Whole-breast Irradiation Research Articles

Dose-escalated simultaneous integrated boost radiotherapy in early breast cancer (IMPORT HIGH): a multicentre, phase 3, non-inferiority, open-label, randomised controlled trial

A tumour-bed boost delivered after whole-breast radiotherapy increases local cancer-control rates but requires more patient visits and can increase breast hardness. IMPORT HIGH tested simultaneous integrated boost against sequential boost with the aim of reducing treatment duration while maintaining excellent local control and similar or reduced toxicity. IMPORT HIGH is a phase 3, non-inferiority, open-label, randomised controlled trial that recruited women after breast-conserving surgery for pT1-3pN0-3aM0 invasive carcinoma from radiotherapy and referral centres in the UK. Patients were randomly allocated to receive one of three treatments in a 1:1:1 ratio, with computer-generated random permuted blocks used to stratify patients by centre. The control group received 40 Gy in 15 fractions to the whole breast and 16 Gy in 8 fractions sequential photon tumour-bed boost. Test group 1 received 36 Gy in 15 fractions to the whole breast, 40 Gy in 15 fractions to the partial breast, and 48 Gy in 15 fractions concomitant photon boost to the tumour-bed volume. Test group 2 received 36 Gy in 15 fractions to the whole breast, 40 Gy in 15 fractions to the partial breast, and 53 Gy in 15 fractions concomitant photon boost to the tumour-bed volume. The boost clinical target volume was the clip-defined tumour bed. Patients and clinicians were not masked to treatment allocation. The primary endpoint was ipsilateral breast tumour relapse (IBTR) analysed by intention to treat; assuming 5% 5-year incidence with the control group, non-inferiority was predefined as 3% or less absolute excess in the test groups (upper limit of two-sided 95% CI). Adverse events were assessed by clinicians, patients, and photographs. This trial is registered with the ISRCTN registry, ISRCTN47437448, and is closed to new participants. Between March 4, 2009, and Sept 16, 2015, 2617 patients were recruited. 871 individuals were assigned to the control group, 874 to test group 1, and 872 to test group 2. Median boost clinical target volume was 13 cm3 (IQR 7 to 22). At a median follow-up of 74 months there were 76 IBTR events (20 for the control group, 21 for test group 1, and 35 for test group 2). 5-year IBTR incidence was 1·9% (95% CI 1·2 to 3·1) for the control group, 2·0% (1·2 to 3·2) for test group 1, and 3·2% (2·2 to 4·7) for test group 2. The estimated absolute differences versus the control group were 0·1% (-0·8 to 1·7) for test group 1 and 1·4% (0·03 to 3·8) for test group 2. The upper confidence limit for test group 1 versus the control group indicated non-inferiority for 48 Gy. Cumulative 5-year incidence of clinician-reported moderate or marked breast induration was 11·5% for the control group, 10·6% for test group 1 (p=0·40 vs control group), and 15·5% for test group 2 (p=0·015 vs control group). In all groups 5-year IBTR incidence was lower than the 5% originally expected regardless of boost sequencing. Dose-escalation is not advantageous. 5-year moderate or marked adverse event rates were low using small boost volumes. Simultaneous integrated boost in IMPORT HIGH was safe and reduced patient visits. Cancer Research UK.

Comparison of photon versus electron for tumor bed boost radiotherapy post-breast conserving surgery

IntroductionThe standard treatment (photon or electron) for tumor bed boost in breast cancer has not yet been clearly established. The aim of this work was to compare photon vs. electron for tumor bed boost radiotherapy post breast-conserving surgery and whole-breast irradiation concerning different dosimetric parameters. MethodsThis study included 51 patients who underwent conservative surgery and adjuvant radiotherapy. Of these, 28 patients had right-sided and 23 patients had a left-sided tumors. All patients in this study were treated with photon and then re-planned with electron plans. ResultsBoth techniques electron and photon plans provided acceptable results while there was a better performance of the latter in terms of target coverage with statistical significance (p < 0.05). The global and maximum dose was significantly higher with electron compared to photon. Homogeneity index (HI) and conformity index (CI) and conformity number (CN) were better in photon plans, especially in deep-seated tumors. The quality of electron plans differed between patients according to depth, irregular shapes, and location of the tumor bed boost. The results of organs at risk (OARs) for ipsilateral lung and heart showed that photon plans were better than electron plans (p < 0.05), especially at a low dose (V2Gy and V1Gy) for ipsilateral lung. For contralateral breast, both photon and electron had nearly comparable results, where the dose delivered to the contralateral breast for both techniques was close to zero. Interestingly, the number of monitor units (MU) was reduced in electron compared to photon by 15.94% (p < 0.001). ConclusionsThis study recommends the use of photon in treatment of tumor bed boost in conservative breast cancer and then electron as a second line when the former is not available.

