ASCO 2014: Bad News From ALTTO for Breast Cancer Drug Development





According to report out yesterday from, doubling up HER2-targeted therapies, from 1 to 2, adds no benefit in the adjuvant (therapy given after primary treatment to reduce risk that cancer will come back) setting and, in fact, exhibits greater toxicity than using Herceptin alone. "Adding lapatinib (Tykerb/Tyverb) to the standard trastuzumab (Herceptin) does not prolong survival and increases toxicity when used after surgery in women with HER2-positive early breast cancer, according to the ALTTO (Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization) trial." This result is a shocker since 2 such therapies ARE better in the neoadjuvant (therapy given to shrink tumor prior to main treatment, usually surgery) setting (link).


Why is this such a surprise?  Because the holy grail of cancer therapy is long-term outcome and meaningful surrogate markers for long-term outcome are needed to, among other things, drive the clinical development of new candidate therapies. In this case, the surrogate marker for long-term outcome is believed to be a variable known as the "pathological complete response rate" [pCR rate]. While there is no standardized definition of pCR (see this article for various definitions from the field), the best definition in breast cancer appears to be no invasive and no in situ residuals in breast and nodes at some time point following surgery and chemotherapy. This definition is "best" because it "...can best discriminate between patients with favorable and unfavorable outcomes in the neoadjuvant setting. " [Note also that this discriminatory power does not extend equally to all forms of breast cancer.] Nonetheless, the use of pCR in the neoadjuvant setting as a surrogate endpoint for beneficial long-term outcome was embraced by the FDA (see this Guidance for Industry) to support accelerated approval of new therapeutics. Indeed, pCR was employed just so in last year's accelerated approval of Perjeta in preoperative breast cancer by the FDA.


Till now, there has been an operative assumption that demonstrated utility via pCR in the neoadjuvant setting should extend to the adjuvant setting, an assumption clearly refuted by the present study. As a result, an important question emerges: do these results from the adjuvant setting undercut the utility of pCR rate as a viable surrogate marker, especially in supporting accelerated approvals of new drugs for early-stage breast cancer? Some think so. Quoting Dr. George Sledge (Stanford University), the article contains this snippet: ""ALTTO represented a reasonable test of the hypothesis that improvements in the pathological complete response rate [seen in NeoALTTO] would be associated with improved disease-free survival. These hopes have now been dashed," said Dr. Sledge."


Dr. Sledge further suggests that we may need to reevaluate the current approach to drug development for early-stage breast cancer. And that is a big deal.



Avastin Wins Approval for New Cancer Use.







    Genentech has won FDA approval for the use of its anticancer antibody bevacizumab (Avastin) as a component in a second line (salvage) therapy regimen for metastatic colorectal cancer, according to a news article appearing in MedPage Today.  Previously, bevacizumab was approved only for first-line therapy of metastatic disease in combination with 5-FU chemotherapy and not for adjuvant therapy.


The FDA’s approval was based on a phase 3 clinical trial showing a 19% reduction in mortality in patients receiving bevacizumab in both first and second line regiments as compared to patients receiving only chemotherapy in the salvage regimen. An overall it increase in median overall survival from 9.8 211.2 months was observed in the patient pool receiving bevacizumab in both first and second line regiments.





Statin Use: Decreased Cancer Mortality?







    A new article by Michael Smith for MedPage Today reports that a Danish study has found that "...Statin use is associated with a lower risk of dying from cancer for people who used the cholesterol-lowering drugs before their cancer diagnosis..." The news article cites a report appearing in the Nov. 8th issue of the New England Journal of Medicine. As noted in the news article, a large pool of patient was followed for over 1 million person years. "....All told, among cancer patients 40 and older, 18,721 had used statins regularly before the diagnosis and 277,204 had never been given the drugs..." and subsequently "... 162,067 patients died of cancer, 14,489 of cardiovascular causes, and 19,038 of other causes..."  Further analysis showed that "... The cumulative incidence of death from cancer, as a function of follow-up time, was significantly lower among statin users than among patients who had never used statins, with a log-rank P<0.001."


    There are several limitations to the study, including the selective population studied [all participants were Danish] and potential confounding effects (such as statin use as a surrogate for health conciousness), but the study clearly lays the ground work for further reseach efforts. In particular, the investigators note that the biochemical pathways targeted by statins are important for cancer cell growth, so possible biochemical modes of action are clear (see, for example, this review). This puts cancer at some advantage compared to other diseases where correlates with statin use exist (e.g. influenza & pneumonia).



