at the University of Texas M.D. Anderson Cancer Center in Houston, quoted in Medscape Medical News states:

“At times, these modalities can actually have a survival effect that could be similar to conventional care…In the academic arena, complementary therapies are known to be used to reduce symptom intensity and improve quality of life during and after cancer treatments.” He and his colleagues “wanted to change this view a bit, and increase the awareness that complementary and integrative medicine can affect survival.

Major effect on cancer survival

Dr. Frenkel further stated to Medscape Medical News:

“This is a point that most integrative oncologists do not emphasize…There is actually quite good evidence from multiple studies that suggest that these therapies — including nutrition, certain supplements, physical activity, and stress reduction — actually do have a major effect on survival.”

Clinical note: Besides common sense lifestyle measures such as wholesome nutrition, physical exercise, smoking cessation, stress reduction with guided imagery, mindfulness meditation, and yoga, etc. specific choices for other interventions, including nutritional supplements, a ‘try this, try that’ approach should be avoided and management guided by targeting genuine needs as indicated by the appropriate objective laboratory tests.