This video features Richard J. Bleicher, MD, FACS presenting on Local Control. This presentation was given at our January 19th 21st Annual Highlights of the 2022 San Antonio Breast Cancer Symposium in 2023.
Hello everybody. Good evening. I'm rick lecture and I want to thank dr Goldstein and Lucia and the organizers for inviting me to give you this talk today. So we're gonna talk about local control and there are five abstracts which we will be dealing with a lot to cover. The first is the Alliance American College of Surgeons Oncology group Z 1 11 02 trial looking at multiple IPs lateral breast cancers and breast conservation. The second is the you breast 06 trial looking at omitting axillary dissection in node positive patients. The downstage to no negative after neo adjuvant chemotherapy. The third is the validation of a profile known as polar. Looking at the benefit of radiotherapy. The fourth is a hyper fraction ation trial for proton radiotherapy. And the fifth is an indian trial looking at hyper fraction ation um uh two versus three weeks phase tree study looking at the acute toxicity. So the first one is the impact of breast conservation therapy on local recurrence in patients with multiple IPs lateral breast cancers. The results from a Kawasaki Z11102. Now we know that because of improving imaging modalities multiple IPs lateral breast cancers are increasingly diagnosed. And historically published literature shows a local regional recurrence rate of 25% in six years or even higher in some cases and many people recommend mastectomies. More recent studies though showed that the local regional recurrence rate with breast conservation is less than 8% at four years. And we certainly have had pathologic and imaging improvements as well as treatment improvements which may be reflecting in those data. Now the aims of this study was to assess for local recurrence in breast conservation therapy for M. I. B. C. S. Multiple IPs lateral breast cancers. They had to have two or three breast lesions. An acceptable local recurrence rate was considered 8% or lower at five years. The group has previously published several secondary outcomes. They found conversion rate domestic to me for positive margins at 7.1% margin negativity at a single operation is 67%. Cosmetic outcome as good or excellent at two years at 71%. And they found that increasing radiation boost volume was associated with acute dermatitis but not worse outcomes Enrollment had to be women 40 and over they had to have two or three fosse of breast cancer. One or more photos I in this group had to have invasive disease. In order to establish what was considered a separate site. The sites had to be two or more centimeters apart and no more than two quadrants with disease and they had to be clinically end zero N one. Now they didn't differentiate between multi centric or multifocal because an 11 30 versus a 12 30 lesion for instance might be very difficult to distinguish when you have a large lesion. The exclusion criteria you can see I won't read them on the right side of your screen. So the protocol was as follows there was registration and they had breast conservation and this should say lumpectomy of 2-3 plus nodal staging. They had chemotherapy at their physician's discretion radiotherapy of whole breast radiotherapy with a boost to all sites endocrine therapy or chemotherapy. Additionally at the position discretion and follow up every six months until five years at the end of whole breast radiotherapy there were 270 patients enrolled at 78 sites. There were 200 for a valuable. They did amend the protocol in 2015 to allow enrollment for patients without an M. R. I. And to allow post surgical enrollment of patients having breast conservation surgery for M. I. B. C. S. The median follow up was 66 born four months and I won't read through the data on the right. But those were the characteristics of the group. The outcomes were as follows. They had no recurrences in the Exelon, four in the hips, lateral breast, one in the skin and one in the chest wall. Four patients developed distant disease. Six developed contra lateral breast cancer. Eight died with one being from breast cancer. Three patients had non breast primaries and six out of 204 developed a local recurrence calculated to be a cumulative five year incidents of 3.1%. The results you can see here. Most of these patients had to focus I rather than three and you can see the phenotype statistically associated with local recurrence was two things breast M. R. I. Which is an unplanned analysis as an F. Y. I. And administration of adjuvant endocrine therapy. Um Note in the Q. And a session 30% of the patients had a single incision, 70% had two incisions. Neither of those were associated with a local recurrence difference. Their conclusions was that in M. I. B. C. Breast conserving surgery with adjuvant radiation with lumpectomy site boosts at a very low local recurrence rate of 3.1% at five years. And this was affected by preoperative M. R. I. To evaluate the extent of disease. Remember that was an unplanned analysis an adjuvant endocrine therapy for a separate positive breast cancer. Concluding what we pretty much knew is that breast conservation therapy is reasonable for M. I. B. C. One major caveat I would