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edge

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Reply with quote  #1 
BRCA Carrier Risk in Perspective
Women with BRCA mutations, that is mutations in BRCA1 or BRCA2 are at dramatically elevated lifetime risk of both breast and BRCA-associated gynecologic cancer (ovarian, fallopian, and primary peritoneal). The data finds that women with mutations in BRCA1 sustain a 35% to 60% chance of developing a BRCA-associated gynecologic cancer by age 70 years, which translates to a relative risk of 30 to 45 compared with women in the general population, while women with mutations in BRCA2 have a 10% to 27% chance of developing a BRCA-associated gynecologic cancer by age 70 years, corresponding to a relative risk of 6 to 20, and of especial note, women with mutations in either of these BRCA genes are in addition at dramatically elevated risk of breast cancer itself, with 56% to 84% of mutation carriers developing breast cancer by age 70 years [as per the findings of the New York Breast Cancer Study Group, and Noah Kauff, Richard Barakat with the Clinical Genetics Service at MSKCC].

There are two risk-reducing surgical options for BRCA mutation carriers:

  1. oophorectomy (OO)
    (aka, prophylactic (bilateral salpingo) oophorectomy (PBSO), and
  2. prophylactic bilateral mastectomy (PBM).
Oophorectomy (OO)
Oophorectomy (OO) is unquestionably of significant risk-reductive value and is currently the prevailing preventive choice for BRCA mutation carriers in the US and Canada. It can reduce the risk of ovarian cancer by about 90% and breast cancer - for BRCA1 but not BRCA2 carriers - by about 50%. Furthermore, Susan Domchek at the Abramson Cancer Center has recently shown that OO reduces not only cancer incidence but also overall mortality. Its the reduction in risk of both breast and ovarian cancer conferred by OO that represents the major advantage of this procedure. And data indicate that the earlier OO is performed, the greater its beneficial effect, with the most risk-reducing effect being observed among premenopausal BRCA1 mutation carriers, as Joan Kramer at NCI has shown. OO also reduces the risk of ovarian and fallopian tube cancer, although there is a small but residual risk of peritoneal cancer in BRCA mutation carriers following OO (between about 3% to 4.3% at 20 years after PBSO). And the findings of Timothy Rebbeck support the practice of performing such prophylactic oophorectomy in BRCA carriers as soon as possible after childbearing is completed because 50.8 is the mean age at diagnosis of ovarian cancer. In contrast, prophylactic oophorectomy decreases ovarian cancer by at least 95% and breast cancer risk by 50% if performed before the age of 40 years. Of the two risk-reductive preventive surgeries, it is typically the case that women more often elect prophylactic oophorectomy (OO) as the initial choice in part because it is not associated with alteration in body image and self-esteem, as can be an issue after prophylactic mastectomy.

Finally, this is also wholly the official guidance from the latest (2006) ASCO/SSO Review of Current Role of Risk-Reducing Surgery in Common Hereditary Cancer Syndromes, which in summary holds that surgical prophylaxis via oophorectomy (OO) represents the best known approach for decreasing ovarian and fallopian tube cancer mortality in BRCA carriers, noting that although prevention using oral contraceptives or other modalities and/or early detection may prove useful in the future, OO remains the standard of care, and should be discussed with all women who are BRCA carrier, whether of BRCA1 or BRCA2 mutations. Furthermore, the earlier OO is performed, the greater its beneficial effect, with the greatest risk-reductive effect observed among premenopausal women, and for that reason OO is typically recommended as a treatment option for women who (1) carry BRCA1/2 mutations, (2) have completed their childbearing, and (3) who are older than 35 years.

