A new chemotherapy drug, Ibrance (palbociclib), was approved last winter by the FDA for use in women with previously treated estrogen receptor positive/Her-2 negative breast cancer.  A new report (PALOMA-3 Trial) from last June in which this drug was used in combination with Faslodex (Fulvestrant), will likely prompt more frequent use of this this combination.

After the results of this study were presented May 30 at the 2015 meeting of the  American Society of Clinical Oncology (ASCO), the online headlines declared the combination “Doubles time to progression.” [1]    These results have now been published officially. [2]

The primary ‘endpoint’ tracked in the trial was progression-free survival (PFS).  It took a median time of 9.2 months in those patients taking the drug combination compared to only 3.8 months in patients taking only the standard hormonal therapy for the cancer to progress.   Well 5.4 months longer to when the disease returned actually sounds like more than double the time.  We should note that once the disease returns it progresses at its typical speed. [3, 4]       “…. the researchers are continuing to follow the women to collect information on overall survival — how long the women live, with or without the cancer growing. Right now, it’s not clear if adding Ibrance to Faslodex will improve overall survival.” [5]

In another recently published study, in this case that combined use of Ibrance with the aromatase inhibitor,  Femara (letrozole), published this month (August, 2015), the addition of Ibrance again doubled progression free survival:

“Median progression-free survival was 10.2 months (95 % CI 5.7–12.6) for the letrozole group and 20.2 months (13.8–27.5) for the palbociclib plus letrozole group (HR 0.488, 95 % CI 0.319–0.748; one-sided p = 0.0004), which correlates to a doubled PFS in favor of the combination group. The overall survival is unknown and the follow-up is ongoing.”  [6]

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Not knowing whether or not overall survival time is improved by this drug, while of critical importance, will not decrease enthusiasm over possible benefit and we will be seeing more patients taking Ibrance in the coming months.

These drugs are used in breast cancers that no longer respond to aromatase inhibitor drugs.  This new drug, Palbociclib targets and inhibits a chemical pathway common in these cancer cells called CDK4/CDK6.

Curcumin, the commercially concentrated extract of the spice turmeric, might have a role to play in conjunction with these new drugs as it also targets these same CDK4 pathways. [7, 8]      Berberine, as well, may also have a desirable effect on these CDK pathways.[9, 10]      Unfortunately use of either botanical extract may be contraindicated for other reasons that we must discuss.

The FDA, on its official webpage on Ibrance, cautions against use of drugs that are either inhibitors or inducers of the liver enzyme CYP3a in conjunction with this drug.    CVP3a breaks down Ibrance.  Drugs that inhibit this CYP3a enzyme will increase the Ibrance’s effect as it will take longer to be broken down.  The FDA also warns against using CYP3A inducers, those drugs that increase the amount of CYP3a made in the body, as doing so will decrease the effect produced by Ibrance; the drug will be broken down faster.

The FDA website provides a pair of lists of drugs or botanicals that have one or another of these effects.

http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207103s000lbl.pdf

Both curcumin and berberine, supplements we like almost all cancer patients to take, may induce CYP3a enzyme so that the body will break down Ibrance faster and thus decrease the benefits gained from using these drugs (Hsieh 2014, Cui  2014). [11, 12]

Thus on first glance we should tell patients to avoid both of these supplements when being treated with Ibrance.  This same mechanism of CYP3a induction is why these patients should not drink grapefruit juice, take steroids or use progesterone.

But do curcumin or berberine actually have an impact human CYP3a?  This isn’t exactly clear.  And if they do does the decrease in Ibrance’s effect outweigh the enhanced, potentially synergistic action these supplements may provide in extending patient survival?  Again, not clear.

The prior Hsieh citation that suggested curcumin changes CYP3a action based its conclusion on data obtained from rats who were given the human dose equivalent of 4 to 8 grams/day.  Cui et al’s 2014 report suggesting that berberine likewise increases CYP3a action was done in vitro, not even in animals.  It is hard to predict based on these data what really will happen in people.

Volak et al in a 2013 study using human subjects were unable to confirm that curcumin increases CYP3a: they reported no significant changes in the pharmacokinetics of drugs that should be sensitive to CYP3a action. [13]

It should be noted that the curcumin Volak’s study participants took was a mixture of curcumin and piperine, a formula that we now rarely use compared to the newer liposomal products.  The later are better absorbed.  Does this make them more or less likely to affect CYP3a?  At this point, no data is available.

An earlier human trial published back in 2010 reported that curcumin affected the elimination of caffeine from the human body by modifying action of CYP1A2 activity (decreased by 28.6%) and CYP2A6 (increased by 50%) but did not provide data on CYP3a, the enzyme that may affect Ibrance.  [14]

Berberine may or may not be a problem as well. A 2011 human clinical trial reported that “Repeated administration of berberine (300 mg, t.i.d., p.o.) decreased CYP2D6, 2C9, and CYP3A4 activities .” Cyp2d6 activity decreased by a factor of nine. [15]    While this is seemingly significant it is the opposite finding of what Cui reported, that berberine increases enzyme action and thus presumably decreases drug effect.

Considering these different studies it would seem that we should be cautious using berberine with Ibrance because this supplement may either decrease or increase the CYP enzymes responsible for breaking down this drug.  As a result berberine may have more impact on the cancer, not so bad, or less impact, and also produce more or less side effects.

