Tag Archives: platinum-resistance

Role For Gemcitabine As Second-line Chemotherapy in Recurrent Clear Cell Ovarian Cancer

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In a recent 2014 retrospective analysis involving 72 recurrent ovarian clear cell patients who underwent second-line therapy at one of 20 Italian centers over a 16-year period, the researchers noted that a small subgroup of patients who received the drug gemcitabine (Gemzar®) appeared to have a higher rate of tumor response, as compared to women who were treated with topotecan (Hycamtin®) or pegylated liposomal doxorubicin (Doxil®).

Clear Cell Carcinoma of the Ovary

Clear Cell Carcinoma of the Ovary

In the July 2014 issue of Oncology, Italian researchers present an interesting retrospective analysis of patients with recurrent clear-cell ovarian cancer [1], a fairly chemoresistant subtype of ovarian cancer that can be difficult to treat.

This retrospective analysis included 72 recurrent ovarian clear cell patients (OCCC), who underwent second-line therapy at one of 20 Italian centers over a 16-year period (as part of the “Multicenter Italian Trial in Ovarian Cancer” or “MITO-9”).

In 56% of the OCCC patients, the clear cell histology was “pure,” meaning the predominant cell type identified within the primary tumor was classified as clear cell (i.e., a subtype of epithelial ovarian cancer) by a molecular pathologist. Twenty-five patients were platinum-resistant, 18 patients were platinum-sensitive with a platinum-free interval (PFI) of 6-to-12 months, and 29 patients had a PFI >12 months. Upon disease recurrence, 47% of patients were treated with platinum chemotherapy (e.g., carboplatin or cisplatin) based upon PFI.

The overall tumor response rate (RR) to the use of platinum drugs was 80%, with 55%, 100%, and 80% RRs in patients with PFIs of 6-to-12 months, >12 months, and >24 months, respectively. The RR to non-platinum drugs in resistant OCCC patients was 33%. Among the non-platinum drugs used in primary and secondary resistant cases, gemcitabine (Gemzar®), administered to 12 OCCC patients, produced higher anti-cancer activity (RR = 66%), as compared to topotecan (Hycamtin®) or liposomal doxorubicin (Doxil®) (number of patients = 31; RRs = 33% and 10%, respectively).

The Italian researchers concluded that the overall study results suggest that the treatment of recurrent OCCC, in general, should be based upon the duration of the patient’s PFI, as is customary in the treatment of other epithelial ovarian cancer subtypes. However, the data relating to the platinum-resistant OCCC patients evaluated in the Italian study suggest that gemcitabine (Gemzar®) was the drug that produced the greatest anti-cancer activity.

Notably, the results reported by the Italian researchers are consistent with the similar findings reported in a small number of previous studies involving an equally small number of recurrent OCCC patients. [2 – 5]

Maurie Markman, M.D.

Also appearing in the July 2014 Oncology issue is a commentary written by Maurie Markman, M.D., the President of the Medicine and Science unit of the Cancer Treatment Centers of America (CTCA).[6] Dr. Markman oversees the CTCA national clinical team, with a focus on the application of all clinical and translational research to patient care. In his commentary, Dr. Markman notes the importance of retrospective studies as a “long-established tradition in clinical cancer investigation.” Dr. Markman highlights the potential inportance of retrospective studies as noted below.

  • Single institutional data or large multicenter efforts examining past experiences can serve both as “hypothesis-generating” elements for a future prospective clinical study, an idea to be explored in a translational laboratory research project, and even as confirmation of the results of a reported study in a more heterogeneous patient population.
  • Retrospective analyses can provide critically relevant data in populations known to be poorly represented in cancer clinical trials and may identify adverse events potentially not recognized in the often highly homogenous groups of study participants.
  • The safety and the efficacy associated with longer observation periods and a more prolonged therapy than reported in many prospective clinical trials can be revealed through retrospective examinations of previously treated patients.

