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Patient with Metastatic Breast Cancer Achieves Stable Disease for 5 Years on Graviola and Xeloda after Progressing on Multiple Lines of Therapy

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Damien Hansra at Cancer Treatment Centers of America, Atlanta
Damien Hansra
  • Cancer Treatment Centers of America, Atlanta
Orlando Silva
Orlando Silva
Orlando Silva
  • This person is not on ResearchGate, or hasn't claimed this research yet.
Ashwin Mehta at Memorial Healthcare System
Ashwin Mehta
Eugene Ahn
Eugene Ahn
Eugene Ahn
  • This person is not on ResearchGate, or hasn't claimed this research yet.
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Advances in Breast Cancer Research, 2014, 3, 84-87
Published Online July 2014 in SciRes. http://www.scirp.org/journal/abcr
http://dx.doi.org/10.4236/abcr.2014.33012
How to cite this paper: Hansra, D.M., Silva, O., Mehta, A. and Ahn, E. (2014) Patient with Metastatic Breast Cancer
Achieves Stable Disease for 5 Years on Graviola and Xeloda after Progressing on Multiple Lines of Therapy. Advances in
Breast Cancer Research, 3, 84-87. http://dx.doi.org/10.4236/abcr.2014.33012
Patient with Metastatic Breast Cancer
Achieves Stable Disease for 5 Years on
Graviola and Xeloda after Progressing on
Multiple Lines of Therapy
Damien Mikael Hansra, Orlando Silva, Ashwin Mehta, Eugene Ahn
Department of Hematology and Oncology, Sylvester Comprehensive Cancer Center at the University of Miami,
Miami, USA
Email: dmhansra@med.miami.edu
Received 8 March 2014; revised 6 April 2014; accepted 5 May 2014
Copyright © 2014 by authors and Scientific Research Publishing Inc.
This work is licensed under the Creative Commons Attribution International License (CC BY).
http://creativecommons.org/licenses/by/4.0/
Abstract
Breast cancer (BC) is the most common malignancy in women and is second to lung cancer in
terms of cancer mortality. Treatment of BC remains a challenge as current therapies are limited by
toxicity and drug resistance. Graviola (Annona muricata) is a tree that grows in the tropics of
North and South America. Traditionally, the leaves and stems from the graviola tree have been
used for a wide range of human diseases including cancer. In vitro and in vivo studies demonstrate
anticancer activity in BC however clinical studies are lacking. We present the first case demon-
strating clinical benefit without side effects using graviola in a patient with BC whose disease was
refractory to multiple lines of chemotherapy including anthracyclines and taxanes.
Keywords
Breast Cancer, Graviola, Therapy
1. Introduction
Breast cancer (BC) is the most common malignancy in women and treatment of BC remains challenge as current
therapies are limited secondary to toxicity and drug resistance. New integrative treatment strategies should be
explored. Graviola (Annona muricata) is an Amazon fruit tree that grows in the tropics of North and South
America and has been used for a wide range of human diseases including inflammatory conditions, rheumatism,
neuralgia, diabetes, hypertension, insomnia, cystitis, parasitic infections, and cancer. Despite graviola being used
D. M. Hansra et al.
85
for centuries, research on its health benefits has been extremely limited. To date there are no published reports
on outcomes using graviola in cancer patients.
2. Methods
A retrospective chart review of one patient diagnosed with BC from 1999-2012. Detailed clinical history was
obtained including age at diagnosis, stage at diagnosis, therapy (chemotherapy, hormone, graviola) and response
to therapy. Review of laboratory data was performed including liver function testing and tumor markers. Finally
imaging with FDG PET CT was reviewed from diagnosis to end of study.
3. Results
A 66-year-old female diagnosed with estrogen and progesterone receptor positive human epidermal growth fac-
tor receptor negative pT2N1M0 stage IIb of the left breast cancer diagnosed in 1998 status post lumpectomy,
adjuvant anthracycline & taxane based chemotherapy followed by breast radiation completed in 1999. She sub-
sequently presented with biopsy proven lung metastasis in 2002. She was started on hormonal therapy and pro-
gressed on Femara, Tamoxifen, and Faslodex. Chemotherapy with Navelbine was initiated from March 2005
until February 2006, Abraxane, Avastin, Gemcitabine (AAG) from Feburary 2006 to May 2007, Doxil from
May 2007 to September 2007. Unfortunately the patient was found to have new liver metastases and she was
started on Xeloda 2500 mg PO daily (2 weeks on 1 week off) at that time. The patient also started using graviola
10 - 12 dry leaves boiled in water for 5 - 7 minutes, 8 oz. PO daily at that time. Tumor markers at time of initia-
tion of graviola and Xeloda were CEA 12.5 ng/ml (0.0 - 3.4 ng/mL), CA 15-3 1249.0 U/ml (0.0 - 25.0 U/mL),
CA 27-29 1295 U/ml (<38 U/mL). Tumor markers in April 2008 were: CEA 5.9 ng/ml, CA 15-3 68.6 U/ml, CA
27-29 113 U/ml. Patient moved to Alaska and continued her regimen, then returned in December 2011 and au-
tonomously discontinued graviola at that time. Labs in March 2012 showed AST 75 U/L (15 - 46 U/L) ALT 84
U/L (9 - 52 U/L), CEA 4.3 ng/ml, CA 15-3 25.7 U/ml, CA 27.29 35 U/ml. Also, PET-CT at that time demon-
strated worsening left upper lung disease. Graviola was re-initiated at this point and labs in November 2012
showed AST 43 U/L, ALT 50 U/L, CEA 2.9, CA 27-29 32 U/ml, CA 15-3 20.7 U/ml. Re-imaging with PET/CT
in November 2012 showed stable disease. So far, patient has had stable disease and experienced no side effects
from therapy for over 5 years.