Single-Institution Prospective Evaluation of Moderately Hypofractionated Whole-Breast Radiation Therapy With Simultaneous Integrated Boost With or Without Lymphatic Drainage Irradiation After Breast-Conserving Surgery

We report treatment outcomes for patients who received adjuvant moderate hypofractionated whole-breast radiation therapy with simultaneous integrated boost (SIB-mhWBRT) after breast-conserving surgery. SIB-mhWBRT for patients with breast cancer was introduced in our department in July 2017. This prospective evaluation includes 424 consecutive patients treated with SIB-mhWBRT for stage I-III invasive breast cancer (n=391) and/or ductal carcinoma in situ (n=33) until December 2021. SIB-mhWBRT was applied with 40 Gy in 15 daily fractions over 3 weeks according to the START B trial, with an SIB dose to the tumor bed of 48 Gy according to Radiation Therapy Oncology Group 1005/UK-IMPORT-HIGH, delivered as 3-dinemsional conformal radiation therapy (RT; n=402), intensity modulated RT (n=4), or volumetric modulated arc therapy (n=18). The mean patient age was 60 years (range, 27-88). Since May 2018, patients with indications for lymphatic pathway RT were included (n=62). Baseline parameters and follow-up data were recorded and reported, including objective assessment of treatment-related outcomes and subjective patient-reported outcome measures (PROMs). Mean/median follow-up was 29/33 months (range, 2-60). Acute toxicity grade 0, 1, 2, and 3 was observed in 25.0%, 61.4%, 13.3%, and 0%, respectively, at the completion of RT. Data of 281, 266, 243, 172, and 58 patients were available for 6-month and 1-, 2-, 3-, and 4-year follow-up, respectively. Grade 2 late effects were identified in 8.5%, 6.0%, 4.9%, 2.2%, and 10.2% and grade 3 in 2.8%, 1.1%, 1.2%, 0%, and 0% of patients at 6-month and 1-, 2-, 3-, and 4-year follow-up, respectively. Medical treatment of breast edema was the only grade 3 late effect observed. PROM cosmesis results were evaluated as excellent-good, fair, and poor in 97.2%, 2.5%, and 0.4%; 96.5%, 3.1%, and 0.4%; 97.4%, 2.2%, and 0.4%; 97.5%, 2.5%, and 0%; and 96.5%, 3.5%, and 0.0% at 6 months and 1, 2, 3, and 4 years post-RT, respectively. For all patients, the 3-year overall, cancer-specific, and disease-free survival rates were 98.2%, 99.1%, and 95.9%, respectively. Three-year risk of any locoregional recurrence was 0.6%. No mortality or relapse was observed in patients with ductal carcinoma in situ. SIB-mhWBRT demonstrated very favorable side effect profiles and cosmesis/PROMs. Three-year results demonstrate excellent locoregional control. This short-term regimen offers substantial patient comfort and improves institutional efficacy.

Cosmetic Outcome and Toxicity After Stereotactic Accelerated Partial Breast Irradiation in Early Breast Cancer: A Prospective Observational Cohort Study