My Perspective on OO
It's important however to be aware of one critical fact often lost in the discussions of the benefits of PBSO: that the reductions of 50% breast cancer risk via PBSO are modest compared with the 90% or greater reductions observed after BPM (bilateral prophylactic mastectomy). Thus it must be remembered that although PBSO is associated with a 46% to 56% (median 50%) breast cancer risk reduction, BRCA mutation carriers start with a 60% to 80% lifetime risk, so that means that their residual risk for breast cancer is still significantly higher than the general population risk. This residual risk requires continued surveillance, and consideration of additional risk-reducing strategies such as chemopreventive agents like tamoxifen / raloxifene (which I have addressed separately elsewhere) or prophylactic bilateral mastectomy (BPM); in addition, recent data from the Hereditary Ovarian Cancer (HOCC) Clinical Study Group under John McLaughlin indicate that oral contraceptives could also be used safely as a means to prevent ovarian cancer in both BRCA1 and BRCA2 mutation carriers, but a recent report From EMBRACE, GENEPSO, GEO-HEBON, and the IBCCS Collaborating Group does not support this perspective fully and so until dispositive data settles the matter, it may at this juncture be premature to deploy OCs in the routine use of ovarian risk reduction in BRCA carriers. But the key take-away message of all this is that additional risk reduction interventions are needed in BRCA carriers who have at most breast conservation surgery, particularly for long-term control of the contralateral (uninvolved) breast.

I also note that the in-press pending publication findings of Richard love's team at Ohio State working with premenopausal breast canacer populations in Vietnam that demonstrated that
combined surgical oophorectomy and tamoxifen was an effective adjuvant therapy in premenopausal women with hormone receptor–positive tumors, with 5- and 10-year disease-free survival (DFS) and overall survival (OS) rates significantly improved following adjuvant oophorectomy plus tamoxifen (OO + TAM), and the benefit was significantly greater than that of tamoxifen only. I note here that ovarian suppression via LHRH/GnRH analogs like goserelin (Zoladex) and leuprolide (Lupron) can affect the same benefits if a reversible menopausal state is desired due to considerations of fertility preservation.

Finally, I should observe that it is to date not wholly clear that OO will have the same impact in carriers of BRCA2 as in BRCA1 mutations.

PBM (Prophylactic Bilateral Mastectomy)
One motivation for PBM is that BRCA mutation carriers are at high risk of what's called in-breast tumor recurrence (IBTR) and contralateral breast cancer (CBC) as well as ovarian cancer after BCT (breast-conserving therapy). In high-risk women, PBM provides an at least 85–100% reduction in risk for breast cancer as demonstrated in descriptive cohort studies: Timothy Rebbeck with the PROSE Study Group in a seminal prospective trial demonstrated that PBM reduced the risk of breast cancer by approximately 95% in women with prior or concurrent PBSO and reduced the risk by approximately 90% in women with intact ovaries (that is, BPM + PBSO). Furthermore, a team from the Lombardi Comprehensive Cancer Center showed that compared with patients who chose breast conservation or unilateral mastectomy, those who chose mastectomy of the affected breast and contralateral prophylactic mastectomy of the unaffected breast did not report diminished quality of life or elevated distress. Here's it's important to note that the evidence suggests therefore that a more-extensive surgical procedure than BCT, such as bilateral prophylactic mastectomy, or additional therapies beyond radiotherapy and tamoxifen, may need to be considered for mutation carriers with a diagnosis of breast cancer in order to reduce the risk of breast cancer recurrence.

Non-Surgical Risk Reductive Interventions
Beyond the risk reductive surgical interventions, there are nonsurgical risk reduction techniques for both breast and gynecologic cancer in hereditary syndromes, and NCCN recommends that women with BRCA1 or BRCA2 mutations participate in intensive breast screening, including both annual mammogram and annual breast MRI beginning at age 25 years, and further recommends participation in gynecologic cancer screening with twice-yearly transvaginal ultrasound (TVU) and serum CA-125.