say is that they did note in the question and answer that 58% of these patients had the M. I. B. C. Identified before M. R. I. But in 42%. So almost half it was the M. R. I. That identified the 2nd and 3rd lesion. The significance of the disease detected on M. R. I. Is really unclear remember that. This is why in part why we think radiotherapy drops our local recurrence rates by 40% and that there are fosse that we don't recognize. So the question is in 42% of these patients did those 2nd and 3rd focus I need the extra lumpectomy seen only on M. R. I. And would radiotherapy have addressed this if they didn't get the M. R. E. We won't actually ever know this because once we see something we don't just leave it in place. The second study was the oncological outcomes following omission of axillary lymph node dissection in node positive patients. Downstage to no negative with neo adjuvant chemotherapy. The U breast 06 trial. We know that node positive patients having neo adjuvant chemotherapy can have a central node false negative rate of 10% or greater. There were no actual recurrence rates in these studies though because they had an ax or dissection. So there was no notes left to evaluate or recur single institutions even such as our own that we did here at Fox Chase were small for local recurrence rates and it's unclear whether tad or targeted axillary dissection where a marker is placed and then removed after neo adjuvant reduces that recurrence rate. Their objective as stated were to evaluate local regional and any invasive recurrence for node positive patients achieving a nodal PcR with neo adjuvant therapy after omission of axillary dissection and to compare actual recurrence rates after central no biopsy with dual tracer versus tad. Now the wording on that one Oz I'll show you is not entirely accurate for what was done. So patients were included If they had T 1 to 4 breast cancer biopsy proven and 123 with a noble pcr central no biopsy was done via dual tracer or had with central node biopsy. So it wasn't central no biopsy versus tad as the objective seemed to state and the tad group could have with was with or without dual mapping for central node. They had to have 10 cases for institution and the exclusion criteria you can see on the right of your screen. There were 25 centers in 11 countries. The data was from prospectively collected databases, but this was a retrospective study And there were 1282 patients accrued 1140 for consecutively included with Central Node vs Tad plus central node performed. The dual Tracer was done in 100% of the sentinel node biopsy clip placed in 23% and removed with localization in 86%. The median followed was 4.2 years. In this retrospective group. In the other retrospective group, dual Tracer was not required. We'll talk about the actual percent in a minute. They didn't give this in The presentation clip was removed in 99% and localized mostly by c localization or wire localization. Media file was about half that in 2.7 years the pathologic characteristics between the groups was poor differentiation in the central node biopsy group and greater her two positivity in the tad group. The treatment characteristics had a central node group, median. In the sentinel node arm of four and tad of three and nodal radiation was more likely in the tad group on the right you can see all of the outcomes, you can see actually recurrence rates combined and for each group local regional recurrence rates and any invasive recurrence rate, none of which were different between the groups. And the conclusions were that early actually recurrence after axillary lymph node dissection omission. In node positive patients who downstage to node negative with neo adjuvant chemotherapy is rare supporting the omission of axillary dissection. In those patients, they noted that recurrence quote was not significantly lower in the tad in Sydney and tad than in sentinel node biopsy but this probably should have instead been have been stated that it's not lower in the tad plus sentinel node biopsy group than in sentinel node biopsy alone. Longer fall was certainly needed and compared to central node biopsy alone they felt had allowed for removal of fewer lymph nodes but it was unknown whether this difference was clinically meaningful on whether tad was cost effective. So a couple of caveats. Again, the objective was to compare rates of axle recurrence after sentinel node biopsy with dual tracer mapping versus tad but that's not exactly what they evaluated. You can see the group's there was sent on a biopsy versus centeno plus tad dual tracer and 100%. Now they didn't give the dual tracer amount. So I inquired from um Giacomo Montana. Um as to what how much dual tracer was done in the other group. They are actually were requested by the reviewers for the manuscript account this and so far with 70 charts to be reviewed yet, they were 85%. The clip is placed in 23% versus 100% and removed in 86% versus 99%. So as you can see, this is a very overlapping set of arms and that may be why there's no difference. Also note the caveat that this is a retrospective study for those achieving a pcR. We only know if there's a pcr post talks so you don't know this pre operatively. The fault was clearly different and this solely states