An HIV Drug Useful for HER-2 Positive Breast Cancer?






    A report out today from MedWire News describes an advance online publication appearing in the Journal of the National Cancer Institute that shows "... the aspartyl protease inhibitor, nelfinavir [Viracept; approved by the FDA in 1997 for treatment of HIV-positive patients], selectively inhibits growth of HER2-positive breast cancer cells in vitro and in vivo, including cell lines with proven resistance to the current HER2-positive agents trastuzumab [Herceptin] and/or lapatinib [Tykerb; a tyrosine kinase inhibitor that acts by binding to the ATP-binding pocket of the EGFR/HER2 protein kinase domain]."


     Moreover, "...nelfinavir was shown to selectively inhibit HER2-positive breast cancer cell lines via phosphorylation of the proteins AKT, ERK1, ERK2, and HER2. The researchers also demonstrate that nelfinavir binds HSP90 at the C-terminal and induces conformational changes in the protein; this is a different mechanism from other HSP90 inhibitors." In contrast, as a HIV protease inhibitor, nelfinavir is believed to block cleavage of the gag and gag-pol polyprotein resulting in the production of immature, non-infectious virus.


     Further, "....When nelfinavir was given to nude mice carrying xenograft HER2-positive tumors at an intraperitoneal dose of 25 mg/kg, or an oral dose of 40 mg/kg, there was a significant decrease in tumor growth compared with animals given a control treatment. No such effect was noted for mice carrying HER2-negative xenograft tumors." The oral dose used here compares well to the standard adult dose for HIV patients of 750 mg TID.


    With such preclinical efficacy and safety data, as well as prior data from the HIV arena, the authors note that the drug is "ready for clinical testing in HER2 breast cancer patients".


     While therapeutics targeting HER2 have provided a dramatic improvement in disease outcomes for many breast cancer patients, many patients are refractory to these therapies or will eventually become resistant after treatment. Thus, overcoming this barrier is a major treatment challenge and much recent work in the area has focused upon novel approaches to overcome resistance to Her2-targeted therapies (see for example this link on a possible IL-6 mediated inflammatory feedback loop driving Herceptin resistance).



Experimental Drug Combo Extends Survival for Liver Cancer






    Germany's 4SC AG has reported Phase II clinical trial data for its drug candidate resminostat. When used in combination with another, approved, cancer drug (Bayer's Nexavar), advanced liver cancer (hepatocellular carcinoma) patients, who had shown proven radiological tumor progression under first-line therapy with the cancer drug sorafenib (Nexavar), showed an extention in overall survival  by 8 months. Resminostat, a histone deacetylase [HDAC] inhibitor, shows only a 4.1 month extention of overall survival when used alone compared to Nexavar's 5.5 months [Nexavar data from another trial]. A median progression-free survival time of 4.7 months was observed in the combination arm, more than twice the rate for resminostat alone.


     Standard treatment of liver cancer is aggressive surgery or a liver transplant for small or slow-growing tumors if they are diagnosed early. However, few patients are diagnosed early. As a result, chemotherapy is employed to treat, but not cure, the disease. Radiation treatments can also be helpful. However, many patients have liver cirrhosis or other liver diseases that make these treatments more difficult. Sorafenib tosylate (Nexavar), a multikinase inhibitor that blocks tumor growth, is approved for patients with advanced hepatocellular carcinoma.


     As noted on Medscape, "...hepatocellular carcinoma is now the third leading cause of cancer deaths worldwide, with over 500,000 people affected. The incidence of hepatocellular carcinoma is highest in Asia and Africa, where the endemic high prevalence of hepatitis B and hepatitis C strongly predisposes to the development of chronic liver disease and subsequent development of hepatocellular carcinoma." (Link)






Intercellular Delivery of an Anti-Cancer Punch: Exosomes & PTEN







    Much of the current research in pursuit of new cancer therapeutics is predicated on targeting defective genes or gene products within (or on the surface of) the cancer cell. Underlying this approach is the tacit assumption that the defective proteins within (or on) cancer cells are the product of synthesis within the cancer cell. However, a startling new paper out in Science Signaling demonstrates that this assumption isn't always correct.


