PMRT for this patient?

[Kroll2013]

Dear colleagues,
i need your opinion concerning this patient:

44 yo patient diagnosed of a bifocal mass of the right breast 5*2*3 cm , UOQ, cN0 , no suspiscious nodes on MRI
biopsy showed a poorly differentiated IDC with extensive high grade DCIS, HR neg, Her2 positive
she received neoadjuvant chemotherapy with complete response.
pathology of the radical right mastectomy with sentinel node showed:
no residual tumor, 0/1 LN, LVSI was not specified.

do you give PMRT taking into consideration her young age, negative HR, large tumor and G3?

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[evilbooyaa]

To summarize: 44yo F w/ cT3N0 HR-,Her2+ s/p NAC with pCR on Mastectomy and SLNB.

I personally would leave her be.

Per B-18/B-27 pooled analysis (Predictors of locoregional recurrence after neoadjuvant chemotherapy: results from combined analysis of National Surgical Adjuvant Breast and Bowel... - PubMed - NCBI), Figure 2, her risk of locoregional recurrence is about 6% in this scenario (regardless if you call her 5cm or 5.1cm). Also to me, bifocal mass adding up to 5cm is different than one large confluent mass spanning 5cm, but that's just my opinion with no data behind it.

OK to have a discussion about potentially trying to take that risk lower if she's absolutely adamant, but I would favor observation. Everyone's cut-off is slightly different for how much risk reduction they want to attempt.

 

[Bequerel]

I respectfully disagree. T3, grade 3, HER 2+, HR- and her age are all increased risk factors for a LRR and I would treat her. A specific limitation of the above listed reference is the absence of receptor data. Those percentages can not be used for this patient.

 

[medgator]

I respectfully disagree. T3, grade 3 and her age are all increased risk factors for a LRR and I would treat her. A specific limitation of the above listed reference is the absence of receptor data. Those percentages can not be used for this patient.

I would feel more strongly about pmrt if she was triple negative, personally

 

[scarbrtj]

I respectfully disagree. T3, grade 3, HER 2+, HR- and her age are all increased risk factors for a LRR and I would treat her. A specific limitation of the above listed reference is the absence of receptor data. Those percentages can not be used for this patient.

I respectfully disagree with your disagreement. For an Her2+ patient that is pT0 after anti-Her2 therapy, local recurrence rates are going to be much lower than the "typical" pre-chemo stage T3N0 patient. Her2+_ is no longer an adverse factor, leastways not for patients that respond to the Her2 therapy. "Prior to the advent of targeted therapies, patients with HER2-amplified (HER2+) breast cancers were at high risk for locoregional recurrence (LRR). The use of HER2 targeted therapy has rendered LRR uncommon among early-stage HER2+ patients."
And T3N0 PMRT is a total grey zone anyways for PMRT.
There is NO (good) data that for a patient that is completely clinically, radiographically, and pathologically node-negative, which this patient was, and T3 and ER- and high grade at presentation, that PMRT affects survival.
Her response to the Her2 therapy will be the biggest driver of her outcome; she has had a good response to it.
Having a positive axillary node is always and forever the best predictor of having a benefit to chest wall RT.
Heck, the survival might be worse with PMRT for cT3N0 that becomes pT0 after NAC. LRR is about 0% without PMRT for ER-, Her2+, ypT0 patients.

 

[medgator]

Having a positive axillary node is always and forever the best predictor of having a benefit to chest wall RT.

Assuming she isn't triple negative

Adjuvant chemotherapy and radiotherapy in triple-negative breast carcinoma: a prospective randomized controlled multi-center trial - PubMed

Patients received standard adjuvant chemotherapy plus radiation therapy was more effective than chemotherapy alone in women with triple-negative early-stage breast cancer after mastectomy.

www.ncbi.nlm.nih.gov

Increased risk of locoregional recurrence for women with T1-2N0 triple-negative breast cancer treated with modified radical mastectomy without adjuvant radiation therapy compared with breast-conserving therapy - PubMed

Women with T1-2N0 TNBC treated with MRM without RT have a significant increased risk of LRR compared with those treated with BCT. Prospective studies are warranted to investigate the benefit of adjuvant RT after MRM in TNBC.

www.ncbi.nlm.nih.gov

 

[scarbrtj]

Assuming she isn't triple negative

Adjuvant chemotherapy and radiotherapy in triple-negative breast carcinoma: a prospective randomized controlled multi-center trial - PubMed

Patients received standard adjuvant chemotherapy plus radiation therapy was more effective than chemotherapy alone in women with triple-negative early-stage breast cancer after mastectomy.

www.ncbi.nlm.nih.gov

Increased risk of locoregional recurrence for women with T1-2N0 triple-negative breast cancer treated with modified radical mastectomy without adjuvant radiation therapy compared with breast-conserving therapy - PubMed

Women with T1-2N0 TNBC treated with MRM without RT have a significant increased risk of LRR compared with those treated with BCT. Prospective studies are warranted to investigate the benefit of adjuvant RT after MRM in TNBC.

www.ncbi.nlm.nih.gov

I said the best predictor, there are others
Personally, I would never PMRT irradiate a cT1N0 triple-negative breast cancer that was pT0N0 after NAC. Would you?