whether tad should be added to central node not instead. And it doesn't really tell us whether single tracer and tad maybe feasible or the results of tad alone as some of these statements may have indicated. The next study we review will review is the polar study the validation of the profile for the omission of local adjuvant radiotherapy. In a meta analysis of three randomized controlled trials for breast conserving surgery with or without radiotherapy. Now the Oxford overview showed radiotherapy reduced recurrence in all subgroups and there is a need for a predictive biomarker for radiation and there are trials ongoing. So the authors had previously published and developed a signature for radiation omission which was validated in a Swedish trial but they felt that additional validation was warranted. So there were three studies that they used for this validation. These all dealt with breast conservation surgery with or without radiotherapy. Whole breast radiotherapy. Specifically, this was a Swedish trial, the princess Margaret trial and the Scottish conservation trial. Now the polar development this signature was developed as follows and I'll briefly run through this. They start up with the Swedish trial where lymph node negative breast cancer patients receiving breast conservation surgery were randomized to radiation or not. Those 1178 patients ultimately had 11 excuse me, 1004 of them having tissue micro raised prepared and two cores punched for RNA extraction. 764 of those had gene expression data obtained 597 of those were receptor positive and her two negative with no systemic therapy from those there was a training and validation group and the training group had 131 of them Um used for the subset to identify the local recurrence genes which resulted in a final set of 16 genes having immune response immune response and proliferation significance. And those scores were then dichotomies at the 25th%ile lower than that being low risk higher than that being high risk. So the methods were to do a patient meta analysis of no negative patients receptor positive and her two negative tumors. From those three trials and examining the polar signature as either being prognostic for local regional recurrence in the absence of R. T. Or being a predictor of benefit from radiation after breast conservation surgery or both. The local recurrence rates were as follows. In the polar low group there was no difference in terms of the benefit of radiotherapy. In the polar high group it did differentiate a benefit with an improvement of about 40 40%. As you can see this is pretty consistent with our current data related to radiotherapy and this was significant when look at the multi variable analysis for local regional recurrence. The polar study in fact was significant as was age as predictors for what was important related to local regional recurrence. But tumor size grade and Luminal status were all not significant. They did also do an interaction test between the polar signature and radiotherapy and that was also significant. So findings low Polar had shown um minimal benefit from radiation after breast conservation surgery and was prognostic both in the universe and multi variable analyses within interaction found. And so Polar is now the first genomic classifier prognostic for local regional recurrence and is predictive of radiotherapy benefit where high score benefits from radiotherapy and low score does not. The caveat is this is a retrospective study and clearly prospective data is going to be needed before this is put in place now in the question and answer. They did note a couple of things with those questions. There was no overlap between these genes and the archetype genes. So that's interesting to know. They have not yet tried this in D. C. I. S. In the Swedish trial there was no systemic therapy and the Scottish trial all had tamoxifen. And ultimately their plan is to make this into a pcR assay. So we eagerly await the results of prospective data and any such as say if that turns out to be positive. Finally we have the phase two randomized trial of conventional versus hyper fraction post mastectomy, proton radiotherapy and as we know for background PMR. T. Involves radiation to reconstruct it or non reconstructed breast sites. And regional lymphatic which reduces local regional and distant recurrence in an overall survival in node positive locally advanced breast cancers. There are disadvantages. Um two photons including heart and lung and other soft tissue exposure and complications. Now proton therapy improves target coverage and organs bearing while maximizing coverage. And it compares with state of the art photons. There are two randomized controlled trials for protons versus photons but these are for 10 year coronary events and we expect results in 2034 protons are increasingly used in trials based upon retrospective reports that use conventional fraction ation but really our photon literature is now moving towards hype of fraction ation. So the objective is whether or not 24 month complication rates of hypo fraction ation at 15 fractions Is acceptable relative to 25 fractions for post mastectomy radiotherapy and the complication definition. You can see here Patients were included 18 or older having breast