The aim of this work was to prospectively evaluate the toxicity and cosmetic outcomes of 5-fraction, stereotactic, accelerated partial breast irradiation (APBI). This prospective observational cohort study enrolled women who underwent APBI for invasive carcinoma or carcinoma in situ of the breast. APBI was delivered using a CyberKnife M6 robotic radiosurgery system at 30 Gy in 5 nonconsecutive, once-daily fractions. Women undergoing whole breast irradiation (WBI) were also enrolled for comparison. Patient-reported and physician-assessed adverse events were recorded. Breast fibrosis was measured using a tissue compliance meter, and breast cosmesis was assessed using BCCT.core (an automatic, computer-based software). Outcomes were collected until 24 months posttreatment according to the study protocol. In total, 204 patients (APBI, n=103; WBI, n=101) were enrolled. Regarding patient-reported outcomes, the APBI group reported significantly less skin dryness (6.9% vs 18.3%; P=.015), radiation skin reaction (9.9% vs 23.5%; P=.010), and breast hardness (8.0% vs 20.4%; P=.011) at 6 months than the WBI group. On physician assessment, the APBI group had significantly less dermatitis at 12 months (1.0% vs 7.2%; P=.027) than the WBI group. Any severe toxicities after APBI were rare in patient-reported outcomes (score ≥3, 3.0%) and physician assessments (grade ≥3, 2.0%). In the uninvolved quadrants, measured fibrosis in the APBI group was significantly lower than that in the WBI group at 6 (P=.001) and 12 (P=.029) months but not at 24 months. In the involved quadrant, measured fibrosis in the APBI group was not significantly different from that in the WBI group at any time. Cosmetic outcomes in the APBI group were mostly excellent or good (77.6%) at 24 months, and there was no significant cosmetic detriment from the baseline. Stereotactic APBI was associated with less fibrosis in the uninvolved breast quadrants than WBI. Patients showed minimal toxicity and no detrimental effects on cosmesis after APBI.

Afterglow/Photothermal Bifunctional Polymeric Nanoparticles for Precise Postbreast-Conserving Surgery Adjuvant Therapy and Early Recurrence Theranostic.

Adjuvant whole-breast radiotherapy is essential for breast cancer patients who adopted breast-conserving surgery (BCS) to reduce the risk of local recurrences, which however suffer from large-area and highly destructive ionizing radiation-induced adverse events. To tackle this issue, an afterglow/photothermal bifunctional polymeric nanoparticle (APPN) is developed that utilizes nonionizing light for precise afterglow imaging-guided post-BCS adjuvant second near-infrared (NIR-II) photothermal therapy. APPN consists of a tumor cell targeting afterglow agent, which is doped with a NIR dye as an afterglow initiator and a NIR-II light-absorbing semiconducting polymer as a photothermal transducer. Such a design realizes precise afterglow imaging-guided NIR-II photothermal ablation of minimal residual breast tumor foci after BCS, thus achieving complete inhibition of local recurrences. Moreover, APPN enables early diagnosis and treatment of local recurrence after BCS. This study thus provides a nonionizing modality for precision post-BCS adjuvant therapy and early recurrence theranostic.

Single-centre Experience Comparing PBI to WBRT and the Effects on Volume of Breast Tissue Treated, Heart and Lung Dosimetry

Purpose: The IMPORT-LOW trial demonstrated non-inferiority of partial-breast radiotherapy (PBI) compared with standard whole breast radiotherapy (WBRT) with regards to local relapse in patients with early breast cancer with equivalent or fewer late normal tissue effects at 5 years [1]. This led to UK practice change, with selected low-risk patients offered PBI [2]. We aim to evaluate our single-centre experience by comparing volume of breast tissue treated, heart and lung dosimetry in patients treated with PBI compared to WBRT.

Significance of Hypofractionated Radiotherapy in Postoperative Irradiation for Breast Cancer: An Asian Multi-institutional Prospective Study

AimsThere is a need for the adequate distribution of healthcare resources in Southeast Asia. Many countries in the region have more patients with advanced breast cancer who are eligible for postmastectomy radiotherapy (PMRT). Therefore, it is critical that hypofractionated PMRT is effective in most of these patients. This study investigated the significance of postoperative hypofractionated radiotherapy in patients with breast cancer, including advanced breast cancer, in these countries. Materials and methodsEighteen facilities in 10 Asian countries participated in this prospective, interventional, single-arm study. The study included two independent regimens: hypofractionated whole-breast irradiation (WBI) for patients who had undergone breast-conserving surgery and hypofractionated PMRT for patients who had undergone total mastectomy at a dose of 43.2 Gy in 16 fractions. In the hypofractionated WBI group, patients with high-grade factors received additional 8.1 Gy boost irradiation sessions for the tumour bed in three fractions. ResultsBetween February 2013 and October 2019, 227 and 222 patients were enrolled in the hypofractionated WBI and hypofractionated PMRT groups, respectively. The median follow-up periods in the hypofractionated WBI and hypofractionated PMRT groups were 61 and 60 months, respectively. The 5-year locoregional control rates were 98.9% (95% confidence interval 97.4–100.0) and 96.3% (95% confidence interval 93.2–99.4) in the hypofractionated WBI and hypofractionated PMRT groups, respectively. Regarding adverse events, grade 3 acute dermatitis was observed in 2.2% and 4.9% of patients in the hypofractionated WBI and hypofractionated PMRT groups, respectively. However, no other adverse events were observed. ConclusionAlthough further follow-up is required, hypofractionated radiotherapy regimens for postoperative patients with breast cancer in East and Southeast Asian countries are effective and safe. In particular, the proven efficacy of hypofractionated PMRT indicates that more patients with advanced breast cancer can receive appropriate care in these countries. Hypofractionated WBI and hypofractionated PMRT are reasonable approaches that can contain cancer care costs in these countries. Long-term observation is required to validate our findings.

