Breast Case

[scarbrtj]

She’s not an 80 year old who neglected a slowly progressive mass for years until it became 6 cm.

I’m making an assumption that she’s a reasonably intellegent and hygienic person who bathes themselves and runs her hand over her breast at least a few times a week. My “guess” is this grew pretty fast. That enters into my “aggressive” phenotype presumption. Unknown if she had a previous mammogram or not.

Way, way back HER2+ LN+ was "aggressive" and associated with worse survival. Then Herceptin, yada yada yada. So nowadays if you get breast cancer you "want" the HER2+ cancer ("being diagnosed with this aggressive cancer is not the dire event it used to be"). A phenotype must be considered within its environment. In an immuntx-free environment, HER2+ would still be considered a more aggressive phenotype. In that vein, the 41yo with a "slow growing" non-pCR-achieving cT3N0 breast mass has a more aggressive tumor (defining aggressive as risk for recurrence and death) than the 41yo with a "fast growing" cT3N0 pCR-achieving tumor. A de novo, pre-tx "aggressive" or "poor prognosis" phenotype is hazy; a post-chemo, pCR phenotype is much more predictable and echoes that "worst to first" thing mentioned in the Herceptin article.

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[Mandelin Rain]

What’s the “targeted” agent in a 41 year old when 90+% of cancer cells don’t overexpress ER and none overexpress PR nor Her2?

What drug is saving the day in this scenario? I get that AC + T achieved a “pCR” in the primary and the one LN sampled, but that’s not necessarily really a real in vivo CR. That’s a CR good enough to evade a PA’s grossing and pathologist’s review of the prepared slides. Also, is limping to a 5 or 10 year survival in any study really enough in a 41 year old?

 

[Mandelin Rain]

Fwiw, in this scenario, I’d very roughly estimate that radiation is the “life saving” treatment at about 5% +/- 1%. I’d simultaneously estimate the chance of radiation giving a life altering physiological (read: not fatal and not cosmetic) side effect at <1%.

In conclusion, I don’t think the benefit of radiation is huge on a population standpoint, but I think it’s at least 5x greater of causing a bad side effect.

 

[Palex80]

Can y'all tell me what the "proven" factors are to irradiate in this case? (First we have to agree what this case is! TNBC? pT0N0? cN1?) "Proven" is a big word to be such a small word.

cT3 is a factor that pops in the majority of all guidelines.

She has an expander and is reconstructed. We all know that ups the ante for XRT morbidity.

A recurrence in a reconstructed breast results in the worst cometic outcome of all. How big is the risk of recurrence (locally) without RT? What do you think?
I'd say 10%, perhaps even up to 15%.

And it's not like XRT is zero morbidity to start with (dramatic link). Even in the best of cases, e.g., in the recent ENI breast trials, the lung morbidity risk is ~5% and lymphedema risks ~10%... when doing ENI.

Pneumonitis with RNI in MA20 was 1,2%.
But hey, who is talking about ENI? Have we agreed to give ENI?

Now add in the potential reconstruction toxicity which ups recon-associated toxicity risks at least 10-20%...

What is worse?
A potentially deadly chest wall recurrence or a necrosis in a reconstructed breast or a grade III pneumonitis? I have made up my mind. You can go ahead and ask the patient.

So I guess irradiate everywhere except the chest wall region, which is where her recurrence risk is ~3-5% (based on literally thousands of patients at this point), because the risk/benefit ratio is too fraught. I guess irradiate her axilla where her recurrence risk is ~1%?
The math doesn't look great.

Who says the risk of recurrence is 3-5% in the chest wall 1% in the axilla in "thousands of patients".

The Mamounas paper from 2012:

16 patients with cT1-3 cN0 tumors and pCR after neoadjuvant chemotherapy. That's the data you have...
And they had 6.2% recurrences without RT (which is basically 1 patient out of 16!).


