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Bren

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Reply with quote  #1 
Hi Constantine,

I would like your thoughts on my latest worry.  I was dx last March with IDC, Stage I, Grade 2, ER 100%+, HR2 borderline, lumpectomy and rads.  A 10x2x2 cm section was removed from left breast.  After tx I was told regular f/u of every six months.  I had my first post tx mammo and checkup with surgeon 2 weeks ago.  Got the all clear and was told to come back in 3 months.  That confused me as I was told initially every six months and the rad onc said he had "cured me."  Yeah right.  Anyway, I got a form letter from imaging saying everything was Aokay.  I also decided to recheck my path report.  I had completely missed the part that said there was MULTIFOCAL LCIS throughout the specimen that was resected.  The doc's never mentioned this to me.  I also requested and got copies of the actual mammo reports from last March and this past Dec.  The most recent noted "underlying breast tissue is dense, limiting mammographic sensitivity. ..... Benign-appearing calcifications are also present.  These are largely unchanged from prior exam."

I will be seeing my PCP soon, who is now managing my meds, and is recommending Evista, as I couldn't tolerate Tamox or Arimidex because of gastrointestinal issues. 

So ... about this LCIS.  What do I do?  Should I have had a mastectomy?  Why didn't the doc's discuss this with me or the fact that I have dense breasts?  (probably a rhetorical question) Should I push for an MRI?  Will Evista help with LCIS?  Is the LCIS why I have to go every 3 months instead of the 6 months like I was told? 

Sorry this is so long, but any insight you can give me would be greatly appreciated.

Thanks a lot,
Bren
edge

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Reply with quote  #2 

Bren:

I haven't forgotten you - I should be able to address your concerns within the next 24 hours. Thanks for you patience.


Constantine Kaniklidis
Breast Cancer Watch
edge@evidencewatch.com
Bren

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Reply with quote  #3 
Thanks Edge,
Take your time .. the LCIS isn't going anywhere! 
edge

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Your questions are excellent and your concerns if not alarming quite justified and prudent. So I'll try to untangle the issues below and provide for you a way to think about these matters b based on the best balance of the evidence to date.

LCIS
First the facts, briefly: for stage I–II breast cancer such as yours, local recurrence occurs in approximately 10%–20% of patients treated with BCS (breast-conserving surgery, aka lumpectomy), which is significantly reduced by postoperative radiotherapy, but the reduction is primarily a reduction of ipsilateral - not contralateral - breast tumor recurrence.

As to LCIS, its biological significance as a "risk indicator" versus a "breast cancer precursor" has been a matter of considerable debate. Note that the risk indicator nature of LCIS is not in dispute - in fact, it is widely accepted that LCIS confers a modest increased risk of development of invasive carcinoma of about 1 to 2% per year, with an 8-year risk of about 4.4 - 4.7%, 10-year risk of between 7% and 8%, a lifetime risk of 30 to 40%, and a relative risk of breast cancer of 8 to 10-fold.

Now, as to the balance of the latest evidence, it suggests:

  1. That LCIS is both a risk indicator and a non-obligate precursor of invasive breast cancer; what this means is that LCIS should be considered a predisposing determinant of risk for subsequent invasive disease in either breast, but as a non-obligate / non-inevitable precursor the development of subsequent invasive carcinoma is not assured, although its risk is elevated, and the invasive carcinoma, should it develop, is not necessarily assured to be of lobular histology.
  2. Nonetheless, as a preneoplastic state from which progression may not be inevitable, LCIS is in general a reversible condition of low biologic potential and typically slow progression to invasive cancer if any.
  3. Local recurrence risk (LRR) varies somewhat with tumor size, with tumors > 3cm sustaining higher risk, and with young age (< 50) being an independent significant factor.
  4. Risk reduction with unilateral mastectomy is only modest, and it is for this reason that PBM (prophylactic bilateral mastectomy) needs to be considered an option for selected patients, based on the cumulative weight of all risk factors.
  5. The landmark NSABP P-1 Study established that progression to invasive disease seems to be significantly inhibited by the use of tamoxifen.
A Warning
Now. although the standard of care with LCIS is currently close follow-up together with chemoprevention via tamoxifen, the recommendation of your PCP to deploy the other SERM, raloxifene (Evista) instead of tamoxifen is in error and wholly against the evidence, and would lead to a false and dangerous illusion of preventive value: as decisively shown in the recent STAR trial, one of the largest breast cancer prevention clinical trials ever conducted, raloxifene (Evista) is of no significant benefit of risk reduction in LCIS; while tamoxifen was been shown to reduce by half the incidence of both LCIS and DCIS, raloxifene (Evista) did not have any appreciable effect on these diagnoses. And this result confirms data reported earlier in 2004 from the large CORE study of raloxifene (Evista). And, unlike tamoxifen which is chemopreventive in both premenopausal and postmenopausal women, raloxifene (Evista) is sanctioned, and of value, only in the postmenopausal setting.