Within this context, Dr. Markman addresses the limitations of the Italian recurrent OCCC retrospective analyses cited above, but he also emphasizes the potential benefit of that study, as follows:

“Of course, it must be emphasized that the very limited sample size does not permit any definitive conclusions regarding the relative utility of any individual strategy, including providing a truly meaningful ‘objective response rate’. However, recognizing the rarity of this specific malignant condition (72 total [OCCC] patients identified in a period of 16 years at 20 centers), this retrospective experience will likely be of some value to individual oncologists needing to consider potential therapeutic options for a patient with recurrent clear-cell ovarian cancer. Further, in the event a multi-institutional prospective trial is ultimately undertaken in this most uncommon clinical setting, the results of this retrospective analysis should surely help to inform the planned study design.” [emphasis added]

At Libby’s H*O*P*E*, we generally recommend that recurrent OCCC patients speak to their doctor about the potential benefits (and limitations) associated with (i) molecular/genomic tumor profiling,  and (ii) chemosensistivity and resistance assay (CSRA) testing. The use of both forms of tumor testing may provide a recurrent OCCC patient and her doctor(s) with additional insights related to specific treatment options. In the event that neither form of tumor testing is possible, the results from the Italian study discussed above suggest that the use of gemcitabine (Gemzar®) to treat recurrent OCCC should be, at a minimum, considered by a recurrent OCCC patient and her doctor.

In addition, we strongly recommend that a newly-diagnosed or recurrent OCCC patient should consider the drugs being currently evaluated, as of this writing, in open OCCC patient-dedicated clinical trials, including as temsirolimus (Torisel®) [7], sunitinib (Sutent®) [8], ENMD-2076 [9], and dasatinib (Sprycel®) [10].

References:

1./ Esposito F et al. Second-line chemotherapy in recurrent clear cell ovarian cancer: Results from the Multicenter Italian Trials in Ovarian Cancer (MITO-9). Oncology 2014;86:351-358. PubMed PMID:24942520.

2./ Yoshino K, et al. Salvage chemotherapy for recurrent or persistent clear cell carcinoma of the ovary: a single-institution experience for a series of 20 patients. Int J Clin Oncol. 2013 Feb;18(1):148-53. doi: 10.1007/s10147-011-0357-5. Epub 2011 Dec 10. PubMed PMID: 22160560.

3./ Komiyama S et al. A heavily pretreated patient with recurrent clear cell adenocarcinoma of the ovary in whom carcinomatous peritonitis was controlled successfully by salvage therapy with gemcitabine. Arch Gynecol Obstet. 2008 Dec;278(6):565-8. Epub 2007 Jun 19. Erratum in: Arch Gynecol Obstet. 2009 Feb;279(2):271. Komiyama, Shin [corrected to Komiyama, Shin-ichi]. PubMed PMID: 17576588.

4./ Ferrandina G et al. A case of drug resistant clear cell ovarian cancer showing responsiveness to gemcitabine at first administration and at re-challenge. Cancer Chemother Pharmacol. 2007 Aug;60(3):459-61. Epub 2007 Apr 11. PubMed PMID: 17429624.

5./ Crotzer DR et al. Lack of effective systemic therapy for recurrent clear cell carcinoma of the ovary. Gynecol Oncol. 2007 May;105(2):404-8. Epub 2007 Feb 9. PubMed PMID: 17292461.

6./ Markman M. A Unique Role for Retrospective Studies in Clinical Oncology. Oncology. 2014;86(5-6):350. doi: 10.1159/000360911. Epub 2014 Jun 12. PubMed PMID:24942408.

7./ A Phase II Evaluation of Temsirolimus (CCI-779) (NCI Supplied Agent: NSC# 683864,) in Combination With Carboplatin and Paclitaxel Followed by Temsirolimus (CCI-779) Consolidation as First-Line Therapy in the Treatment of Stage III-IV Clear Cell Carcinoma of the Ovary. ClinicalTrials.gov Identifier: NCT01196429.

8./ A Phase II Evaluation of the Efficacy of Sunitinib® in Patients With Recurrent Ovarian Clear Cell Carcinoma. ClinicalTrials.gov Identifier: NCT01824615.

9./ A Phase II Study of Oral ENMD-2076 Administered to Patients With Ovarian Clear Cell Carcinomas. ClinicalTrials.gov Identifier: NCT01914510.