Please bear in mind that both NSABP-18 & -27 included full axillary dissection for all patients, not SLNB.
I leave it up for discussion whether or not SLNB after NAC in a 6cm (practically) tripple negative tumor is the "right" way to go to assess the axilla (if you are not planning to irradiate)...

 

[Palex80]

I suppose you've been taking hydroxychloroquine prophylactically What can it hurt?
EDIT
But in fact if you want randomized data there is that mild, niggling trend toward worse survival in pN0 with PMRT

Showing that graph and making the argument that PMRT is bad in pN0 breast cancer patients, is like showing the PORT metaanalysis-graphs and saying that ANY postoperative RT for NSCLC is bad.

These curves were not done on cT3 cN0 patients, those are all-comers.

 

[scarbrtj]

Fwiw, in this scenario, I’d very roughly estimate that radiation is the “life saving” treatment at about 5% +/- 1%. I’d simultaneously estimate the chance of radiation giving a life altering physiological (read: not fatal and not cosmetic) side effect at <1%.

In conclusion, I don’t think the benefit of radiation is huge on a population standpoint, but I think it’s at least 5x greater of causing a bad side effect.

Agree borderline case, RT not necessarily unreasonable, etc etc. But people are glossing over the immediate reconstruction. Toxicity risk MUCH MUCH greater than 1% for a patient like this, not to mention the risk of carrying a hard, constantly mildly achy lump (the reconstruction) on your chest for years. The lymphedema risk according to the MA20 nomogram around 5% as well. We could more easily discount these worries if we felt RT was giving more bang for buck, i.e. if she didn't have a pCR or was initially cN1.

Long-Term Results and Reconstruction Failure in Patients Receiving Postmastectomy Radiation Therapy with a Temporary Expander or Permanent Implant in Place

The biggest risk factor for developing a chest wall recurrence (aside from gross positive margins), and it has been shown time and time again, is having an axillary node positive. And when an axillary node is positive, the overall risks for "events" anywhere is distant>local>regional (see MA20 and EORTC relapse patterns e.g.). This is straight Fisher Hypothesis thinking whereas "...radiation oncologists are obsessed with locoregional control." Of course PMRT can be survival-improving, distant-metastasis improving... but we have to choose pretty carefully when the systemic therapies dramatically impact distant and locoregional relapses as they do in ypT0N0 pCRs.

If we go all Wisdom of Crowds, it seems we are all saying the locoregional recurrence risk is roughly in that 5-10% neighborhood. I'm more 5% and others more 10% or 10-plus I suppose; but to re-iterate @Palex80's graph, the actual local CW recurrence risk when you are cTxN0 and go pCR ypT0N0 from NAC is probably closer to 0-5%. It is tough for RT to have a LR impact when the local recurrence risk is 0% or close to it; it's nigh impossible for it to have a survival impact. This is a weird case where I might sound even weirder by saying "OK, if you must irradiate... don't irradiate her chest wall" whereby factoring in the CW recurrence risk and the expander in place.

 

[Mandelin Rain]

I’m not sure the average of nodes taken on MA20, but I know it’s more than 1. 2/3 of patients had >10. Quoting Lymphedema risk from that trial for this patient is like quoting the risks of pneumonectomy for an SBRT patient.

maybe I’m wrong, but since Z11 I’ve seen very few sleeves and gauntlets in clinic. Even after nodal radiation. She had by definition the most limited SLNBx possible, so much so that if left one “suspicious” node entirely unaddressed pathologically. Quoting what was largely “dissection” data seems bizarre.

 

[w00tz]

Voting for radiation (young age, triple-negative like receptor status, T3, questionable nodes). Definitely wish she had not gotten reconstruction. I think the OP's point was that she got immediate reconstruction immediately, as if radiation was not even a consideration. I think it definitely warranted a discussion upfront. Now we have to weigh in the effect of radiation on the reconstructed chest.

 

[evilbooyaa]

Sorry if I missed it, but was there path fibrosis or treatment effect in the node on the sentinel node ?

