Calling all TNs
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BRCA Mutations Common in Triple-Negative Breast Cancer
Elsevier Global Medical News. 2010 Sept 30, K Wachter
The incidence of BRCA mutations in women with triple-negative breast cancer appears to be greater than previously thought, which may have important screening and treatment implications. In all, 20% of unselected patients with triple-negative breast cancer had BRCA mutations in a small study of 77 patients. Surprisingly, the mutations were associated with significantly better recurrence-free survival and a trend toward better survival.The study obtained DNA from tumor and normal tissue samples that had been taken from each of 77 patients with triple-negative breast cancer. The samples had been stored in a tissue bank.The researchers sequenced BRCA1/2 exons and flanking regions, and patients were classified as having mutant or wild-type BRCA1/2. Sequencing was performed on both tumor and normal tissue to differentiate the mutations as either germline or somatic.In all, 15 of 77 patients (20%) had BRCA mutations (BRCA1 mutations, 12 patients; BRCA2 mutations, 3 patients). All but one (a BRCA1 mutation) were germline mutations found in both normal and tumor cells. Six of 14 germline mutation carriers and the one somatic BRCA1 mutation carrier had not been referred for genetic analysis. Nine of the 14 germline mutation carriers had no first-degree family history of breast or ovarian cancer.A rate of "almost 20% mutations in an unselected population is quite high," said Dr. Gonzalez-Angulo of the department of breast medical oncology at the University of Texas M.D. Anderson Cancer Center in Houston. "So I think that we probably have to start lowering our [threshold] for at least sending these patients for genetic counseling," she said.Dr. Jennifer C. Obel, moderator of the press briefing, agreed. "We have long known that women with BRCA mutations develop triple-negative breast cancer at a higher rate. Researchers in this study asked the flip side of the question. They found that women with triple-negative breast cancer have BRCA mutations more frequently than expected," she said."We may need to consider offering genetic testing to more of these patients in order to better screen them for more BRCA-associated malignancies, and to extend testing for their family members, who may also be at risk," said Dr. Obel, a medical oncologist at Northshore University Health System and a clinical faculty member at the University of Chicago.If the findings are replicated, they may have treatment implications for triple-negative breast cancer patients.BRCA is a DNA-repair enzyme. "So tumors that have BRCA mutations are basically very, very sensitive to agents that damage DNA," said Dr. Gonzalez-Angulo. Although there are conventional chemotherapy drugs to consider, newer investigational agents - such as PARP (ADP ribose polymerase) inhibitors - are particularly promising. Several of these agents are under investigation in clinical trials, with promising early results reported so far in breast and ovarian cancers.BRCA1 or 2 mutations can cause errors in DNA repair that lead to breast cancer. Basically PARP-inhibiting drugs block PARP from compensating for the loss of BRCA function and from repairing DNA damage. With no functioning repair mechanism in place, the cell dies in a process called synthetic lethality."It may become important to identify women with these mutations because the mutation provides a rational target for treatment with PARP inhibitors - a class of drugs currently under development," said Dr. Obel.That BRCA mutations were associated with better survival outcomes was a surprise to the investigators. Over a median follow-up of 43 months, there were 33 recurrences and 35 deaths in the study population. The estimated 5-year recurrence-free survival rates were 51.7% for patients with wild-type BRCA 1/2 vs. 82.6% for patients with a BRCA mutation. This difference was significant.The estimated 5-year overall survival rates were 52.8% for patients with the wild-type gene, compared with 73.3% for patients with BRCA mutations. This difference was not significant, however.Disclosures: Three of the study authors reported significant financial relationships with Myriad Genetics Inc., a company that has a monopoly on molecular diagnostic testing for BRCA1 and 2. -
Age, Tumor Characteristics Predict Locoregional Failure After Neoadjuvant Breast Cancer Therapy
Elsevier Global Medical News. 2010 Oct 4, H Splete