   The protein under study in this report is PTEN, a well known tumor suppressor protein. PTEN (phosphatase and tensin homolog deleted on chromosome 10) is an intracellular protein found in the nucleus and the cytoplasm. PTEN is a lipd phosphatase, a master cellular regulator, and a default gatekeeper against cancer development (see this review).  PTEN  acts as a tumor suppressor by antagonizing the kinase PI3K and thereby inhibiting another kinase, Akt, that acts downstream of PI3K. The net result of this modulation of a signaling pathway is reduced cellular proliferation. Loss of tumor suppression activity can occur due to mutations in PTEN and indeed mutations in PTEN are found in many different tumors, notably glioblastoma and prostate cancer.


    The key finding of the present report is that normal cytoplasmic PTEN can be bundled into vesicular packages call exosomes, exported from the cell and then be taken up by other cells, reconstituting tumor suppression in the target cell.


     And what is an exosome? An exosome is a multi-lamellar [multi-compartmental] vesicle derived from the cell's endosomal system that is spit out/secreted/released from cells. Formation of an exosome has the same origin as any endosomal vesicular component: budding from the plasma membrane. Some of these new endosomal vesicles, now intracellular, can repeat the budding process again and again, forming a multi-lamellar vescicle. In doing so, these multi-lamellar vesciles entrap cytoplasmic proteins and RNAs associated with the plasma membrane, such as PTEN [perhaps by virtue of one of PTEN's many post-translational modifications; see this review]. A secreted multi-lamellar vesicle is an exosome and exosomes can be taken up by other cells and unpackaged in reverse. Long thought of as only vesicles that "take out the trash", exosomes are now appreciated as yet another means of trafficking cellular components between cells, enabling new pathways to cancer therapeutics.



The Global Impact of Cancer Still Enormous






    A not-so-gentle reminder of the enormous socio-economic cost of cancer globally has surfaced in the latest edition of The Lancet. In a sobering early on line article, a European team of investigators has published their study, entitled "Global burden of cancer in 2008: a systematic analysis of disability-adjusted life-years in 12 world regions", showing that in 2008 over 150 million DALYs (disability-adjusted life-years; the WHO defines a DALY for a disease or health condition as the sum of the Years of Life Lost (YLL) due to premature mortality in the population and the Years Lost due to Disability (YLD) for incident cases of the health condition) were lost to cancer. In 2008, there were 7.6 million deaths worldwide attributable to cancer.


     The authors conclude: "Age-adjusted DALYs lost from cancer are substantial, irrespective of world region. The consistently larger proportions of YLLs in low HDI than in high HDI countries indicate substantial inequalities in prognosis after diagnosis, related to degree of human development. Therefore, radical improvement in cancer care is needed in low-resource countries."




Denosumab Treatment May Result in Slower Onset of Pain in BC






    As reported on Medscape, denosumab (Xgeva), a fully human monoclonal antibody appoved for the prevention of skeleton-related events in patients with bone metastases from solid tumors and for osteoporesis, may have a stronger effect than zoledronic acid in delaying the development of severe pain in women with advanced breast cancer. This conclusion stems from a secondary analysis of a randomized, double-blind study originally published in 2010 in the Journal of Clinical Oncology. There was, however,  no significant difference between the two groups (Xgeva-treated vs. zolendronic acid-treated) in time to pain improvement or decreased pain interference in daily life activities.





Preop MRI No Help in Breast Cancer Outcomes






    In a report on Medpage Today, Dr. Jan H. Wong of East Carolina University in Greenville, N.C., and colleagues, have looked at five years of patient records in their facility and concluded that additional surgeries were just as frequent in breast cancer patients who underwent MRI scans prior to full or partial mastectomy as in those who did not have the preoperative imaging.


      At issue is the increasing use of MRI scans in newly diagnosed breast cancer patients "... "to rule out multicentric disease that may preclude breast conservation therapy". And for good reason, too.  Though "...mammography and ultrasonography remain the standard imaging" in breast cancer, MRIs have been shown to pick up more tumors in the contralateral as well as the index breast.  However, false positives in MRI scans are common and a detailed assessment of the utility of pre-op MRI scans has not been previously studied.


     Writing in the Archives of Surgery, the investigators conclude that, based on their retrospective analysis, the "... selective use of preoperative MR imaging to decrease reoperation in women with breast cancer is not supported by these data. In a considerable number of patients, MR imaging overestimates the extent of disease." As noted in the accompanying Invited Critique by Dr. Sharon Lum, Dr. Wong's group has "...added to the burgeoning body of literature questioning the usefulness of breast MR imaging..." .





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