This has not been mentioned and to me is an important determinant in this case. @Reaganite you've got the forum on pins and needles

 

[scarbrtj]

Quoting Lymphedema risk from that trial for this patient is like quoting the risks of pneumonectomy for an SBRT patient.

Like Rummy said, "You go to war with the army you have not the army you want." It's the data we have (or the "best" of which I'm aware... I love nomograms TBH), and the lymphedema nomogram calculator includes up to only 1 LN removed. And the nomogram shows what a big effect body habitus has on lymphedema, independent of RT. This lady's lymphedema risk is anywhere from 2.9% to 13.0% depending on whether her BMI is 20 or less to 40 or more and whether limited versus extensive RNI is undertaken. So in theory, just on the basis of the MA20 nomogram, one can quote (estimate, more precisely) lymphedema risk from the MA20 even for one LN dissected. I would think it would be valid to say if the patient is obese, and extensive RNI (ie IMC coverage, full axillary coverage) were used, her lymphedema risk is 10+%. Now add in a 1 out of 4 chance of needing reconstruction revision after RT. She has maybe a 1-(0.9*0.75)=32.5% chance, or 1 out of 3 chance, of having some RT associated toxicity. Don't even add the pneumonitis or (potential, was it left sided?) coronary risks yet. The RT benefit has a long row to hoe in any PMRT reconstruction case, depending on one's viewpoint.

 

[Reaganite]

This has not been mentioned and to me is an important determinant in this case. @Reaganite you've got the forum on pins and needles

Sorry! No mention of scarring in the node. Just call it a "benign node" on final path.

 

[Mandelin Rain]

That nomogram includes a 1 SLNBx as the same risk group as a 7 LN dissection.

Obviously worthwhile.

Id rather use my brain than some half baked nomogram from a study that included VERY few people like her (1% T3, mostly dissection, median node was 12, etc...).

my brain tells me that life altering lymphedema (grade III or worse) after 1 LN is removed and nodal Radiation is less than 1%. Maybe I’ve had VERY good luck in my life with these patients. But that’s my story and I’m sticking to it.

Concern over comesis is well taken but doesn’t move me. Never good to have the best reconstruction in the graveyard. There are certainly expectations to manage regarding reconstruction outcome after XRT but if worse come to worse you lose the implant and life goes on. Easy for me to say, I know, but as an oncologist my interest is in the cancer. Most patients share this mindset in my experience. Especially young ones.

 

[CodeRedDew]

Also would like to add that per ALLIANCE, the false-negative rate for SLNBx following neoadjuvant CHT increases significantly (~10%?), but can be improved with removal of > 3 SLNs and/or dual tracer method -- in addition to the clinicoradiographic response of the LNs following NACT (which certainly could've been by chance), there is also the uncertainty of false-negative SLNBx, so I'd be more inclined to treat her as if the initial CNB was a false-negative given age and borderline HR+, especially if patient is at lower risk for tx-related morbidity (not obese, no diabetes, favorable anatomy, etc).

And I think someone asked the question as what the utility of the biopsy is if you're going to think it's a false-negative, I would argue that it provides information if it's positive, but is probably rendered less useful if negative in a patient "high-risk" disease.

 

[evilbooyaa]

And I think someone asked the question as what the utility of the biopsy is if you're going to think it's a false-negative, I would argue that it provides information if it's positive, but is probably rendered less useful if negative in a patient "high-risk" disease.

Anytime you do a test, decide what you are going to do based on the results of the test. If the answer is the same regardless of what the test shows, do not do the test.

If we're all going to say that every node on US that shrinks with chemotherapy is automatically cancer, then why biopsy any suspicious LNs? Most if not all nodes will shrink with chemotherapy regardless of whether they have cancer in them or not, which is why number of nodes identified in patients undergoing ALND after NAC are frequently lower than upfront ALND.

If the previously clipped node has no evidence for treatment effect, why are we still assuming the initial biopsy was a false negative?

