new restrospective: Chemosensitivity and Outcome of BRCA1- and BRCA2-Associated Ovarian Cancer Patie

lindaprocopio
lindaprocopio Member Posts: 1,980
Chemosensitivity and Outcome of BRCA1- and BRCA2-Associated Ovarian Cancer Patients After First-Line Chemotherapy Compared With Sporadic Ovarian Cancer Patients

Ann Oncol. 2011 Jan 12;22(6):1346-1352, PMLH Vencken, M Kriege, D Hoogwerf, S Beugelink, MEL van der Burg, MJ Hooning, EM Berns, A Jager, M Collée, CW Burger, C Seynaeve

In this retrospective cohort analysis comparing outcomes in patients with BRCA-associated vs sporadic ovarian cancer, response to first-line chemotherapy and survival were improved in patients with BRCA mutations.

TAKE-HOME MESSAGE
In this retrospective cohort analysis comparing outcomes in patients with BRCA-associated vs sporadic ovarian cancer, response to first-line chemotherapy and survival were improved in patients with BRCA mutations.

SUMMARY
An estimated 10% of women with epithelial ovarian cancer (EOC) carry a BRCA mutation. Studies comparing outcomes among women with BRCA-associated EOC vs sporadic EOC show that those with BRCA mutations have longer survival, with a single, but small, study available suggesting that this may be due to better response to standard-of-care first-line (platinum-based) chemotherapy. It is largely unknown how outcomes compare between women with BRCA2- vs BRCA1-associated EOC, although a few studies have reported better outcomes in those with BRCA2 mutations. In this retrospective analysis, Vencken et al compared response to primary therapy, which included first-line chemotherapy, and survival in patients with BRCA1-associated, BRCA2-associated, or sporadic EOC.

The investigators used the database of the Family Cancer Clinic of the Erasmus University Medical Center–Daniel den Hoed Cancer Center (Rotterdam, Netherlands) to identify patients who were diagnosed with EOC between January 1, 1980, and January 1, 2009, and who had a proven BRCA1 or BRCA2 mutation. These patients were matched 1:2 (by age at diagnosis and duration of diagnosis) with patients with sporadic EOC who were selected from the cancer registry of the institution or from the Rotterdam Comprehensive Cancer Center; any patients with a family history of breast or ovarian cancer were excluded from the sporadic EOC group. For study inclusion, a patient’s medical files needed to include essential data concerning patient and tumor characteristics, first-line chemotherapy administered as part of primary treatment, and follow-up.

The major study endpoints were response to first-line chemotherapy, progression-free survival (PFS), and overall survival (OS). A total of 334 patients (mean age at diagnosis, 52 years) met eligibility criteria and were included in the analysis. Within each patient group (BRCA1-positive EOC [n = 99], BRCA2-positive EOC [n = 13], and sporadic EOC [n = 222]), response to chemotherapy was measured overall (all treatment regimens combined) and separately for patients specifically treated with platinum with paclitaxel, platinum without paclitaxel, or a non–platinum based regimen. Treatment response was evaluated after the completion of first-line chemotherapy using World Health Organization (WHO) criteria, with differences in response among the patient groups tested with the Pearson chi-square test or Fisher’s exact test (for small numbers). PFS and OS were measured using the Kaplan–Meier survival method, with differences among the groups examined in a multivariate Cox proportional hazard regression model, adjusted for possible confounders.

Both BRCA patient groups had a better response after first-line chemotherapy compared with the sporadic EOC group. A complete response (CR) or no evidence of disease (NED) was achieved in 87% of patients (83/99) in the BRCA1 group vs 71% of patients (158/222) in the sporadic EOC group (P = .002), with progressive disease (PD) observed in 2 patients (2%) vs 34 patients (15%), respectively. CR/NED was achieved by 92% of patients (12/13) in the BRCA2 group, with no patients in this group having PD (P = .27).