Multifocality
Multifocal disease describes cases in which two or more discrete tumors can be detected clinically, radiographically, or pathologically in the same breast; the term multicentric is used to describe multiple independent primary tumors in one breast, in contrast to multifocal which describes multiple tumor nodules derived from a single primary tumor and that occur close (in the same quadrant as the primary tumor) to the primary lesions. Multifocality is well-established as a significant risk factor for local recurrence, largely because it is thought to represent intramammary spread, but this is in part dependent on whether it is a case of multifocal LCIS versus multifocal DCIS: currently, the significance of multifocal LCIS differs from multifocal DCIS, as there is considerable doubt as to the malignant potential of the cells in LCIS, but nonetheless the multifocal LCIS incurs non-obligate elevated risk of local recurrence, which may not develop inevitably, and which may be countered by effective preventive intervention, either chemoprevention and/or prophylactic surgery.

Breast Density
Dense breasts - breast that are highly fibroglandular and so contain proportionately less fatty tissue - is one of the most consistently established factors for elevated breast cancer and recurrence. The stock explanation which you quoted from the mammography report, is that "underlying breast tissue is dense, limiting mammographic sensitivity" suggesting that the elevated risk is largely consequent to compromised detection, but in fact the risk is known to be wholly independent of this: carcinoma in breast fatty tissue is exceedingly rare, as it commonly embeds in the connective tissues (lobes and ducts) and collagen structures of the breast - even if it were perfectly detectable without error, the risk remains since dense breasts simply contain far more "at risk" structures.


The good news is that breast density can be appreciably reduced if not wholly eradicated by various effective interventions: robust physical exercise, minimal near-null consumption of alcohol, and a low-(saturated) fat diet as lifestyle interventions, and calcium (1500mg/daily in three divided doses as the citrate or phosphate salt, not carbonate) and HD-D3, that is, high-dose Vitamin D3 (3000 IUs/daily) as nutritional interventions, all can appreciable reduce breast density, and therefore, associated risk.

Surveillance
Given breast density, and the elated risk of LCIS and multifocality, mammography should be supplemented by MRI, which is demonstrably superior in detecting multifocal lesions, and in detecting any potential malignancy in dense breasts. I typically advise an "interleaved" scheduling - both yearly, but one (either) six months after the other rather than at the same time, assuring no more than six months before another surveillance is scheduled. In addition CBE (clinical breast examination) is of value if not rushed and in the hands of an expert.

I am unaware of any compelling evidence that surveillance more frequently than at the six month point is of material benefit, but should you want to "simulate" it, ultrasound scheduled at at least one 3 month point may provides some modest extra assurance. (As to calcifications, being declared benign, the only concern would be a rare malignant foci hiding among the benign calcifications, but a multimodal surveillance program of mammography, MRI and intermittent ultrasound is the best means of addressing any such small eventuality).

Another Warning
Now be aware that an in-press study that is due to appear in JCO within the next several weeks by the radiation oncologist Lawrence Solin at the University of Pennsylvania is likely to make a considerable splash and be massively misinterpreted by the popular and even medical literature - indeed, the accompanying editorial by Monica Morrow at Fox-Chase is entitled "Magnetic Resonance Imaging in the Breast Cancer Patient: Curb Your Enthusiasm", but I reviewed the study pre-publication, and there are some significant limitations: (1) nonrandomized, retrospective analysis of a cohort of patients from a single institution, and (2) with an 8-year rate of local recurrence of about 4% for patients not doing a breast MRI study, this baseline rate is sufficiently low that demonstrating a statistical improvement would be exceedingly difficult and unlikely in a retrospective cohort study like this, and in any event would require a substantially larger sample size than the tiny 756 patients evaluated. In addition, more critically compromising is (3) the limitation of the treated patients to largely ones at low risk for local recurrence, with predominantly negative margins, predominantly small tumors, and a high rate of adjuvant systemic therapy for those patients with invasive carcinomas.