NATIONAL HARBOR, Md. (EGMN) - Age 50 years or older, initial clinical tumor size greater than 5 cm, and pathologic tumor response to neoadjuvant chemotherapy were significant independent predictors of locoregional failure in women who underwent neoadjuvant chemotherapy in two large breast cancer trials.Investigators presented these results from a 10-year follow-up study of 2,961 patients in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 and NSABP B-27 trials at the 2010 Breast Cancer Symposium. Dr. Eleftherios P. Mamounas of Aultman Hospital in Canton, Ohio, and his colleagues reported the 10-year incidence of local or regional failure based on type of surgery was 12.3% in patients who had mastectomies and 10.3% in those who had lumpectomies plus chemotherapy. The incidence of local failure was 8.9% in the mastectomy group and 8.1% in the lumpectomy plus chemotherapy group. The incidence of regional failure was 3.4% and 2.2%, respectively.In a multivariate analysis based on 318 locoregional failure events in all 2,961 patients, the overall significant predictors of locoregional failure included age 50 years or older (hazard ratio 0.79, P = .04), clinical tumor size greater than 5 cm (HR 1.52, P = .0005), and positive clinical nodal status (HR 1.64, P less than .0001). In addition, being node negative without pathologic complete response (HR 1.65, P less than .001) or node positive with pathologic complete response (HR 2.77, P less than 0.001) were significant predictors as well.The lack of data on predictors of locoregional failure after neoadjuvant chemotherapy has raised questions about whether to use radiation therapy and when to perform sentinel node biopsies in these patients, said Dr. Mamounas.He also presented data on locoregional failure in lumpectomy patients and mastectomy patients separately, for the purpose of developing separate treatment nomograms for each procedure. A majority of the locoregional failures in the lumpectomy patients were in-breast recurrences. In mastectomy patients, rates of chest wall recurrence were inversely correlated to pathologic nodal response, Dr. Mamounas said. "The effect of age (in lumpectomy patients), clinical tumor size (in mastectomy patients), and clinical nodal status at locoregional failure appears to diminish with increasing pathologic response in the breast and axillary nodes," said Dr. Mamounas. The neoadjuvant chemotherapy regimens were one of two: doxorubicin (Adriamycin) and cyclophosphamide (AC) for four cycles, or the AC regimen for four cycles followed by four cycles of neoadjuvant/adjuvant docetaxel (Taxotere). Patients in the B-27 trial received tamoxifen in addition to their neoadjuvant chemotherapy. Lumpectomy patients were treated with radiation, but mastectomy patients were not.The independent predictors were incorporated into two nomograms: one for mastectomy and one for lumpectomy plus breast radiation, Dr. Mamounas explained. Additional studies are planned to include treatment effects in the development and validation of the nomograms, he said. Dr. Mamounas disclosed serving as a consultant for Eli Lilly & Co. and receiving honoraria from AstraZeneca and Sanofi-Aventis. -
PARP Inhibitor Adds Nearly 5 Months to Breast Cancer Survival
Elsevier Global Medical News. 2010 Oct 11, P Wendling
MILAN (EGMN) - Final results from an open-label phase II study confirm the survival advantage of adding an investigational PARP inhibitor to gemcitabine and carboplatin chemotherapy in metastatic triple-negative breast cancer.Although not a prespecified outcome, median overall survival increased from 7.7 months to 12.3 months (hazard ratio, 0.57; P = .014,), lead author Dr. Joyce O'Shaughnessy reported in a late-breaking abstract at the the annual congress of the European Society for Medical Oncology. Median survival in this aggressive form of breast cancer is about 13 months after developing metastases.Progression-free survival also increased significantly from a median of 3.6 months with gemcitabine (Gemzar) and carboplatin alone to 5.9 months with the addition of iniparib, a poly (adenosine diphosphate-ribose) polymerase-1 (PARP1) inhibitor also known as BSI-201 (HR, 0.59; P =.012).The clinical benefit rate rose as well from 33.9% in the chemotherapy-alone arm to 55.7% in the iniparib arm (P = .015). This seemed to be driven by the overall response rate, which was 32.3% with chemotherapy alone and 52.5% with the addition of iniparib (P = .023). The clinical benefit rate (complete or partial response or stable disease for at least 6 months) was a coprimary end point with safety and tolerability.Thirty of the 62 patients in the gemcitabine-carboplatin arm crossed over to receive iniparib plus chemotherapy. An unconfirmed partial response was reported in 1, stable disease in 4, and progressive disease in 18, while 7 were not evaluable.The study's rationale was that inhibiting PARP, an enzyme that helps the cell to repair DNA damage, would enhance the effectiveness of chemotherapy damaging DNA. Dr. O'Shaughnessy reported on 123 women with estrogen receptor-, progesterone receptor- and HER2-negative breast cancer and a median of three metastatic sites who had received not more than two prior cytotoxic regimens. Of these, 62 were randomized to gemcitabine 1,000 mg/m² IV and carboplatin (AUC = 2) IV on days 1 and 8 every 3 weeks, and 61 to the same regimen plus iniparib 5.6 mg/kg IV on days 1, 4, 8, and 11.In a special PARP symposium at the