Both BRCA patient groups also had significantly longer PFS and OS compared with the sporadic EOC group. Median PFS was 2.1 years (95% CI, 1.7–2.5; P = .006) for BRCA1 patients and 5.6 years (95% CI, 0.0–11.5; P = .008) for BRCA2 patients vs 1.3 years (95% CI, 1.1–1.5) for the sporadic EOC group. Median OS in the three patient groups was 5.9 years (95% CI, 4.7–7.0; P < .001), >10 years (95% CI not calculable; P = .002), and 2.9 years (95% CI, 2.2–3.5), respectively. At 5 and 10 years, both PFS and OS trended higher among patients with BRCA2 mutations than among those with BRCA1 mutations. Adjusted multivariate analysis showed that BRCA carriership was significantly associated with both improved PFS (BRCA1: hazard ratio [HR], 0.67; 95% CI, 0.50–0.89; BRCA2: HR, 0.45; 95% CI, 0.21–0.97) and improved OS (BRCA1: HR, 0.54; 95% CI, 0.39–0.74; BRCA2: HR, 0.38; 95% CI, 0.16–0.94).

Although retrospective, this study is the first to compare first-line chemotherapy response and survival in patients with BRCA1-associated, BRCA2-associated, or sporadic EOC. In this study, carriers of the BRCA mutation had a better chemotherapy response and longer survival than patients with sporadic EOC. The most favorable outcomes were seen in patients with BRCA2-associated EOC, although conclusions about these findings must be made with caution due to the small number of patients in the BRCA2 group.

http://annonc.oxfordjournals.org/content/22/6/1346.abstractHYPERLINK "javascript:void(0);"Access this article »

Comments

  • eward
    eward Member Posts: 210
    how are you feeling
    Linda?
  • gdpawel
    gdpawel Member Posts: 523 Member
    Also about BRCA-related ovarian carcinoma
    J Clin Pathol doi:10.1136/jcp.2010.086405

    Melphalan as a treatment for BRCA-related ovarian carcinoma: can you teach an old drug new tricks?

    Deidra J Osher (1,2), Yaël B Kushner (3), Jocelyne Arseneau (3), William D Foulkes (1,2)

    1. Department of Medical Genetics, McGill University Health Centre, Montreal, Quebec, Canada

    2. Program in Cancer Genetics, Departments of Oncology and Human Genetics, McGill University, Montreal, Quebec, Canada

    3. Department of Pathology, McGill University Health Centre, McGill University, Montreal, Quebec, Canada

    Correspondence to Dr William D Foulkes, Program in Cancer Genetics, Gerald Bronfman Centre for Clinical Research in Oncology, 546 Pine Avenue West, McGill University, Montreal, Quebec H2W 1S6, Canada

    Published Online First 4 March 2011

    Abstract

    Late-stage ovarian carcinoma is almost universally fatal. BRCA mutations are associated with an improved outcome and enhanced sensitivity to platinum chemotherapy, yet recurrence and platinum resistance remain a major problem and highly effective regimens following platinum failure do not yet exist. Here we report a remarkable case of cure following platinum-resistant stage III ovarian carcinoma in a woman with a BRCA2 mutation. The patient was subsequently treated with oral melphalan therapy and has not recurred in over 25 years. Melphalan is a bifunctional alkylator that creates inter- and intra-strand DNA cross-links. In a pharmaceutical screen, melphalan was shown to be selectively toxic to BRCA2-deficient breast cancer cell lines and produced a longer relapse-free survival in mice than did cisplatin or olaparib. There is increasing evidence to consider BRCA mutation status when selecting chemotherapy regimens, and melphalan treatment for BRCA-related ovarian cancer merits further investigation. Focusing attention on long-term survivors may provide new mechanistic insights into the biology of chemo-responsiveness.

    Poly ADP ribose polymerase (PARP) is a nuclear enzyme associated with response to DNA damage. Following single strand DNA breaks, the enzyme attaches a backbone of ADP and ribose that serves to initiate DNA repair. Certain classes of chemotherapeutics, specifically alkylating agents, can induce injury that results in extensive poly ADP ribosylation resulting in the exhaustion of intercellular pools of NAD and ATP ultimately leading to cell death.

    My wife was treated for her orginal ovarian primary in 1972 with total abdominal hysterectomy and Chlorambucil (Leukeran). This postoperative chemotherapy drug is among the slowest acting and least toxic of the alkylating agents (well tolerated oral drugs).