10./ A Phase II Trial of DCTD-Sponsored Dasatinib (NSC #732517) in Recurrent/Persistent Ovary, Fallopian Tube, Primary Peritoneal, and Endometrial Clear Cell Carcinoma Characterized for the Retention or Loss of BAF250a Expression. ClinicalTrials.gov Identifier: NCT02059265.

 

 

Phenoxodiol Used In Combination With Platinum or Taxane-Based Chemotherapy Is Active In Platinum & Taxane-Resistant Ovarian Cancer

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Phase II clinical study results suggests phenoxodiol is active in platinum and taxane drug-resistant ovarian cancer patients when administered intravenously in combination with platinum or taxane-based chemotherapy

Marshall Edwards, Inc., an oncology company focused on the clinical development of novel therapeutics targeting cancer metabolism, recently announced the publication of results from a phase II clinical trial of intravenous phenoxodiol in combination with cisplatin or paclitaxel in women with platinum–refractory/resistant ovarian cancer. The publication is now available on the International Journal of Gynecological Cancer website, and the print edition will appear the May issue of the journal.

The study, conducted at Yale-New Haven Hospital, showed that the combination of intravenous phenoxodiol, a novel NADH oxidase inhibitor, with cisplatin (a platinum-based chemotherapy) or paclitaxel (a taxane-based chemotherapy), was well tolerated.

Robert D. Mass, M.D., Acting Chief Medical Officer, Marshall Edwards.

In the study, 32 patients were randomized to one of two treatment arms according to their previous treatment responses: (1) platinum refractory/resistant patients received weekly cisplatin (40 mg/m intravenous), combined with weekly phenoxodiol (3 mg/kg); and (2) taxane refractory/resistant patients received weekly paclitaxel (80 mg/m intravenous), combined with weekly phenoxodiol (3 mg/kg). The study patients continued on treatment until complete response, disease progression, unacceptable toxicity, or voluntary withdrawal.

In the cisplatin study arm, there were 3 partial responses, 9 patients (56%) achieved stable disease, 4 patients (25%) progressed, and the overall best response rate was 19%. In the paclitaxel study arm, there was one complete response and 2 partial responses, 8 patients (53%) achieved stable disease, 4 patients (27%) progressed, and the overall best response rate was 20%. Response rate in this study was defined as the percentage of patients whose tumor demonstrated a radiologically confirmed reduction or disappearance after treatment.

There were no treatment-related deaths in the study, and there was only one treatment-related hospitalization and two grade 4 (i.e., life-threatening or disabling) adverse events.

Based upon the foregoing results, the researchers concluded that the combination of intravenous phenoxodiol with cisplatin or paclitaxel was well tolerated.  Moreover, the researchers stated that the cisplatin-phenoxodiol combination was particularly active and warrants further study in patients with platinum-resistant ovarian cancer.

“These results suggest that the combination of intravenous phenoxodiol with cisplatin has a good safety profile and may be capable of reversing resistance to platinum-based chemotherapy,” said lead author Michael G. Kelly, M.D., a gynecologic oncologist at Tufts Medical Center and former fellow at Yale University School of Medicine.” This study provides early clinical proof-of-concept for the combination of NADH oxidase inhibitors with standard-of-care chemotherapy and lays the groundwork for the development of more potent next-generation compounds.”

To date, phenoxodiol, an investigational drug, has been introduced into more than 400 patients in multiple clinical trials via oral or intravenous routes and has been well tolerated. Marshall Edwards has identified a next-generation compound called “NV-143,” which has demonstrated significantly more activity than phenoxodiol against a broad range of tumor cell lines. In addition to being more active as a single agent, NV-143 appears to be superior in its ability to synergize with platinum-based chemotherapy in pre-clinical studies. As a result, Marshall Edwards plans to initiate a phase I clinical trial of intravenous NV-143 later this year, followed immediately thereafter by randomized phase II trials in combination with chemotherapy.