 

[KHE88]

Because the pretest probability of axillary mets in this patient was high.
I agree with Dew's reasoning above as to why to biopsy if you are still going to consider the possibility of a false negative. Additionally, the test (biopsy) is a simple low risk procedure. Even if a negative result doesn't mean as much as a positive result to you, it's not unreasonable to do anyway if it doesn't change management if negative.

Reganite, I would ask this question on MedNet. Maybe reference the discussion here. I'm curious what the breast experts would say. I would guess that if you polled practicing rad oncs, >90% would say treat.

 

[KHE88]

cT3 is a factor that pops in the majority of all guidelines.


A recurrence in a reconstructed breast results in the worst cometic outcome of all. How big is the risk of recurrence (locally) without RT? What do you think?
I'd say 10%, perhaps even up to 15%.


Pneumonitis with RNI in MA20 was 1,2%.
But hey, who is talking about ENI? Have we agreed to give ENI?


What is worse?
A potentially deadly chest wall recurrence or a necrosis in a reconstructed breast or a grade III pneumonitis? I have made up my mind. You can go ahead and ask the patient.


Who says the risk of recurrence is 3-5% in the chest wall 1% in the axilla in "thousands of patients".

The Mamounas paper from 2012:
View attachment 308188
16 patients with cT1-3 cN0 tumors and pCR after neoadjuvant chemotherapy. That's the data you have...
And they had 6.2% recurrences without RT (which is basically 1 patient out of 16!).


Please bear in mind that both NSABP-18 & -27 included full axillary dissection for all patients, not SLNB.
I leave it up for discussion whether or not SLNB after NAC in a 6cm (practically) tripple negative tumor is the "right" way to go to assess the axilla (if you are not planning to irradiate)...

Agree entirely. It's worth noting that triple negative tumors weren't singled out in the Mamounas analysis. And of course not in the EBCTCG meta analysis referenced.

Where's the data specifically for cT3N0 TNBCs that have a pCR to NAC without having an ALND? I'm not aware of any. We are taking some mighty big assumptions with the more generalized data we do have to try and apply it to this specific patient.

Your question about chest wall only vs. chestwall + ENI vs. nodes only is interesting. I was trained to always treat nodes when doing PMRT. I am aware that some guidelines offer the option of considering chestwall only in certain situations. I am not aware of a situation where one would treat nodes and omit chestwall.

Like Rummy said, "You go to war with the army you have not the army you want." It's the data we have (or the "best" of which I'm aware... I love nomograms TBH), and the lymphedema nomogram calculator includes up to only 1 LN removed.

So if there's no good data for the case you are trying to treat, you try and cram some other data that maybe kinda might apply a little bit? How about falling back to basic principles and what we know about the biology and aggressiveness of high grade, hormone negative/light breast cancers? In the end, it might just be a judgement call and having to say, there's no good data and we have to make a decision to err on the side of causing extra toxicity (lymphedema risk in the 5% range, lung toxicity in the 1% range), or erring on the side of overtreating to prevent a potentially lethal, and certainly cosmetically disfiguring recurrence? What's that recurrence risk? Probably 5-10% but we don't know. Certainly higher that the risk of major toxicity.

 

[Palex80]

If we go all Wisdom of Crowds, it seems we are all saying the locoregional recurrence risk is roughly in that 5-10% neighborhood. I'm more 5% and others more 10% or 10-plus I suppose; but to re-iterate @Palex80's graph, the actual local CW recurrence risk when you are cTxN0 and go pCR ypT0N0 from NAC is probably closer to 0-5%. It is tough for RT to have a LR impact when the local recurrence risk is 0% or close to it; it's nigh impossible for it to have a survival impact. This is a weird case where I might sound even weirder by saying "OK, if you must irradiate... don't irradiate her chest wall" whereby factoring in the CW recurrence risk and the expander in place.

"My graph" are 16 patients... Hardly evidence based. Had one more patient out of those 16 developed a recurrence, you would be looking at a 12% recurrence rate.