meeting, chair Dr. Johann de Bono of the Royal Marsden Hospital and Institute of Cancer Research in Sutton, England, took issue with the study's dosing. "I'm concerned that it was an insufficient dose of carboplatin in the control arm; was that the right dose to do - maybe. [But] was it even ethical?" he asked. "I think that's a real key issue."When this concern was raised during the discussion of the study, Dr. O'Shaughnessy said they didn't know for sure whether carboplatin AUC 5 or 6 given every 3 weeks in metastatic breast cancer would be superior. Indirect evidence from two phase II trials in unselected breast cancer patients showed response rates of 30% with carboplatin AUC 5 given every 3 weeks and with AUC 2.5 given every other week with gemcitabine 1,500 mg/m². "When we gave 2.5 every other week, after about two [to] three cycles, patients went down on their AUC to 2; that's why we choose 2 as opposed to 2.5," she said. "We couldn't get the 2.5 in consistently."Invited discussant Dr. Richard Bell of the Andrew Love Cancer Centre in Geelong, Australia, said the difference in progression-free survival between study arms is clinically meaningful, but urged caution as the outcomes were investigator reported and other enthusiastically received phase II trials have fallen short in phase III evaluation."The big issue is would this work in other breast cancer types or in other cancer types," he said.A confirmatory phase III trial using the same schema has completed enrollment of 500 patients with triple-negative breast cancer, including women with BRCA mutations, said Dr. O'Shaughnessy. She noted that a recent study from M.D. Anderson Cancer Center found that 20% of 77 unselected triple-negative breast cancer patients carried a BRCA1/2 mutation. Predictive biomarker evaluation is underway to identify subsets of triple-negative breast cancer patients likely to benefit from iniparib. Preoperative and adjuvant trials of iniparib in this setting are planned. Iniparib is also being studied in phase II and III trials in ovarian, uterine, and brain tumors.Dr. Bell expressed surprise at the lack of toxicity reported with the addition of iniparib to chemotherapy. Although there is great excitement over the use of PARP inhibitors, with no less than 49 trials now in various stages, most have the potential to enhance toxicity, particularly hematologic toxicity, when used in combination with other drugs.Iniparib was well tolerated and did not potentiate the toxicities of gemcitabine and carboplatin, said Dr. O'Shaughnessy of the Baylor Sammons Cancer Center in Dallas. Grade 3 or 4 adverse events, mainly hematologic toxicity, were similar at 81% in the chemotherapy alone arm and 86% in the iniparib arm.Grade 4 neutropenia occurred in 16 patients in each group; grade 4 thrombocytopenia in 10 in the chemotherapy group vs. 11 in the iniparib group. There were no grade 4 anemia or leukopenia events in either arm.Two deaths occurred with chemotherapy alone vs. three with iniparib, all due to disease progression, Dr. O'Shaughnessy said. In all, 14% in the iniparib group and 27% in the chemotherapy alone group discontinued treatment because of adverse events. Dose reductions were similar between study arms.Dr. O'Shaughnessy reported no conflicts of interest. Several coinvestigators are employees of study sponsor Bipar Sciences Inc., which is developing iniparib with its parent company, Sanofi-Aventis. -
Thanks for info, Heidi. Always good to know that there are so many active studies for BC in general and TNs specifically.
Navy
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Thanks Hiedi- I'll be seeing a specialist at SK Nov. 23. I'm sure that will be mentioned. Also thanks for all of the info.
MBJ- Hope you feel better soon. Congrats on great check-up.
I hope everyone had a great day. The best thing that happened to me today was getting my final drain removed. Still was at about 35ML's but BS said he had to remove it today because my tissues were growing around the drains after 4 1/2 weeks after surgery. Ouch!! Is all I could say. Well there was a couple of moans and groans too. (Not the good ones, LOL) But and I say BUT! I got the 'script after and bought my new bra and falsy. I can wear a t-shirt tomorrow if I want to. Yeah!!!
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T-shirt? How warm is it down there? Too cold in Chicago for T-shirts. Have a great day everyone.
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Ok..I'm stupid..what is locoregional failure?
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Hi Titan - I believe that would be local/regional recurrence but not distant recurrence.
Heidi - thanks for posting the information pieces.
I hope everyone is having a nice day.
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Swanny -- it was high 70's to low 80's depending where you were in the LA area. November is a great time to be in LA.
Colleen (native Wisconsite who now believes it is better to shake than shovel).