My perspective on Non-Surgical Interventions
However my own review suggests caution: of the available screening techniques, transvaginal ultrasonography and CA-125 serology have low predictive value for early cancer detection, as established by Diane Stirling's group at the Southeast of Scotland Clinical Genetic Services reported in JCO who demonstrated that annual surveillance by transvaginal ultrasound scanning and serum CA-125 measurement in women at increased familial risk of ovarian cancer was ineffective in detecting tumors at a sufficiently early stage to significantly influence prognosis, and that with the positive predictive value of 17% and a sensitivity of less than 50%, the performance of ultrasound would not even satisfy WHO screening standards, and also troubling, the combined protocol exhibited a particularly high false-positive rate in premenopausal women, leading to unnecessary surgical intervention. This is further supported by results of Roelien Ovilier's team at the Netherlands Cancer institute, which found that the combination diagnostic tool of CA125 + TVU appear to be only sensitive in detecting ovarian cancer at an advanced stage (three of four tumors with early-stage disease in their series had normal screening tests prior to the diagnosis).

In conclusion, therefore, it is in part for these reasons that surveillance alone is insufficient as a defensive posture against the elevated risk of BRCA mutation, motivating the risk-reductive surgical intervention OO, and possibly also BPM.

Constantine Kaniklidis
Breast Cancer Watch
edge@evidencewatch.com

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Reply with quote  #2 
How lucky are we to have Constantine?????
THANK YOU MY FRIEND!


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FLLoriK

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Reply with quote  #3 

thanks! Wow! I think I now have my work cut out. First, I need to have the BRAC1 and 2 tests done! Then I will be better prepared to make additional decisions.

edge

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Reply with quote  #4 
How to Think about the Benefits of Oophorectomy

Let me clarify some principles for how to think about the risk-reductive benefits of oophorectomy in order to assist in making this difficult and personal decision. Here are the principles:

Just Another Endocrine / Hormonal Therapy
Ovarian ablation - whether it's surgical ablation, that is, oophorectomy, or medical ablation called ovarian suppression which uses LHRH/GnRH agents like goserelin (Zoladex) and leuprolide (Lupron) - should be thought of as just another, the fourth, form of endocrine (hormone) therapy, along with (1) tamoxifen (TAM), (2) aromatase inhibitors (AIs), and (3) the pure antiestrogen fulvestrant (Faslodex), and like all endocrine therapies like TAM, AIs, and FULV (fulvestrant), it reduces the risk of breast cancer, and of its relapse and recurrence for all women who are hormone-response (ER+ or PR+ or both).

Oophorectomy Versus Ovarian Suppression
Oophorectomy induces an irreversible menopausal state compared to the reversible menopausal state induced by ovarian suppression (via Zoladex or Lupron), but both are true and reliable menopausal states (in contrast to the erratic chemotherapy-induced amenorrhea). Both therefore allow, by this reliable induction of menopause, a women to go beyond tamoxifen therapy, and benefit also from AIs or fulvestrant (Faslodex). In addition, oophorectomy has one major advantage over ovarian suppression, in contrast to its potential disadvantage of irreversibility, namely that it also reduces the chance of ovarian (endometrial) cancer. Therefore ovarian suppression is mainly attractive, over oophorectomy, to women to whom fertility preservation is important, while oophorectomy is mainly attractive to women without this concern or who are still premenopausal but are, or consider themselves, past child-bearing years.

Premenopausal versus Postmenopausal
Of the four endocrine (hormonal) therapies, TAM is of benefit to both pre- and postmenopausal women, while AIs, FULV, and ovarian ablation, including oophorectomy, are relevant only to postmenopausal women: neither oophorectomy nor ovarian suppression is of any benefit to a women who is already truly menopausal (but as I noted in my other postings, a women with chemotherapy-induced amenorrhea is not truly and reliably menopausal), since the goal of these endocrine options is to induce a true menopausal state which is always prognostically more favorably than a premenopausal state. It is a fundamental principle of breast cancer therapy that the risk of breast cancer and its recurrence or relapse is always favored (and hence reduced significantly) by rendering a woman truly postmenopausal.