 

[Palex80]

Your question about chest wall only vs. chestwall + ENI vs. nodes only is interesting. I was trained to always treat nodes when doing PMRT. I am aware that some guidelines offer the option of considering chestwall only in certain situations. I am not aware of a situation where one would treat nodes and omit chestwall.

Good points!

I was trained to not always give RNI when treating post-mastectomy cases.
Back in those days (10+ years ago) when I trained, RNI was not given for patients with less than 4 involved nodes. However, we were trained to treat the chestwall only if high-risk features for a chest-wall recurrence existed. For example a pT3 pN1 (1/16) post-mastectomy patient would receive chest-wall RT only. Later on, data emerged pointing out at a survival benefit from RNI in patients with positive nodes (with BCS or masteecomy), so now we are treating more cases with RNI than we used to do.

I have only rarely treated RNI solely without chest wall.
The few cases I have seen were patients post BCS (including RT to the breast only) who then developed a solitary regional recurrence (mostly in the axilla) and had an indication for treatment post-ALND for that recurrence. We skipped the already irradiated breast / chest wall (some patients opted for a mastectomy together with the ALND - despite no sign of recurrent disease in the breast - just to be sure) and treated with RNI only (without IM).
Rare scenario however.

 

[Reaganite]

Thank you for all of the extremely thoughtful responses. You guys are awesome. At time of consult, I basically said what several others have said: young, rapidly growing tumor, ER "low", 1 SLN removed, etc. and if you're my family member, I'd treat. But I fully acknowledged a case could be made not to treat, that path CR portends much better prognosis, etc. I'll post it over on the mednet and see what they have to say!

 

[scarbrtj]

So if there's no good data for the case you are trying to treat, you try and cram some other data that maybe kinda might apply a little bit? How about falling back to basic principles and what we know about the biology and aggressiveness of high grade, hormone negative/light breast cancers?

A modern basic principle, IMHO, is that pCR in the tumor and nodes is good biology (or, at least, not bad) irrespective of TNBC or 10% ER+ tumors. Agree to disagree!

"My graph" are 16 patients... Hardly evidence based. Had one more patient out of those 16 developed a recurrence, you would be looking at a 12% recurrence rate.

Maybe ~10000 patients, of which ~2000 had a pCR, would give more confidence... (about ~1500 had T3 and ~4500 had N0 here but I don't see the staging quanta teased out in the article but FWIW T1-3 grouped together as if it doesn't matter)... it's a good article. Lots to chew on.

For example a pT3 pN1 (1/16) post-mastectomy patient would receive chest-wall RT only.

Very European. And very reasonable given that this T3N1 patient's highest LRR risk is chest wall. Too bad two milquetoast studies made it seem gauche!

 

[Palex80]

Oh, no... You quoted the German paper.
This paper has been heavily criticized in Europe (and especially Germany) for one reason: The authors "forgot" to look into which patients got radiation therapy and which ones didn't... They merely stated:
"The trial protocols contained recommendations regarding the use of adjuvant radiotherapy according to national and international guidelines. The indication for radiotherapy was mainly based on clinical tumour and nodal stages, as well as age, lymphovascular invasion, margin status and presence of inflammatory signs. Indication for regional nodal irradiation was mainly based on nodal stage and, to a lesser part, tumour location (in regard to internal mammary node irradiation). "
That's it.

Noone knows (including the authors) which patients got RT and which ones didn't.

So any assumption on recurrence risks without radiotherapy based on this paper is not possible.

By the way, the case presented would have received adjuvant radiation therapy in Germany.
The guideline clearly says that "Recommendation for adjuvant radiation therapy should be based on the pretherapeutic (meaning pre-NAC) stage".

cT3 --> RT, no room for discussion.