    By giving chemotherapy more often, at lower doses, it can prevent the regrowth of blood vessels that feed tumors (angiogenesis). Depression of the immune system is slow and reversible, allowing it to regenerate and contribute to recovery. A malfunctioning immune system can fail to stop the growth of cancer cells.

    Alkeran (Melphalan) is an oral-dose alkylator agent used for ovarian cancer patients. The thing about both Leukeran and Alkeran is it is inexpensive and usually well-tolerated oral drugs used for many, many years.

    Meta-analysis has shown that platinum-based combination therapy has not been superior to single-agent alkylator therapy. And with its superior toxicity profile and equivalent survival benefit compared to other regimens, would be more acceptable.

    There is a caveat involving Alkeran, and that is its absorption is severely inhibited by food in the stomach, so some care must be taken in this regard (check with your doctor).

    Well over a decade ago, Alkeran-based regimens were more usual. Leukeran was often used in combination with Alkeran. However, this combo was discouraged because of the high percentage of secondary leukemias and myelodysplasias produced in patients treated with the combo.

    Alkeran and Leukeran have been around for some time. Nowdays, platinum-based chemotherapy regimens, those incorporating one of the taxenes are used for the treatment of ovarian cancer. Single agent Carboplatin has the same mechanisms that Alkeran and Leukeran has: alkylating agent.

    According to The Lancet, single-agent Carboplatin is acceptable as first-line chemotherapy for ovarian cancer, with its superior toxicity profile and equivalent survival benefit compared with taxene regimens.

    http://cancerfocus.org/forum/showthread.php?t=1156
  • carolenk
    carolenk Member Posts: 907 Member
    gdpawel said:

    Also about BRCA-related ovarian carcinoma
    J Clin Pathol doi:10.1136/jcp.2010.086405

    Melphalan as a treatment for BRCA-related ovarian carcinoma: can you teach an old drug new tricks?

    Deidra J Osher (1,2), Yaël B Kushner (3), Jocelyne Arseneau (3), William D Foulkes (1,2)

    1. Department of Medical Genetics, McGill University Health Centre, Montreal, Quebec, Canada

    2. Program in Cancer Genetics, Departments of Oncology and Human Genetics, McGill University, Montreal, Quebec, Canada

    3. Department of Pathology, McGill University Health Centre, McGill University, Montreal, Quebec, Canada

    Correspondence to Dr William D Foulkes, Program in Cancer Genetics, Gerald Bronfman Centre for Clinical Research in Oncology, 546 Pine Avenue West, McGill University, Montreal, Quebec H2W 1S6, Canada

    Published Online First 4 March 2011

    Abstract

    Late-stage ovarian carcinoma is almost universally fatal. BRCA mutations are associated with an improved outcome and enhanced sensitivity to platinum chemotherapy, yet recurrence and platinum resistance remain a major problem and highly effective regimens following platinum failure do not yet exist. Here we report a remarkable case of cure following platinum-resistant stage III ovarian carcinoma in a woman with a BRCA2 mutation. The patient was subsequently treated with oral melphalan therapy and has not recurred in over 25 years. Melphalan is a bifunctional alkylator that creates inter- and intra-strand DNA cross-links. In a pharmaceutical screen, melphalan was shown to be selectively toxic to BRCA2-deficient breast cancer cell lines and produced a longer relapse-free survival in mice than did cisplatin or olaparib. There is increasing evidence to consider BRCA mutation status when selecting chemotherapy regimens, and melphalan treatment for BRCA-related ovarian cancer merits further investigation. Focusing attention on long-term survivors may provide new mechanistic insights into the biology of chemo-responsiveness.

    Poly ADP ribose polymerase (PARP) is a nuclear enzyme associated with response to DNA damage. Following single strand DNA breaks, the enzyme attaches a backbone of ADP and ribose that serves to initiate DNA repair. Certain classes of chemotherapeutics, specifically alkylating agents, can induce injury that results in extensive poly ADP ribosylation resulting in the exhaustion of intercellular pools of NAD and ATP ultimately leading to cell death.

    My wife was treated for her orginal ovarian primary in 1972 with total abdominal hysterectomy and Chlorambucil (Leukeran). This postoperative chemotherapy drug is among the slowest acting and least toxic of the alkylating agents (well tolerated oral drugs).