4. Discussion
Breast cancer (BC) is the most common malignancy in women and is second to lung cancer in terms of cancer
mortality. An estimated 234,580 Americans will be diagnosed with BC and 40,030 will die of the disease in the
United States in 2013 [1]. Treatment of BC remains a challenge as current therapies are limited secondary to
toxicity and drug resistance and alternative treatment strategies should be explored. Furthermore the incidence
of breast cancer has been steadily increasing over the past few decades [2] necessitating development of greater
preventative strategies. It is well established that increased consumption of fruits and vegetables is associated
with a reduced risk of most cancers [3]. The beneficial effect is partly due to the fact that fruits and vegetables
contain antioxidants, fiber, and other potentially antineoplastic compounds. For this reason, natural products
have been investigated as potential anticancer agents with the most attractive feature of these agents being li-
mited side effect profiles as compared to conventional chemotherapeutic drugs. Specific bioactive compounds in
foods, notably sulfur-containing gluconsinolates and green tea polyphenols are associated with reduced risk of
BC risk [4] [5]. Graviola (Annonaceous muricata L.) is an Amazon fruit tree that grows in the tropics of North
and South America and is also known as soursop and guanabana. Traditionally, the leaves and stems from the
graviola tree have been used for a wide range of human diseases including inflammatory conditions, rheumatism,
neuralgia, diabetes, hypertension, insomnia, cystitis, parasitic infections, and cancer [6] [7]. Graviola has been
widely consumed by indigenous people for centuries however research on its health benefits are extremely li-
mited. To date there are no published reports on outcomes using graviola in cancer patients. We present the first
case demonstrating clinical benefit using graviola in a patient with BC. Arguably, the patient was taking single
agent chemotherapy however the median progression free survival on single agent Xeloda in the metastatic set-
ting is only a few months [8]. Also, the patient’s liver function tests were elevated off graviola in the absence of
other non-metastatic causes of hepatic injury and then normalized once graviola was resumed. This further sup-
D. M. Hansra et al.
86
ports the notion that graviola stabilized our patient’s disease. The exact mechanism of graviola in cancer cells is
under investigation. Annonaceous acetogenins, the major bioactive components in graviola, are derivatives of
long chain fatty acids that are selectively toxic to cancer cells, including multidrug resistant cancer cell lines
[9]-[13] [14]. One study found that graviola inhibited tumorgenicity and metastasis in pancreatic cancer cells in
vitro and in vivo by inhibiting multiple signaling pathways that regulate metabolism, cell cycle, survival, and
metastatic properties in pancreatic cells [15]. Another study demonstrated that graviola induced growth inhibi-
tion of human breast cancer cells in vitro and in vivo through a mechanism involving the EGFR/ERK signaling
pathway [16]. In terms of toxicity, graviola may cause movement disorders and myeloneuropathy with symp-
toms mimicking Parkinson’s disease [17]. Our patient did not suffer any significant side effects. Further clinical
research is required to determine the efficacy, effective dose, potential drug interactions and toxicity so this
plant-derived extract could potentially gain approval for usage in breast cancer patients.
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... Its leaves are also known as "cancer killers" due to their possible anticancer effects [11]. Annonaceous acetogenins, which are derivatives of long-chain fatty acids, are the major bioactive components in Annona muricata that exhibit selective toxicity to cancer cells, including those that are multidrug-resistant [12]. Acetogenins are natural compounds that exert anticancer effects by inducing tumour cell death via various mechanisms such as controlling the cell cycles (causing cell arrest in the G1 phase), and promoting apoptosis by inhibiting multiple proteins while also inducing autophagy [13]. ...
... The titles and abstracts of 475 papers were screened for potential relevance, excluding 464 for being irrelevant to the review. Eleven full-text papers were obtained and evaluated, resulting in exclusion of six papers (two case reports [12,38], two non-human trials [39,40], one not involving cancer patients [41], and one ongoing trial [42]. Five studies fulfilled all eligibility criteria and were included in the review. ...