 

[Palex80]

I would treat.

Chest wall is a given in my opinion. There are multiple factors for local recurrence (age, size, ER/PR status).

The big question is what to do with the regional nodes.
If you put her data into the MSKCC nomogram

Breast Cancer Nomogram: Sentinel Lymph Node Metastasis | Memorial Sloan Kettering Cancer Center

nomograms.mskcc.org

you come up with a high probability for positive sentinel nodes at diagnosis, it's 68% from the information we have. I know it's just a nomogram, but at least it's validated.
So, if the sentinel was done at diagnosis before the neoadjuvant chemo, there is a 2 out of 3 chance that it would have been positive.
This is a typical scenario where an initial sentinel procedure can move the indication for PMRT from the less clear state we are now in to a more clear situation.

 

[Palex80]

I said the best predictor, there are others
Personally, I would never PMRT irradiate a cT1N0 triple-negative breast cancer that was pT0N0 after NAC. Would you?

Noone really knows. The Chinese randomized trial on triple-negative showed a large benefit with PMRT, but it did not include patients with NAC.
The main question is if a major response to NAC can change the indication for PMRT. The ongoing trial will show that. Until then, I do not consider response to NAC a valid factor when it comes to decide whether to irradiate or not, because there simply is not enough data to support it.

 

[medgator]

I said the best predictor, there are others
Personally, I would never PMRT irradiate a cT1N0 triple-negative breast cancer that was pT0N0 after NAC. Would you?

Nccn says you can't use chemo response to make xrt decisions. Have you ever seen a TNBC have a path CR to chemo? I haven't personally. They are aggressive as it gets

 

[scarbrtj]

Nccn says you can't use chemo response to make xrt decisions. Have you ever seen a TNBC have a path CR to chemo? I haven't personally. They are aggressive as it gets

Yes, rare admittedly, but when an early stage TNBC gets a pCR, they do not seem to be as aggressive as it gets. Staging still drives outcomes regardless of molecular considerations; however, when there are chemo-induced pCRs, biologies seem quite different (and much more favorable). Also see here. I'm aware the NCCN says you "can't" do that. On the other hand, who'm I gonna believe... NCCN or my lyin' eyes. In a "grey zone" case, and we all have those, I would definitely consider NAC pCR.

Noone really knows. The Chinese randomized trial on triple-negative showed a large benefit with PMRT, but it did not include patients with NAC.
The main question is if a major response to NAC can change the indication for PMRT. The ongoing trial will show that. Until then, I do not consider response to NAC a valid factor when it comes to decide whether to irradiate or not, because there simply is not enough data to support it.

Her2 therapies flipped the script. Those of us old enough to have been seeing breast CA patients in the 90's recall how "bad" Her2+ was. Now, I would much rather have Her2+ early stage disease than Her2-. The outcomes are better. ESPECIALLY if you have a pCR to treatment. I remember first seeing the large trial(s) Her2 LRR and OS curves and feeling nervous about XRT's role for those ladies. It's IMHO the most impactful cancer therapy of the last 30 years.

For OP's Her2+ patient, who was Stage II regardless if her tumor was T2 or T3 (technically it was T2), who had a pCR... just really no one is going to convince me to irradiate. I'll need a phIII trial or something. I keep in mind the "If" you had sampled the axilla pre-NAC nomogram(s) you mentioned. However, we both know that there is an obvious disconnect between the nomograms' N+ predictive ability (the nomograms say the number needed to treat for axillary sampling is like 1.5 to 2 patients in high risk cN0) and the derivation of benefit from PMRT in clinically and post-NAC pathologically stage N0 patients (the data say the number needed to treat for PMRT in N0 is high, like maybe 25-50 patients).

But anyhoo... you gents are saying you'll PMRT an early stage TNBC with pCR? Not saying it's wrong. It is interesting though 'cause I think you're both smart, and seems you would; I would not, ever (except like positive margin or something), irradiate a T1N0 TNBC that was pCR after NAC. Controversy!

 

[Mandelin Rain]

I tend to be really aggressive with PMRT, so I'd treat this woman.

