March 7th /text and/or podcast: PARP Inhibitors and the Challenges of Developing Ovarian Cancer Therapeutics - Cancer Network Dr's Ledermann/Birrer

Blogger's Note: podcast and/or text available, registration required (free)
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PARP Inhibitors and the Challenges of Developing Ovarian Cancer Therapeutics - Cancer Network

Jonathan Ledermann, Cancer UK, London; Michael Birrer, Harvard Medical School, Dana-Farber Institute

AUDIO:
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PARP Inhibitors and the Challenges of Developing Ovarian Cancer Therapeutics

Interviewed by Anna Azvolinsky, PhD | March 7, 2012

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Ovarian cancer is notoriously difficult to treat because it is usually diagnosed at an advanced stage, and because of the high variance in the types of mutations that are found in individual tumors. This creates hurdles for the development of efficacious treatments.
CancerNetwork presents an interview with two prominent ovarian cancer researchers from both sides of the Atlantic. Dr. Jonathan Ledermann is professor of medical oncology at the UCL Cancer Institute in London, England. He treats gynecological cancers and is heavily involved in ovarian cancer clinical trials. Dr. Michael Birrer is a professor of medicine at the Harvard Medical School and is part of the Dana-Farber/Harvard Cancer Center where he also treats gynecological cancers and leads an effort to molecularly characterize gynecological cancers.......

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"CancerNetwork: Despite promising results at ASCO last year, with one of the PARP inhibitors, olaparib, showing positive progression-free survival (PFS) benefit, the phase II trial was stopped in mid December because this PFS benefit was not likely to translate to an overall survival benefit. I would like to get both of your perspectives on this and then what the future holds for other PARP inhibitors in development.



Dr. Ledermann: Mike Birrer will want to comment on this, but can I just correct you on a point of fact. The phase II trial was not stopped. In fact it is still going. There are still patients on treatment, and it has not been unblinded. What the company that manufactures olaparib, which is one of the PARP inhibitors, said in their press release was they were not going to continue development of olaparib in high-grade serous ovarian cancer because, as you said, the interim analysis of survival didn’t show the benefit they wanted to see in relation to the benefit in PFS that I reported at the ASCO conference. But the trial is still continuing and a final analysis will be done probably toward the end of this year."

Re-operation outcome in patients referred to a gynecologic oncology center with presumed ovarian cancer FIGO I-IIIA after sub-standard initial surgery

Re-operation outcome in patients referred to a gynecologic oncology center with presumed ovarian cancer FIGO I-IIIA after sub-standard initial surgery:

Publication year: 2012

Background 
Surgery is the mainstay of treatment for early ovarian cancer both as therapeutic and comprehensive staging. Only the latter allows appropriate tailoring of systemic treatment. However, the compliance with guidelines for comprehensive staging has been reported to be only moderate and, therefore, re-staging procedures are commonly indicated to avoid undertreatment. The purpose of our study was to evaluate re-operation in a tertiary gynecologic oncology unit after primary operation for presumably ovarian cancer FIGO I-IIIA in general gynecology departments.

Material and methods 
Forty consecutive patients after primary surgery in the outside institutions for presumed early ovarian cancer with assumed tumor spread limited to the pelvis (FIGO I-IIIA) admitted to our department between 1999 and 2007 were included. In 35 cases re-staging surgery in our unit was indicated. The intra- and post-operative results were compared with initial diagnosis and sites of undetected disease were evaluated. Reasons for re-staging and referral pattern were studied. Results 40 patients were enrolled of whom 53% came by self-referral. Only 18% were referred by the primary surgeon and the remaining patients were referred by their home gynecologist. Only 5 patients (13%) were classified as having had a comprehensive staging by surgical records and pathology reports and 35 patients underwent comprehensive re-staging laparotomy after which 20 patients (50%) experienced an upstaging including 13 patients with final diagnosis of FIGO stage IIIC. Most frequent sites of primarily undetected tumor were peritoneum (pelvic 34%, diaphragm 13%, paracolic 8%), lymph nodes (para aortic 32%, pelvic 11%), intestines 24%, and residual omental tissue 18%. The indication for post-operative chemotherapy was modified in 53% of patients.