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  • Sep 2010
  • Biochim Biophys Acta
Pancreatic cancer (PC) is a highly lethal malignancy with near 100% mortality. This is in part due to the fact that most patients present with metastatic or locally advanced disease at the time of diagnosis. Significantly, in nearly 95% of PC patients there is neither an associated family history of PC nor of diseases known to be associated with an increased risk of PC. These groups of patients who comprise the bulk of PC cases are termed as "sporadic PC" in contrast to the familial PC cases that comprise only about 5% of all PCs. Given the insidious onset of the malignancy and its extreme resistance to chemo and radiotherapy, an abundance of research in recent years has focused on identifying biomarkers for the early detection of PC, specifically aiming at the sporadic PC cohort. However, while several studies have established that asymptomatic individuals with a positive family history of PC and those with certain heritable syndromes are candidates for PC screening, the role of screening in identifying sporadic PC is still an unsettled question. The present review attempts to assess this critical question by investigating the recent advances made in molecular markers with potential use in the early diagnosis of sporadic PC - the largest cohort of PC cases worldwide. It also outlines a novel yet simple risk factor based stratification system that could be potentially employed by clinicians to identify those individuals who are at an elevated risk for the development of sporadic PC and therefore candidates for screening.
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Tumor cell growth inhibition by several Annonaceous acetogenins in an in vitro disk diffusion assay
Article
  • Oct 1995
  • CANCER LETT
The cell inhibition activities of several Annonaceous acetogenins, covering the three major structural classes of bis-adjacent, bis-non-adjacent, and single tetrahydrofuran (THF) ring compounds and their respective ketolactone rearrangement products, were tested in an in vitro disk diffusion assay against three murine (P388, PO3, and M17/Adr) and two human (H8 and H125) cancerous cell lines as well as a non-cancerous immortalized rat GI epithelial cell line (I18). The results demonstrate a dose-dependent inhibition of cancerous cell growth, while non-cancerous cell growth is not inhibited by the same dosages. All of the acetogenins, irrespective of their various structural types, inhibit the growth of adriamycin resistant tumor cells and non-resistant tumor cells at the same levels of potency. These results show that the Annonaceous acetogenins are an extremely potent class of compounds, and their inhibition of cell growth can be selective for cancerous cells and also effective for drug resistant cancer cells, while exhibiting only minimal toxicity to 'normal' non-cancerous cells.
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Structure−Activity Relationships of Diverse Annonaceous Acetogenins against Multidrug Resistant Human Mammary Adenocarcinoma (MCF-7/Adr) Cells
Article
  • Jul 1997
Fourteen structurally diverse Annonaceous acetogenins, representing the three main classes of bis-adjacent, bis-nonadjacent, and single-THF ring(s), were tested for their ability to inhibit the growth of adriamycin resistant human mammary adenocarcinoma (MCF-7/Adr) cells. This cell line is resistant to treatment with adriamycin, vincristine, and vinblastine and is, thus, multidrug resistant (MDR). Among a series of bis-adjacent THF ring acetogenins, those with the stereochemistry of threo-trans-threo-trans-erythro (from C-15 to C-24) were the most potent with as much as 250 times the potency of adriamycin. A spacing of 13 carbons between the flanking hydroxyl of the THF ring system and the gamma-unsaturated lactone seems to be optimum with a spacing of 11 and 9 carbons being significantly less active. Several single-THF ring compounds were also quite potent with gigantetrocin A (11) being the most potent compound tested. The acetogenins may, thus, have chemotherapeutic potential, especially with regard to MDR tumors.
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Toxicity of Annonaceae for dopaminergic neurons: Potential role in atypical Parkinsonism in Guadeloupe
Article
  • Jan 2002
In the French West Indies there is an abnormally high frequency of levodopa-resistant parkinsonism, suggested to be caused by consumption of fruit and infusions of tropical plants, especially Annona muricata (corossol, soursop). To determine whether toxic substances from this plant can cause the neuronal degeneration or dysfunction underlying the syndrome, we exposed mesencephalic dopaminergic neurons in culture to the total extract (totum) of alkaloids from Annona muricata root bark and to two of the most abundant subfractions, coreximine and reticuline. After 24 hours, 50% of dopaminergic neurons degenerated with 18 microg/ml totum, 4.3 microg/ml (13 microM) coreximine, or 100 microg/ml (304 microM) reticuline. The effects of the alkaloid totum were not restricted to the population of dopaminergic cells since GABAergic neurons were also affected by the treatment. Nuclei in dying neurons showed DNA condensation or fragmentation, suggesting that neuronal death occurred by apoptosis. Cell death was not excitotoxic and did not require toxin uptake by the dopamine transporter. Neurodegeneration was attenuated by increasing the concentration of glucose in the culture medium, which also reduced the effect of the dopaminergic neurotoxin MPP+, a mitochondrial respiratory chain inhibitor. Toxin withdrawal after short-term exposure arrested cell death. Acute treatment with totum, coreximine, or reticuline reversibly inhibited dopamine uptake by a mechanism that was distinct from that causing neuronal death. GABA uptake was not reduced under the same conditions. This study suggests that alkaloids from A. muricata can modulate the function and the survival of dopaminergic nerve cells in vitro. It is therefore conceivable that repeated consumption could cause the neuronal dysfunction and degeneration underlying the West Indian parkinsonian syndrome.
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