 

[scarbrtj]

Oh, no... You quoted the German paper.
This paper has been heavily criticized in Europe (and especially Germany) for one reason: The authors "forgot" to look into which patients got radiation therapy and which ones didn't... They merely stated:
"The trial protocols contained recommendations regarding the use of adjuvant radiotherapy according to national and international guidelines. The indication for radiotherapy was mainly based on clinical tumour and nodal stages, as well as age, lymphovascular invasion, margin status and presence of inflammatory signs. Indication for regional nodal irradiation was mainly based on nodal stage and, to a lesser part, tumour location (in regard to internal mammary node irradiation). "
That's it.

Noone knows (including the authors) which patients got RT and which ones didn't.

So any assumption on recurrence risks without radiotherapy based on this paper is not possible.

By the way, the case presented would have received adjuvant radiation therapy in Germany.
The guideline clearly says that "Recommendation for adjuvant radiation therapy should be based on the pretherapeutic (meaning pre-NAC) stage".

cT3 --> RT, no room for discussion.

Haha neat. Those Germans. Definitely not a Triumph des Willens then. OK. But we could in converse also say "In all the 'classic' T3N0 PMRT analyses, we don't know what proportion got a pCR to NAC." I get it. Knee-jerk PMRT for all T3N0. Uncle! Actually if I'm not mistaken I think we can look back at some of the classic European PMRT studies and see the cutoff wasn't T3N0 for PMRT in some studies but any tumors 4cm or greater.*

* May have also been MDACC data

 

[Mandelin Rain]

I’m not a knee jerk T3N0 = PMRT by any means. 75 year old who had no mammo for years and felt this thing growing slowly for years and had no suspicious nodes on imaging and 90% strong ER+ With low/intermediate grade and no LVSI Ain’t getting PMRT in my clinic. She could probably have a couple higher risk factors and still not get it.

this isn’t that.

 

[scarbrtj]

I’m not a knee jerk T3N0 = PMRT by any means. 75 year old who had no mammo for years and felt this thing growing slowly for years and had no suspicious nodes on imaging and 90% strong ER+ With low/intermediate grade and no LVSI Ain’t getting PMRT in my clinic. She could probably have a couple higher risk factors and still not get it.

this isn’t that.

As I'm wont to do... there's data that 41yo's with cT3N0 (TNBC or HR+) who get a pCR have essentially the same long-term behavior as the 75yo case you mentioned at least in terms of LRR. And as mentioned there's (compelling, old) data to support PMRT in certain T2 cases which are not classically considered PMRT indications in today's days and times. I remember when the classical indication was 4 or more LNs+, and people held on to that like scripture from the Bible. But for years the EBCTCG had been showing unpublished meta-analysis data at meetings that there was more PMRT benefit overall in the 1-3 LN+ subset! It drove me crazy.

Clearly the issue won't be put to bed in many minds 'til the currently running avoid-XRT-after-NAC-pCR trials are accrued and published. The avoidance of PMRT by the tumor board in Reaganite's case was hypermodern from afar; but who knows if it was just that some geezers got freaked out by the reconstruction.

 

[Mandelin Rain]

Methinks it was the radiation oncologist telling the surgeon what the surgeon wanted to hear; as radiation oncologists at large are wont to do.

 

[scarbrtj]

A timely prologue.

Highlights
• PMRT is associated with improved survival in patients with pT3N0 breast cancer.
• PMRT benefit is limited to pT3N0 patients who do not receive adjuvant chemotherapy.
• PMRT does not improve survival for cT3N0 disease after neoadjuvant chemotherapy.
• PMRT may benefit patients with cT3N0 disease who respond poorly to chemotherapy.

 

[KHE88]

A timely prologue.

Highlights
• PMRT is associated with improved survival in patients with pT3N0 breast cancer.
• PMRT benefit is limited to pT3N0 patients who do not receive adjuvant chemotherapy.
• PMRT does not improve survival for cT3N0 disease after neoadjuvant chemotherapy.
• PMRT may benefit patients with cT3N0 disease who respond poorly to chemotherapy.

NCDB huh?

Where's the data for triple negative cT3N0 tumors with favorable response to chemo without an ANLD in women < 45?

 

[Palex80]

Oh no! It's more retrospective bias-infested data!