Conclusion
Comprehensive staging of presumed early ovarian cancer has been described as major problem especially outside gynecologic oncology units. Re-staging results in our department confirmed this deficiency by showing a considerable proportion of upstaging associated with alterations of recommendations for systemic treatment. However, series like this may even underestimate the problem, because incomplete staging is unfortunately accompanied by non-systematic referral practices not reflecting staging quality.

open access: Progression-free Survival Decreases with Each Subsequent Therapy in Patients Presenting for Phase I Clinical Trials (study included various cancers including ovarian cancer) note: patient warning before reading

Blogger's Note: patient warning - this is not a 'good news' paper so caution advised

Table I 
Patient Diagnoses, Gender, Median Age at Diagnosis and Median Number of Therapies  (Blogger's Note: total patients = 142; ovarian cancer patients = 11)

Patient Characteristics

"We reviewed the patient records of 165 unique patients that were evaluated for participation in six phase I trials. Due to a lack of specific start/stop dates, 25 patients had at least one treatment censored for analysis; with one of these patients not having PFS that could be calculated for this study. Seventeen of these twenty-five patients were diagnosed as having less than stage IV disease, with the majority of censored treatments (radiation, surgery, or neoadjuvant or adjuvant chemotherapy) occurring in the non-advanced/metastatic setting. One hundred forty-four patients met criteria for receiving at least one prior non-investigational systemic therapy for advanced/metastatic cancer prior to coming for a phase I treatment evaluation. There were 77 men and 65 women; median age at cancer diagnosis was 55.3 years (range, 9.4 - 81.6 years). The most common types were: colorectal cancer (n=20 (13.9%)), other gastrointestinal cancer (n=17 (11.8%)), adenocarcinoma of the prostate (n=17 (11.8%)), non-small cell lung cancer (NSCLC) (n=13 (9.0%)), breast cancer (n=12 (8.3%)), ovarian cancer (n=11 (7.6%)), and adenocarcinoma of the pancreas (n=9 (6.3%)) (Table I). Patients had a median of three chemotherapy or hormonal treatments (mean, 3.32 treatments; range, 1 - 11 treatments).
Two of the 144 patients did not receive a second systemic therapy prior to evaluation at our center, so PFS could be calculated for the remaining 142 patients. The PFS from tx_n to tx_n+3 was significantly decreased (p = 0.001850) (Figure 1). Few advanced cancers have more than four lines of FDA-approved or consensus guidelines recommendations for systemic therapy, thus we examined the time to progression of the first five treatments (p = 2.938e-07) (Figure 2)."

open access journal (international) - Journal of Cancer

About this journal

Journal of Cancer is an open access, peer-reviewed journal with broad scope covering all areas of cancer research, especially novel concepts, new methods, new regimens, new therapeutic agents, and alternative approaches for early detection and intervention of cancer. The Journal is supported by an international editorial board consisting of a distinguished team of cancer researchers. Journal of Cancer aims at rapid publication of high quality results in cancer research while maintaining rigorous peer-review process.
Types of articles:

• Research paper
• Short research communication
• Review
• Letter to the editor

open access: Does the Loss of ARID1A (BAF-250a) Expression in Endometrial Clear Cell Carcinomas Have Any Clinicopathologic Significance? A Pilot Assessment (note comments re: clear cell ovarian)

"....Accordingly, their loss of function has been associated with malignant transformation. ARID1A (the expression of whose product, BAF250a, a key complex component, is lost when mutated) has recently been identified as a tumor suppressor gene that is mutated in 46-57% of ovarian clear cell carcinoma (CCC). The purposes of this study are to assess the frequency of loss of BAF250a expression in endometrial CCC and whether this loss has any discernable clinicopathologic implications....."

"....The fact that BAF250a expression is lost in only a small percentage of endometrial CCC may suggest that ARID1A mutations plays a significant role in only a small proportion of CCC, or that these mutations represent only a small component of the genesis of this specific tumor type. It may also bolster the argument that endometrial CCC represents a phenotype that arises via a multitude of different pathways (3,7), with no one pathway being notably dominant. However, it is unclear if those clear cell carcinomas whose pathogenesis does involve ARID1A mutations, represents a clinicopathologically distinct group with definable characteristics."