Across the Board Benefits
The evidence strongly demonstrates that the risk-reductive benefits of oophorectomy applies to all hormone-responsive women, regardless of age, stage, and BRCA status: that is, oophorectomy delivers a clear and significant risk-reductive benefit to both BRCA carriers and non-BRCA carriers alike, so it is important to not make the mistake that although oophorectomy is often the standard of care for risk reduction in high risk women including those with BRCA mutations, nonetheless it is of benefit across the board of hormone-responsive women regardless of BRCA status.

Playing the Numbers

    • The real question is what degree of benefit do you get from oophorectomy (or ovarian suppression, which is clinically comparable in benefit)? In the most typical adjuvant setting, at five years the disease-free survival of OO + TAM (oophorectomy added to tamoxifen therapy) for ER+ women is 83% compared to 61% for observation (no therapy) alone, a gain of 22%; at the same five years for ER+ women, the overall survival would be 88% for women on OO + TAM compared to 74% for women on observation alone, a 24% added benefit. The numbers decline a bit at 10 years given the continued residual forward risk of hormone-positive disease, but still significant, and impressive: 10-year DFS stands at 66% for OO + TAM compared to just 47% for observation alone (a 19% benefit), while 10-year OS stands at 82% for OO + TAM compared to 49% for observation alone (a 33% benefit) [data from the in-press pending publication findings of Richard love's team at Ohio State: Survival After Adjuvant Oophorectomy and Tamoxifen in Operable Breast Cancer in Premenopausal Women, to appear in JCO, forthcoming].
    • By comparison, according to t he latest data from the EBCTCG (Early Breast Cancer Trialists’ Collaborative Group, tamoxifen alone reduces the annual breast cancer mortality rate by 31% at 5 years, while ovarian ablation (oophorectomy) or ovarian suppression (via Zoladex or Lupron) alone was statistically as effective, reducing the annual breast cancer mortality rate by 29%.
    • Bottom-line:
      Therefore to take one salient comparison, namely overall survival at 5 years, an ER+ woman can receive:
      • a 31% reduction in the risk of mortality from tamoxifen alone,
      • a 29% reduction in the risk of mortality from either oophorectomy alone or ovarian suppression alone,
      • a 88% reduction in the risk of mortality from TAM + OO, that is from oophorectomy added to tamoxifen therapy.

A Suggestion for FLLoriK
I would strongly agree with the advice you received from others here on this forum, that a second opinion is highly advisable. If it is the case as our moderator states that you're in Florida, there are many excellent candidates, but one of the most attractive in my opinion would be Charles Vogel with the Cancer Research Network and Aptium Oncology at the Lynn Regional Cancer Center West Campus in Boca Raton; besides being a leading clinical investigator and a universally acknowledged exceptional breast cancer expert, I and others consider him one of the foremost authorities in the world on endocrine / hormonal therapy so he would be a particularly fine choice for you as a second consult (and he is a rare humane and compassionate oncologist). His contact information is:

Charles Vogel
Aptium Oncology
Lynn Regional Cancer Center West Campus
Phone: 561-883-7600 (General number at Aptium: 323-966-3400)
Email: drcvogel@aol.com

Constantine Kaniklidis
Breast Cancer Watch
edge@evidencewatch.com
BMD

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Reply with quote  #5 

Why would you take Tamoxifen after an ooph? Maybe I am not reading this informaiton right but my onc put me on Femara even before I had my ooph because she knew I was planning to have the surgery. As it turned out I started Femara in Feb and did not have my ooph until June. My onc was not happy with the time but I had a hard time getting in for the ooph sooner. Anyway I thought once the ooph was done then Tamoxifen was not the recommended med of choice. An AI would be.