I think it's more difficult to find a subset who doesn't benefit from PMRT than it is to find those who do. If only because T1/2 N0 patients don't tend to have mastectomies. Max benefit is obviously with node positivity, but that doesn't mean no benefit in other populations. Premenopausal, high-grade, ER-, T3 seems like at least 15%ish LRR risk to me. It's hard to project what impact a pCR to dual neoadjuvant HER2 directed therapy will have on long term LRR risk. Maybe a lot. Maybe not. For time being, I'd treat.

 

[evilbooyaa]

What do with cT3N0 continues to be an area of argument. For the record, I don't think that doing PMRT is wrong here, and I think everyone's going to have their own gestalt to their recommendations without great data.

For the record - a main consideration that I said no RT was because I don't think most patients with cT3N0 requires PMRT. I believe that HER2+ in the era of Herceptin and Perjeta in PTCH is not the same boogeyman that it used to be before widespread use of one or both of those drugs. If this patient had ypT3N0 disease, I would push for RT.

Additionally, if this patient was node positive up front (either T2N1 or T3N1), then yes, I would treat (off-protocol, if I couldn't enroll her on B51).

I would treat.

Chest wall is a given in my opinion. There are multiple factors for local recurrence (age, size, ER/PR status).

The big question is what to do with the regional nodes.
If you put her data into the MSKCC nomogram

Breast Cancer Nomogram: Sentinel Lymph Node Metastasis | Memorial Sloan Kettering Cancer Center

nomograms.mskcc.org

you come up with a high probability for positive sentinel nodes at diagnosis, it's 68% from the information we have. I know it's just a nomogram, but at least it's validated.
So, if the sentinel was done at diagnosis before the neoadjuvant chemo, there is a 2 out of 3 chance that it would have been positive.
This is a typical scenario where an initial sentinel procedure can move the indication for PMRT from the less clear state we are now in to a more clear situation.

If I was going to do PMRT, I would do CW and regional nodes. The only situation that I, personally, seriously consider CW alone is if I'm doing PMRT for T1-2N0 with a positive margin not amenable to re-resection.

Sentinel biopsy upfront is generally not favored in the US. We generally go by radiographical N0 as being sufficient - if there's anything suspicious, put a needle in it. We know that upfront SLNB would make this patient ineligible for enrollment on trials such as NSABP-B51.

Nccn says you can't use chemo response to make xrt decisions. Have you ever seen a TNBC have a path CR to chemo? I haven't personally. They are aggressive as it gets

I have seen pCR with TNBC w/ neoadjuvant chemo especially with AC-TC. Rates of PCR I've seen are generally in the 20-30% (33% in this study: The survival benefit of neoadjuvant chemotherapy and pCR among patients with advanced stage triple negative breast cancer). Not as common as for those that are HER2+, but nothing to sneeze at. TNBC more likely to have pCR than HR+,Her2-.


I would not blanket offer PMRT to all cT3N0 non-TNBC or T1N0 Triple negative cancers, even without neoadjuvant CT. I personally think even blanket PMRT for T2N0 triple negative is too aggressive. Despite the results of the cited 2011 Chinese study the needle does not seem to have shifted in terms of mandating PMRT in T2N0 TNBC. One certainly can, in the same way one can do RNI in high-risk node negative patients (like per MA-20).

 

[scarbrtj]

good discussion.

I think it's more difficult to find a subset who doesn't benefit from PMRT than it is to find those who do.

I wouldn't say difficult per se. Easiest subset to find: cN0/pN0.
"For 700 women with axillary dissection and no positive nodes, radiotherapy had no significant effect on locoregional recurrence (two-sided significance level [2p]>0·1), overall recurrence (rate ratio [RR], irradiated vs not, 1·06, 95% CI 0·76-1·48, 2p>0·1), or breast cancer mortality (RR 1·18, 95% CI 0·89-1·55, 2p>0·1." On top of that, there is fair amount of non-randomized data that PMRT has survival worsening trends for T1/2,N0 who get pCR from NAC.

If only because T1/2 N0 patients don't tend to have mastectomies.

"Tend to," no. But they do; about 1/4 women with early stage disease get mastectomy. The incidence is increasing.

I would not blanket offer PMRT to all cT3N0 non-TNBC or T1N0 Triple negative cancers, even without neoadjuvant CT. I personally think even blanket PMRT for T2N0 triple negative is too aggressive.

Agree w/all. Gotta remember, even if this lady was T2 or T3, she was Stage II at presentation I believe. And T0N0 after NAC for Her2+, a big deal.

 

[seper]

Seems to me R vs L side is missing from this discussion... Affects therapeutic ratio, IMO.