International Women's Day 2012

International Women's Day 2012

Behind the Headlines - Can endometriosis guide cancer tests? | GPonline.com

abstracts: 42nd annual SGO meeting - Gynecologic Oncology | Vol 125, Supplement 1, Pgs S1-S188, (March, 2012)

open access: Nature Reviews: Key Advances in Medicine - Ovarian Cancer/Markman page 15-16

Key Advances in Medicine (book)


Nature Reviews Clinical Oncology  (page 15)S11 ovarian cancer | Mutations and non-inferiority analyses show a way forward Maurie Markman      (page 15-16)






Highly clinically relevant ovarian cancer clinical research in 2011 focused on an increased understanding of the biology of the malignancy, limitations of strategies for early detection and screening, and the provocative reports of alternative primary and second-line management strategies.

"Although there were a number of very interesting
preliminary reports of therapeutic
advances in ovarian cancer in 2011 (for
example, bevacizumab in the first-line and
second-line management of the malignancy,
and olaparib  (Blogger's Note: links to Olaparib (parp inhibitor) - Cancer Research UK)  as maintenance therapy for
high-grade serous cancers), as of the writing
of this commentary these studies have not
appeared in the peer-reviewed oncology literature......."

Key advances
■■ There are currently no evidence-based
data supporting the clinical utility of any
ovarian cancer screening strategy in
non‑high-risk populations1
■■ Provocative data suggest there may be a
clinically meaningful difference between
the presence of a BRCA1 or a BRCA2
mutation in influencing outcome in ovarian
cancer6
■■ Under specific circumstances (for example,
neuropathy) it might be reasonable to
substitute pegylated liposomal doxorubicin
for paclitaxel in the front-line chemotherapy
management of ovarian cancer7

Markman, M. Nat. Rev. Clin. Oncol. 9, 69–70 (2012); published online 20 December 2011; doi:10.1038/nrclinonc.2011.200

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"The articles included in Nature Reviews Key Advances in
Medicine were originally published in the February 2012
issues of the eight clinical Nature Reviews journals. The journals’
editors commissioned international experts to write a short
essay highlighting up to five key papers that made the biggest
contribution to their field in 2011."

The molecular basis of EPCAM expression loss in Lynch syndrome-associated tumors : Modern Pathology

The molecular basis of EPCAM expression loss in Lynch syndrome-associated tumors

Abstract

Germline deletions affecting the Epithelial cell adhesion molecule (EPCAM) gene lead to silencing of MSH2 and cause Lynch syndrome. We have recently reported that lack of EPCAM expression occurs in many, but not all tumors from Lynch syndrome patients with EPCAM germline deletions. The differences in EPCAM expression were not related to the localization of EPCAM germline deletions. We therefore hypothesized that the type of the second somatic hit, which leads to MSH2 inactivation during tumor development, determines EPCAM expression in the tumor cells. 

To test this hypothesis and to evaluate whether lack of EPCAM expression can already be detected in Lynch syndrome-associated adenomas, we analyzed four carcinomas and two adenomas from EPCAM germline deletion carriers for EPCAM protein expression and allelic deletion status of the EPCAM gene region by multiplex ligation-dependent probe amplification. 

In four out of six tumors we observed lack of EPCAM expression accompanied by biallelic deletions affecting the EPCAM gene. In contrast, monoallelic retention of the EPCAM gene was observed in the remaining two tumors with retained EPCAM protein expression. These results demonstrate that EPCAM expression in tumors from EPCAM deletion carriers depends on the localization of the second somatic hit that inactivates MSH2. 

Moreover, we report lack of EPCAM protein expression in a colorectal adenoma, suggesting that EPCAM immunohistochemistry may detect EPCAM germline deletions already at a precancerous stage.

Treatment for stromal tumors of the ovary - ACS

Treatment for stromal tumors of the ovary
Last Medical Review: 12/05/2011
Last Revised: 01/11/2012

YouTube video - Dealing With Recurrence - Dr John Comerci (NOCC) 43 minutes

"We know that the topic of recurrence in cancer patients can be an overwhelming and scary issue for any ovarian cancer survivor. In this video, Dr. John Comerci leads a discussion on recurrence and openly answered many questions from our survivor audience – hopefully yours will be one of them.
We appreciate Dr. Comerci’s contribution of his time and Magee Womnens Hospital of UPMC for providing the resources to make this lecture series possible."