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Reply with quote  #6 

I was giving the survival data and not in any way making a recommendation as to choice of endocrine therapy (I would in any case actually favor fulvestrant over either AI or tamoxifen for reasons I have expressed elsewhere), and the most mature and long-term data on OO + endocrine therapy comes from OO + TAM - indeed, it is for that reason that many oncologists favor that regimen and are somewhat more reluctant to deploy OO + AI, and my experience both directly with oncologists and guideline groups, and across multiple forums like YSC and BCO among others, is that the prevailing practice (whether wholly evidence-based or not) is indeed to favor OO + TAM, a consensus these oncologists would share with most standards organizations like NCCN and ASCO. In any case, although one could reason that once menopausal via OO, then the scenario should be treated as with natural menopause, most oncologists do no such thing and exhibit a lingering doubt as to the clinical coextensiveness of the OO-induced menopausal state versus the natural biologically-achieved menopausal state [and indeed there are some subtle differences]. And some are reluctant to induce the more radical estrogen deprivation state that AIs institute in recently premenopausal women because of the greater inducement of adverse menopausal events and symptoms on AIs compared to tamoxifen, which tend to be somewhat more QoL-adverse in premenopausal women induced to menopause versus biologically postmenopausal women.

But although less robust, there are some data on OO + other endocrines therapies, so much hinges on the individual perspective of the oncologist, with considerable variability across practitioners. (And outside of your report, I am unaware before encountering this of any oncologist placing a premenopausal woman on aromatase inhibitor therapy without prior initial absolute assurance of menopausal induction).


Constantine Kaniklidis
Breast Cancer Watch
edge@evidencewatch.com
BMD

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Reply with quote  #7 
Constantine-Thank you so much for you information. I questioned my onc's decision and I really think she thought I would have the ooph sooner than I did. Unfortunately I had an ob/gyn that was unfamiliar with Femara at all and just kept letting me slip between the cracks. I finally found out she was waiting for another doctor to assist her in my ooph because of my previous tram surgery. I ended up using the ob/gyn my onc referred me to who got me in for surgery within 2 weeks. I am going to see my onc for a 4 month follow-up this month and will ask her about it. I wonder if using the Femara to start with had some adverse effect on me. I have had SE's but have been able to live through them. Sometimes they are worse or a new one pops up. Thinning of hair is the most recent. I guess what you are saying is that since I was premenopausal prior to dx and chemo the Femara could have been more difficult for me to take than the Tamoxifen. Is that right?
 
My dx was 2.5cm in left breast. No nodes. ER/PR+, Her2-. 45 years old. BRCA negative. Bilateral mast w/immediate pedicle tram. 6 TAC. Femara and ooph.
 
My onc assured me that I did everything possible. I have 2 small children and wanted to fight with everything I had.

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Reply with quote  #8 

BrendaBMD:

Not to worry, I really don't see any significant cause for concern here: even without knowing the tumor pathology details from your path report, it's still the case that you have the most favorable tumor biology possible in breast cancer, namely double hormone-positive and HER2-negative, coupled with node-negativity, and double positive hormone tumor are typically quite indolent in growth pattern so that even after a few months tumor burden is unlikely to advanced much if at all beyond what it was in February, and a highly optimal environment of oophorectomy coupled with an AI like letrozole (Femara), added to a preexisting BPM (to say nothing of TAC-6), should be able to aggressively bring the tumor context in check with no appreciable compromise to your health going forward.
 
And oddly but true, it is the case that the fact of your suffering any side effects at all on the Femara during your premenopausal state - although regrettable - does rather suggest the AI was actually exerting some efficacy (there is some association between the experience of SEs on endocrine therapy and efficacy). And as I said although clear stats on the benefit of OO + AI are Spartan, nonetheless we do know it will not be less in efficacy than OO + TAM, probably somewhat better (my sense also from the few hints leaking out from some ongoing OO + AI trials), and may indeed hit the nineties in percentage mortality reduction (by some rather complex and arcane extrapolation), so no need for any distress.

And I perfectly understand your motivation, plenty to fight for and you'll be fine, so keep on fighting!

Best fortune to you.

Constantine Kaniklidis
Breast Cancer Watch
edge@evidencewatch.com
BMD

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Reply with quote  #9 

Thank you again for your encouraging words.


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