    By giving chemotherapy more often, at lower doses, it can prevent the regrowth of blood vessels that feed tumors (angiogenesis). Depression of the immune system is slow and reversible, allowing it to regenerate and contribute to recovery. A malfunctioning immune system can fail to stop the growth of cancer cells.

    Alkeran (Melphalan) is an oral-dose alkylator agent used for ovarian cancer patients. The thing about both Leukeran and Alkeran is it is inexpensive and usually well-tolerated oral drugs used for many, many years.

    Meta-analysis has shown that platinum-based combination therapy has not been superior to single-agent alkylator therapy. And with its superior toxicity profile and equivalent survival benefit compared to other regimens, would be more acceptable.

    There is a caveat involving Alkeran, and that is its absorption is severely inhibited by food in the stomach, so some care must be taken in this regard (check with your doctor).

    Well over a decade ago, Alkeran-based regimens were more usual. Leukeran was often used in combination with Alkeran. However, this combo was discouraged because of the high percentage of secondary leukemias and myelodysplasias produced in patients treated with the combo.

    Alkeran and Leukeran have been around for some time. Nowdays, platinum-based chemotherapy regimens, those incorporating one of the taxenes are used for the treatment of ovarian cancer. Single agent Carboplatin has the same mechanisms that Alkeran and Leukeran has: alkylating agent.

    According to The Lancet, single-agent Carboplatin is acceptable as first-line chemotherapy for ovarian cancer, with its superior toxicity profile and equivalent survival benefit compared with taxene regimens.

    http://cancerfocus.org/forum/showthread.php?t=1156

    Malfunctioning immune system
    Dear Greg

    Wouldn't you say that everyone with cancer has a malfunctioning immune system?

    I'm glad to see that single-agent carbo is acceptable as first-line chemo for ovarian cancer as it appears that I can't handle taxol...or rather, I can't handle the standard dose of taxol.

    thanks,

    Carolen
  • gdpawel
    gdpawel Member Posts: 523 Member
    carolenk said:

    Malfunctioning immune system
    Dear Greg

    Wouldn't you say that everyone with cancer has a malfunctioning immune system?

    I'm glad to see that single-agent carbo is acceptable as first-line chemo for ovarian cancer as it appears that I can't handle taxol...or rather, I can't handle the standard dose of taxol.

    thanks,

    Carolen

    Dose-Intense vs Low-Dose
    Carolen

    I would agree that you (or most cancer patients) can't handle the standard dose (dose-intense) Taxol.

    Low-Dose Chemotherapy Protocol

    http://cancerfocus.org/forum/showthread.php?t=3467

    Who Needs Taxol? This paper was from the dose-intense protocol.

    http://cancerfocus.org/forum/showthread.php?t=2871

    Greg
  • carolenk
    carolenk Member Posts: 907 Member
    gdpawel said:

    Dose-Intense vs Low-Dose
    Carolen

    I would agree that you (or most cancer patients) can't handle the standard dose (dose-intense) Taxol.

    Low-Dose Chemotherapy Protocol

    http://cancerfocus.org/forum/showthread.php?t=3467

    Who Needs Taxol? This paper was from the dose-intense protocol.

    http://cancerfocus.org/forum/showthread.php?t=2871

    Greg

    I tried to talk the GYN/ONC
    I tried to talk the GYN/ONC into giving me 100mg of Taxol instead of 150mg but he wouldn't go along with it. I ended up in the ER & the ER doctor thought I was drunk or on drugs! It was really scary.

    After reading the info you posted with the link, I think it was my good fortune that I stopped the Taxol after just a few doses.

    Carolen
  • gdpawel
    gdpawel Member Posts: 523 Member
    carolenk said:

    I tried to talk the GYN/ONC
    I tried to talk the GYN/ONC into giving me 100mg of Taxol instead of 150mg but he wouldn't go along with it. I ended up in the ER & the ER doctor thought I was drunk or on drugs! It was really scary.

    After reading the info you posted with the link, I think it was my good fortune that I stopped the Taxol after just a few doses.

    Carolen

    ER experience
    Carolen

    I certainly hope the ER doc was able to stabilize your situation. That does seem scary! Best wishes.

    Greg