“These published results combined with data from previous studies reinforce our conclusion that intravenous administration is the optimal route of delivery for this class of drugs and give us added confidence moving forward as we develop our next-generation compound NV-143 for the clinic,” said Robert D. Mass, M.D., Acting Chief Medical Officer of Marshall Edwards.

About Marshall Edwards

Marshall Edwards, Inc. is a San Diego-based oncology company focused on the clinical development of novel anti-cancer therapeutics. The Company’s lead programs focus on two families of small molecules that result in the inhibition of tumor cell metabolism. The first and most advanced is a NADH oxidase inhibitor program that includes lead drug candidate NV-143. The second is a mitochondrial inhibitor program that includes NV-128 and its next-generation candidate NV-344. Both programs are expected to advance into the clinic in 2011. For more information, visit www.marshalledwardsinc.com.

About Novogen Limited

Novogen Limited is an Australian biotechnology company based in Sydney, Australia. Novogen has a consumer healthcare business, and conducts research and development on oncology therapeutics through its 71.3% owned subsidiary, Marshall Edwards, Inc.

Sources:

Researchers Identify “Missing Link” Underlying DNA Repair & Platinum Drug Resistance

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Researchers have discovered an enzyme crucial to a type of DNA repair that also causes resistance to a class of cancer drugs most commonly used against ovarian cancer.

Scientists from The University of Texas MD Anderson Cancer Center and the Life Sciences Institute of Zhejiang University in China report the discovery of the enzyme and its role in repairing DNA damage called “cross-linking” in the Science Express advance online publication of Science.

Junjie Chen, Ph.D., Professor and Chair, Department of Experimental Radiation Oncology, University of Texas M.D. Anderson Cancer Center

“This pathway that repairs cross-linking damage is a common factor in a variety of cancers, including breast cancer and especially in ovarian cancer. If the pathway is active, it undoes the therapeutic effect of cisplatin and similar therapies,” said co-corresponding author Junjie Chen, Ph.D., professor and chair of MD Anderson’s Department of Experimental Radiation Oncology.

The platinum-based chemotherapies such as cisplatin, carboplatin and oxaliplatin work by causing DNA cross-linking in cancer cells, which blocks their ability to divide and leads to cell death. Cross-linking occurs when one of the two strands of DNA in a cell branches out and links to the other strand.

Cisplatin and similar drugs are often initially effective against ovarian cancer, Chen said, but over time the disease becomes resistant and progresses.

Scientists have known that the protein complex known as FANCI–FANCD2 responds to DNA damage and repairs cross-linking, but the details of how the complex works have been unknown. “The breakthrough in this research is that we finally found an enzyme involved in the repair process,” Chen said.

The enzyme, which they named FAN1, appears to be a nuclease, which is capable of slicing through strands of DNA.

In a series of experiments, Chen and colleagues demonstrated how the protein complex summons FAN1, connects with the enzyme and moves it to the site of DNA cross-linking. They also showed that FAN1 cleaves branched DNA but leaves the normal, separate double-stranded DNA alone. Mutant versions of FAN1 were unable to slice branched DNA.

Like a lock and key

The researchers also demonstrated that FAN1 cannot get at DNA damage without being taken there by the FANCI-FANCD2 protein complex, which detects and moves to the damaged site. The complex recruits the FAN1 enzyme by acquiring a single ubiquitin molecule. FAN1 connects with the complex by binding to the ubiquitin site.

“It’s like a lock and key system, once they fit, FAN1 is recruited,” Chen said.

Analyzing the activity of this repair pathway could guide treatment for cancer patients, Chen said, with the platinum-based therapies used when the cross-linking repair mechanism is less active.

Scientists had shown previously that DNA repair was much less efficient when FANCI and FANCD2 lack the single ubiquitin. DNA response and damage-repair proteins can be recruited to damage sites by the proteins’ ubiquitin-binding domains. The team first identified a protein that had both a ubiquitin-binding domain and a known nuclease domain. When they treated cells with mitomycin C, which promotes DNA cross-linking, that protein, then known as KIAA1018, gathered at damage sites. This led them to the functional experiments that established its role in DNA repair.