Curcumin is less clear. We do not know for sure whether curcumin actually does affect these enzyme pathways in humans or only in rats. This is a situation where being cautious and not using curcumin may decrease benefit as much as using it might.  We need some form of outcome study to balance the benefits versus risks associated with curcumin use with this new drug.  While Ibrance may stall time to disease progression, it has not yet been shown to prolong overall survival, a measurement of far greater importance.  Prolonging progression free survival unfortunately does not predict long-term effects.  What if curcumin or berberine were to help do this?  Unfortunately we do not have the answers to this fundamental question as of yet.  Suffice to say we are following this matter closely.

 

References:

1. http://www.curetoday.com/articles/adding-ibrance-to-faslodex-delays-progression-of-hormone-receptor-positive-breast-cancer#sthash.eIZDPCoy.dpuf

2.  J Hematol Oncol. 2015 Aug 13;8(1):98. doi: 10.1186/s13045-015-0194-5.

Palbociclib: a first-in-class CDK4/CDK6 inhibitor for the treatment ofhormone-receptor positive advanced breast cancer.

Lu J.

3.  N Engl J Med. 2015 Jul 16;373(3):209-19. doi: 10.1056/NEJMoa1505270. Epub 2015 Jun 1.

Palbociclib in Hormone-Receptor-Positive Advanced Breast Cancer.

Turner NC1, Ro J, André F, Loi S, Verma S, Iwata H, Harbeck N, Loibl S, Huang Bartlett C, Zhang K, Giorgetti C, Randolph S, Koehler M, Cristofanilli M.

4.  http://www.cancernetwork.com/asco-2015-breast-cancer/palbociclib-fulvestrant-delays-hr-positive-breast-cancer-progression#sthash.ploQs5Rm.dpuf

5.  http://www.breastcancer.org/research-news/ibrance-offers-benefits-as-second-line-tx

6. J Hematol Oncol. 2015; 8: 98.

Published online 2015 Aug 13. doi:  10.1186/s13045-015-0194-5

PMCID: PMC4534142

Palbociclib: a first-in-class CDK4/CDK6 inhibitor for the treatment of hormone-receptor positive advanced breast cancer

Janice Lu

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4534142/

7.  Mol Biol Rep. 2013 Oct;40(10):5825-31. doi: 10.1007/s11033-013-2688-y. Epub 2013 Oct 11.

In vivo study on the effects of curcumin on the expression profiles of anti-tumour genes (VEGF, CyclinD1 and CDK4) in liver of rats injected with DEN.

Huang CZ1, Huang WZ, Zhang G, Tang DL.

8. Asian Pac J Cancer Prev. 2014;15(3):1403-10.

Reversal of resistance towards cisplatin by curcumin in cervical cancer cells.

Roy M1, Mukherjee S.

9.  Berberine inhibits the proliferation of human uterine leiomyoma cells.

Wu HL, Chuang TY, Al-Hendy A, Diamond MP, Azziz R, Chen YH.

Fertil Steril. 2015 Apr;103(4):1098-106. doi: 10.1016/j.fertnstert.2015.01.010.

10.  Carcinogenesis. 2006 Oct;27(10):2018-27. Epub 2006 Apr 18.

Berberine inhibits growth, induces G1 arrest and apoptosis in human epidermoid carcinoma A431 cells by regulating Cdki-Cdk-cyclin cascade, disruption of mitochondrial membrane potential and cleavage of caspase 3 and PARP.

Mantena SK1, Sharma SD, Katiyar SK.

11.  Sci Rep. 2014 Oct 10;4:6587. doi: 10.1038/srep06587.

Oral intake of curcumin markedly activated CYP 3A4: in vivo and ex-vivo studies.

Hsieh YW1, Huang CY1, Yang SY2, Peng YH2, Yu CP2, Chao PD2, Hou YC3.

12. J Ethnopharmacol. 2014 Dec 2;158 Pt A:388-96. doi: 10.1016/j.jep.2014.10.018. Epub 2014 Oct 31.

In vitro studies of berberine metabolism and its effect of enzyme induction on HepG2 cells.

Cui HM1, Zhang QY2, Wang JL2, Chen JL2, Zhang YL2, Tong XL3.

13.  Br J Clin Pharmacol. 2013 Feb;75(2):450-62. doi: 10.1111/j.1365-2125.2012.04364.x.

Effect of a herbal extract containing curcumin and piperine on midazolam, flurbiprofen and paracetamol (acetaminophen) pharmacokinetics in healthy volunteers.

Volak LP1, Hanley MJ, Masse G, Hazarika S, Harmatz JS, Badmaev V, Majeed M, Greenblatt DJ, Court MH.

14.  Ann Pharmacother. 2010 Jun;44(6):1038-45. doi: 10.1345/aph.1M533. Epub 2010 May 18.

Plant polyphenol curcumin significantly affects CYP1A2 and CYP2A6 activity in healthy, male Chinese volunteers.

Chen Y1, Liu WH, Chen BL, Fan L, Han Y, Wang G, Hu DL, Tan ZR, Zhou G, Cao S, Zhou HH.

15.   Eur J Clin Pharmacol. 2012 Feb;68(2):213-7. doi: 10.1007/s00228-011-1108-2. Epub 2011 Aug 26.

Repeated administration of berberine inhibits cytochromes P450 in humans.

Guo Y1, Chen Y, Tan ZR, Klaassen CD, Zhou HH.

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