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Has anyone been prescribed Zometa? When I went for a check up with an oncologist at MSK she said "We are not to the point of recommending Zometa to everyone, but we are prescribing it for many patients. Talk with your local oncologist about it." I did talk with my local Onc, with whom I've done the chemotherapy, and he said he was willing to prescribe it for my Osteopenia, but not my breast cancer. He did not feel it should be used for breast cancer except in the case of mets. We left it hanging, as I know there are significant side effects to Zometa and I wanted to give this some thought. I've been on Fosomax for Osteopenia for years, and could transition to the IV Zometa. The MSK onc seemed to think it had preventative benefits that made it worth consideration for Stage 2 patients.
Have any of you discussed Zometa with your doctors? Or do you have information about this?
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I am currently part of a Zometa clinical trial where I am recieving regular infusions.
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Hey Chinablue. Are you in the S0307 trial? Please, are you taking Zometa, and if so, how often and do you have side effects? (Of course, only answer if you feel like sharing the information.)
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hi everyone!!! been really busy but I think of you all often!!
xxoo
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Michele: Great to hear from you. Hope you are doing well!
Heidi: Thanks for all of the info on Parps. I hope that this helps those that need it. Good to know there are being more studies done.
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Hi!
Day 21, I now only feel the need for 1 prescription vicodin at bedtime, and radiation burn under breast should be healed by time of December 8th follow-up radiation oncologist visit. Maybe able to wear bra after X-mas.
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Teka: Congratulations! You're almost there!
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MBJ,
Thank You! I found that taking 1 prescription Vicodin every 4 hours was killing my appetite.
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teka- vicodin makes me throw up. bleck. glad you are on the home stretch.
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MicheleS,
I never feel good while taking any prescription pain medication.
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Never took any pain meds either..thought a glass of wine was much better...plus it was more "social"..if you know what I mean.
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Titan,
Sounds good.
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Hi Everyone
I got my Taxol infusion today and find that it is nowhere as bad as AC. So far, I feel it may be tolerable but the fatigue is quite a lot. Right now I am functioning with all the steriods which they have put in me, but when that gets out of the system, I am sure I will be more fatigued. But I don't feel the nausea as badly as with AC and all the digestive issues, although I am now taking zantag 150 mg. daily. I feel like doing the happy dance, but maybe that is a little too premature. The next 5 days will tell the true story. I have 3 more Taxol treatments to go. I mostly slept through the infusion and later when I woke up, there was only an hour to go. Thanks to all of you who made this possible for me, that is to calm me down and give me so many pointers.
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Lovelyface: So glad that you tolerated the Taxol. That is such good news. 3 more to go and then you are done with chemo!
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Just finished chemo June 16, 2010 and had my first follow up with onc (nurse pract) the first week in November and everything was "fine". Two days ago my armpit was tender so I felt around and felt nothing. Last night I felt a lump in my armpit......I am sick to my stomach with worry. My Dr's office opens at 8am and will be calling for an appt......
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Our worst fear, recurrence! I don't even know what to say except that our hearts go out to you...having to experience the fear and anxiety. Take a deep breath and please keep us posted. Hugs!
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Called Onc office about lump that I found - they cant get me in today and I am waiting for a call from the nurse. I am not going to be able to make it thru the day....Do I call my primary Doctor, Surgeon, or Breast Clinic to try to be seen?
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Hi Kelley~ I'd call all 3 and try to be seen. It isn't worth the stress of waiting.
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Kelley: I can feel the fear you're having right now. I hope you get a hold of one of those docs and are able to put your mind at ease today. I wanted to throw out there that other types of infections can cause swelling in your armpit area. Maybe it's an infection right under the skin.. pore... hair follicle. And the lymph nodes take care of other types of infection in the body too. People without cancer have swellings in the armpit from totally benign conditions. I'll be watching to see when you post next on the outcome and will be thinking of you today.
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Thank you everyone for the calming/thoughtful words. The nurse from my Onc office called and they are "squeezing" me in today at 12:30 for a mammo and ultra-sound. I asked a few questions and she said that if they find anything to the lump, they will do a needle biopsy and those results will be know within 48 hours...My mind is going crazy! I will keep you posted...
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Kelley - cc4npg is correct, there are many other things it could be. Case in point....I'm sitting here right now with gauze taped under my arm for a cyst/boil in a hair follicle that has gotten infected. I'm on antibiotics. And, it's on my cancer side. Prior to this whole (very painful) ordeal, which started last week, there was a bump in the area that I'd had for a very long time. Take care and please keep us posted.
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