cancer and mastectomy with or without immediate reconstruction and appropriate for post mastectomy radiotherapy. Actually, staging was required and radiotherapy within 12 weeks of last surgery, the exclusions were on the right of your screen and they assumed a 24 month complication rate of 10% in the control arm and a 5% decrease in the experimental arm. The schema looked at patients with breast cancer, mastectomies and nodal surgery and indications for post mastectomy radiotherapy. They were stratified by reconstruction and randomized to conventional fraction ation 50 gray and 25 fractions versus hyper fraction ation 40 gray and 15. The treatment technique for a radiation oncology colleagues is that they utilized a multi field optimized pencil beam scanning proton therapy. This is different from aperture and compensate er based proton therapy allowing some skin sparing such as those having nipple sparing techniques and on the bottom of your screen you see the differences between the heart mean dose and the lateral lung volumes that were covered. The result said that the groups were well balanced and there were no differences in all of these variables. Most of the patients had breast reconstruction with 2/3 in 25 fractions and three quarters in 15 fractions. The results were not different in terms of the 24 month complication rate with a follow up of 39 months Because the upper bound of the 95% confidence interval was more than 10%. Non inferiority could not be claimed. And on university analysis it was only immediate breast reconstruction that was associated with complications. The adverse events were similar. They looked at acute versus late which were differentiated by the 90 day mark. And all of these events. I won't go through them all. But two suffice to say radiation dermatitis ended up being better in the hyper fraction ation arm and breast infection skirted significance for being better in the standard fraction ation arm For progression free survival at 36 months there was no different with a similar number of low events. And the conclusions were that pencil bean proton therapy provided excellent local regional control and normal tissue sparing with no difference in overall complication rates between the two non inferiority of 15 fractions could not be established probably because of sample size and the results from larger photon hyper fraction. Nation trials are awaited with further study warranted in the question and answer. They were able to improve tissue sparing even with breath holding techniques and patient reported outcomes are being analyzed plan followed his five years because of end of rage Biology concerns cost is similar per fraction between photons and protons. And we don't have data yet about details related to complications and the types of reconstruction. The bottom line is this is a good start but we need more follow up and the issue may be that capital outlay for this. If it proves to be superior will be significant. Finally we have the H. R. B. C. Trial from India looking at acute toxicity of a phase three randomized study. The H. R. B. C. Phase three randomized open label study of radiation and breast cancer patients studied three weeks of radiation versus two weeks. The cohort was for invasive breast cancer 18 to 80 breast conservation surgery or mastectomy. They had to have access restaging, complete excision T 124 and 0 to 3 and informed consent. I won't go through the exclusion criteria. The primary aim was local recurrence at five and 10 years. And the secondary looked at acute toxicity with R. T. O. G. Grading, cosmetic outcomes, disease free and overall survival at five and 10 years. The schema was 1130 patients assessed for eligibility. 1121 met criteria and were randomized to either the study arm of 34 gray and 10 fractions over two weeks or the control arm to either chest wall 35 gray 15 fractions in three weeks or breast 40 gray 15 fractions in three weeks. This was between 2015 and 2020. The boost dose was indicated was eight gray and two fractions in both arms they had planned on since they were planned on the simulator with two tangential fields to the breast and chest wall with an incident super particular fossil field. Um And this was given if no positive or T. Three and internal memory node radiation when the inner quadrant T. Three lesions existed or accessory into invaded chest wall or pre op or pre neo attachment therapy. The patients were well matched. The pathology was well matched except more node positive in the two week arm and receptor positive in the three week arm. The treatments were well matched except more mastectomy patients in the two week arm and endocrine therapy in the three week arm. But the radiotherapy details were the same in both arms. There was no difference in skin toxicity, but Kaz Missus was different and improved in the three week sumi improved for excellent and good. Um In the two week arm. So two versus three weeks of radiation had comparable acute skin toxicity with a cosmetic outcome better in the two week arm. The caveat now is that we're all looking at one week of radiotherapy. So what is the utility? But they are doing a one week radiotherapy trial. So thank you for your attention and while take questions when the time is appropriate.