Somehow it does not seem to have occurred to the study authors nor to the normally sensible Monica Morrow that using a study population of predominantly low-risk patients to evaluate the benefit of breast MRI, a technology of known benefit and applicability to high-risk patients, by definition, is against common sense. Given these considerations, had I been on the reviewing panel I would have strongly advised against publication of both the original study and the accompanying editorial. Regrettably, the field will have to shortly deal with the long-term fallout of this study's misinterpretation and highly circumscribed relevance (if any).

Final Thoughts
The elevation of risk by the combined factors of LCIS, multifocality, and breast density (and possibly age, although I am unaware of yours in this case) motivates (1) both robust surveillance as I outlined above, (2) possibly surgical prophylaxis in the form of BPM (prophylactic bilateral mastectomy) and/or (3) some component of oncoprevention. As to one form of prevention, namely chemoprevention, here, assuming tamoxifen has proved intolerable, and knowing that raloxifene (Evista) is of zero benefit as I indicated above, your options - assuming you are not already postmenopausal - are ovarian ablation, either surgical as oophorectomy, or medical, as ovarian suppression via LHRH/GnRH analogs like goserelin (Zoladex) or leuprolide (Lupron) to induce a true menopausal state which then makes you a candidate for aromatase inhibitor chemoprevention (and of course if already postmenopausal, then AI therapy is motivated).

And of course, you are quite right, a frank discussion of the prognostic significance and impact of LCIS, multifocality, and breast density (and young age and/or premenopausal status if relevant) should have been systematically presented to you, and all these preventive and risk reductive options weighed and explored, so that surveillance alone not be construed as your only, or best, defensive posture.

A Bombshell Before I Close
Finally, I should just note that there is emerging evidence, especially some forthcoming seminal findings from Kirstin Jensen at Stanford, that the assay bar for HER2-positivity should be lowered to a ratio of 1.5, far below the current recommended cut point of 2.2, a position I have been a strong and long-term advocate of (and which our ever-insightful moderator Gina hit upon early on, and we harmonized), and although we need more critical mass of supporting data to be absolutely dispositive - which I believe is indeed arriving from various quarters - this may entail the option of anti-HER2 therapy for you, given as you state borderline HER2 status, and I would even now take that as tantamount to sufficient HER2-positivity to treat you as endocrine and HER2 responsive.

Constantine Kaniklidis
Breast Cancer Watch
edge@evidencewatch.com
Bren

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Reply with quote  #5 
Constantine,

Thank you for the information.  I did find an article which stated that perhaps the pathologists who discovered LCIS in the 1950's erred in naming it a carcinoma.  Nevertheless, the risk factor is obvious.  I'm 52 now and 9 months post lumpectomy, rads ended 6 months ago.  I also had a total hysterectomy years ago.  I think I will first talk to my PCP, who is now managing my meds, rather than my surgeon who I am to f/u with in three months, about trying Tamoxifen again.  Perhaps if I start at 5 mg a.m. and 5 mg p.m. and gradually titrate to 20 mg a day, I will be better able to manage the gastro SE's.  The mood swings (crankiness and irritability) and hotflashes were awful, but bearable.  The chronic vomiting and nausea were not.  I will also talk to her about Donnagel, as you recommended in an earlier post, as opposed to Donnatal.

As for my HR2 status, the path report only states HR2 ++ and my doc said that was borderline and therefore was considered negative. No further testing was done.  My tumor was 6.5 mm with 6 mm margins. 

Again, I really appreciate all the time you took to put all that information together.  I've been really anxious and scared about what to do now, but knowing the facts is the first step is moving forward. 

Thanks again,
Bren
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