They renamed the protein FAN1, short for Fanconi anemia-associated nuclease 1. The FANCI-FANCD2 complex is ubiquitinated by an Fanconi anemia (FA) core complex containing eight FA proteins. These genes and proteins were discovered during research of FA, a rare disease caused by mutations in 13 fanc genes that is characterized by congenital malformations, bone marrow failure, cancer and hypersensitivity to DNA cross-linking agents.

Chen said the FANCI-FANCD2 pathway also is associated with the BRCA1 and BRCA2 pathways, which are involved in homologous recombination repair. Scientists know that homologous recombination repair is also required for the repair of DNA cross-links, but the exact details remain to be resolved, Chen said. Mutations to BRCA1 and BRCA2 are known to raise a woman’s risk for ovarian and breast cancers and are found in about 5-10 percent of women with either disease.

Co-authors with Chen are co-first author Gargi Ghosal, Ph.D., and Jingsong Yuan, Ph.D., also of Experimental Radiation Oncology at MD Anderson; and co-corresponding author Jun Huang, Ph.D., co-first author Ting Liu, Ph.D., of the Life Sciences Institute of Zhejiang University in Hangzhou, China.

This research was funded by a grant from the U.S. National Institutes of Health and the Startup Fund at Zhejiang University.

Sources:

European Researchers Find Estrogen Receptor Gene Amplification Occurs Rarely in Ovarian Cancer

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“… ESR1 [gene] amplification is an uncommon mechanism for estrogen receptor overexpression in ovarian cancer occurring in about 2.1% of the total number of ovarian cancers. In general, this frequency parallels the fraction of ovarian cancers reported to show complete response to antiestrogenic [anti-hormonal] therapies. Given the strong predictive power of ESR1 [gene] amplification for response to tamoxifen in breast cancer, an evaluation of such treatments in ESR1 [gene] amplified ovarian cancers appears justified.”

Abstract:

“Amplification of the gene encoding estrogen receptor-alpha occurs in about 20% of breast cancers and is an important mechanism for estrogen receptor overexpression in this tumor type. In ovarian cancer, overexpression of estrogen receptor protein has been described in more than two thirds of cases.

To study a potential role of estrogen receptor-alpha gene amplification for estrogen receptor overexpression in ovarian cancer, a tumor tissue microarray containing 428 ovarian cancers was analyzed by fluorescence in situ hybridization [FISH] for estrogen receptor-alpha gene amplification and immunohistochemistry [IHC] for estrogen receptor expression. The estrogen receptor-alpha gene status was successfully determined in 243 of 428 arrayed cancers.

Estrogen receptor gene amplification was found in 5 of 243 (2%) of tumors. Amplification levels were usually low, with 4-8 estrogen receptor-alpha gene copies. However, one case had a high-level amplification, with more than 30 estrogen receptor-alpha gene copies. All five amplified tumors were estrogen receptor positive, with 3 of 5 tumors showing highest (Allred score, 7-8) estrogen receptor levels. The data demonstrate that estrogen receptor-alpha amplification occurs only rarely in ovarian cancer.”

Article Discussion Points:

  • “The results of this study show that ESR1 amplification is rare in ovarian cancers (2.1%). More than one-third of ovarian tumors showed immunohistochemically detectable estrogen receptor protein expression, most abundant in serous and endometroid subtypes. This is in line with previous studies done on the classical paraffin blocks. The good concordance between our data and previous studies demonstrates the representation of our tumor tissue microarray data obtained on a 0.6 mm tissue spot per tumor and enhances the results of other studies used in this method.”
  • “A small subset of ESR1 [gene] amplified estrogen receptor-positive cases was indeed found in ovarian cancers. In comparison, some other genes showed higher rates of amplifications in these cancers. For example, the amplification of ERBB2 ranges (0-66%),  EGFR (3.65-12%),  CCND1 (0-19%), C-MYC up to 54.5,  and KRAS (31%).”
  • “The significant frequency of estrogen receptor positivity in ovarian cancers had prompted treatment efforts using hormonal therapy early on. In addition their relatively little toxicity was another provoking factor to continue going on to achieve more advance in this therapeutic field. Monotherapy studies using tamoxifen, aromatase inhibitors, and GnRH analogues had yielded variable results with objective response rates ranging between 0 and 56%.  Combinatorial treatment regimens combining tamoxifen and goserelin or tamoxifen and Gefitinib had obtained results with objective response rates of up to 11.5%.”
  • “The role of estrogen receptor expression for response prediction to anti-hormonal drugs has been much better studied in breast cancer, where a strong association between estrogen receptor positivity and response to anti-hormonal drugs is well established. … More than 20% of breast cancers had amplified or at least elevated ESR1 [gene] copy number. Possible explanations for the predictive effect of ESR1 [gene] amplification could be a particularly high expression of amplified as compared to non-amplified cancers. Alternatively, it could be speculated, that ESR1 [gene] amplified are more dependent on the estrogen receptor pathway than other tumors that express estrogen receptors together with many other growth receptors. If this latter hypothesis was true, visualization of ESR1 [gene] amplification would pinpoint toward an ‘Achilles tendon‘ of a tumor that could be most successfully targeted.”
  • “The frequency of ESR1 [gene] amplified ovarian cancers (2.1%) is much lower than that in breast cancer. Interestingly, this fraction somehow parallels the percentage of ovarian cancers reported to show strong responses to hormonal therapies.”
  • “For example, in retrospective analysis was conducted of patients who received tamoxifen at a dose 20 mg twice daily for the treatment of advanced epithelial ovarian cancer,
    • Karagol et al found that out of 29 eligible patients included in the study, there were 1 (3%) complete response, 2 (7%) partial response, 6 (21%) stable disease, and 20 (69%) progressive disease.
    • Papadimitriou et al have studied response rate in 27 patients treated with letrozole at a dose of 2.5 mg once a day. Patients with measurable or evaluable disease (n=21) and those with only increasing CA-125 serum levels (n=6) were eligible. Among the 21 patients with measurable or evaluable disease, 1 complete response (5%) and 2 partial responses were observed (10%) for an objective response rate of 15%.
    • Other studies, in which the combined regiment had been implicated, patients were given oral tamoxifen 20 mg twice daily on a continuous basis and subcutaneous goserelin 3.6 mg once a month until disease progression. In total, 26 patients entered this study, of which 17 had platinum–resistant disease, using the definition of endocrine response that included patients with stable disease of 6 months or greater, the overall response rate (clinical benefit rate) was 50%. This included one complete response (3.8%), two partial responses (7.7%), and 10 patients with stable disease (38.5%).”
  • “In summary, ESR1 [gene] amplification is an uncommon mechanism for estrogen receptor overexpression in ovarian cancer occurring in about 2.1% of the total number of ovarian cancers. In general, this frequency parallels the fraction of ovarian cancers reported to show complete response to antiestrogenic [anti-hormonal] therapies. Given the strong predictive power of ESR1 [gene] amplification for response to tamoxifen in breast cancer, an evaluation of such treatments in ESR1 [gene] amplified ovarian cancers appears justified.”

Quoted Source:  Estrogen receptor gene amplification occurs rarely in ovarian cancer, Issa RM et. al., Mod Pathol. 2009;22(2):191-196, reprinted in From Modern Pathology, Medscape Today, February 18, 2009. [Free Medscape subscription required to view full text article.]

Comment:  This study indicates that the occurrence of estrogen positivity (ER+)/ESR1 gene amplification with respect to ovarian cancer is significantly lower than such occurrence in the breast cancer area.  Nevertheless, it is prudent to request your doctor to have your ovarian cancer tumor tissue tested by a pathologist for estrogen positivity or ESR1 gene amplification (through IHC or FISH testing, respectively).  If your ovarian cancer tissue tests ER+, you may respond to anti-estrogen drugs.  Although this type of pathology testing is commonplace in the breast cancer area, it is not in the ovarian cancer area due to the much lower percentage of ER+ ovarian cancer tumors.  As the study above notes, further research of anti-estrogen therapy use within the area of ovarian cancer is needed, especially given the potential high effectiveness and low toxicity of such therapies.