V5 and High Sensitivity Cardiac Troponin T for Early Detection of Cardiac Toxicity During Left Breast Cancer Irradiation.

The high sensitivity cardiac troponin T (Hs-cTnT) is a myocardial damage biomarker that could have a predictive value in patients who undergo radiotherapy for left sided breast cancer. The aim of this study was to evaluate the early effect of left whole breast radiotherapy (WB-RT) on serum Hs-cTnT levels and its correlation with pre-existing factors. The study was conducted from December 2017 to May 2018. Forty-five patients with early stage left-sided breast cancer who received adjuvant breast hypofractionated RT without prior chemotherapy were included. Serum levels of Hs-cTnT were obtained before, weekly during RT, and within one week after the end of treatment. Considering the physiological variations of serum levels, an increase in Hs-cTnT (∆Hs-cTnT) of more than 30% from the baseline value was chosen as a threshold. The main cardiovascular risk factors were recorded. Dose volume histograms (DVHs) were used to provide a quantitative analysis for the whole heart, left ventricle, and left anterior descending artery (LAD). Twelve of 45 patients (26.6%) showed a ∆Hs-cTnT ≥30%. The maximum Hs-cTnT level was recorded in the last week of treatment. ∆Hs-cTnT was strongly associated with heart V5 (p=0.05) and hypertension (p=0.05). Multivariate analysis confirmed the importance of the heart V5 and correlated with ∆Hs-cTnT. The increase in Hs-cTnT serum levels during adjuvant WB-RT suggested a correlation with the cardiac radiation dose in chemotherapy-naive breast cancer patients. A longer follow-up is needed to correlate Hs-cTnT values with cardiac events.

Three-Fraction Accelerated Partial Breast Irradiation (APBI) Delivered With Interstitial Brachytherapy Is Safe: First Results From the Tri-fraction Radiation Therapy Used to Minimize Patient Hospital Trips (TRIUMPH-T) Trial

Shorter courses of breast radiotherapy are offered as an alternative to 4 weeks of whole-breast irradiation after lumpectomy, including brachytherapy. A prospective phase 2multi-institution clinical trial to study 3-fraction accelerated partial breast irradiation delivered by brachytherapy was conducted. The trial treated selected breast cancers after breast-conserving surgery with brachytherapy applicators that delivered 22.5 Gy in 3 fractions of 7.5 Gy. The planning treatment volume was 1 to 2 cm beyond the surgical cavity. Eligible women were age ≥45 years with unicentric invasive or in situ tumors ≤3 cm excised with negative margins and with positive estrogen or progesterone receptors and no metastases to axillary nodes. Strict dosimetric parameters were required to be met and follow up information was collected from the participating sites. Two hundred patients were prospectively enrolled; however, a total of 185 patients who were enrolled were followed for a median of 3.63 years. Three-fraction brachytherapy was associated with low chronic toxicity. There was excellent or good cosmesis in 94% of patients. There were no grade 4 toxicities. Grade 3 fibrosis at the treatment site was present in 1.7% and 32% percent had grades 1 or 2 fibrosis at the treatment site. There was 1 rib fracture. Other late toxicities included 7.4% grade 1 hyperpigmentation, 2% grade 1 telangiectasias, 1.7% symptomatic seromas, 1.7% abscessed cavities, and 1.1% symptomatic fat necrosis. There were 2 (1.1%) ipsilateral local recurrences, 2 (1.1%) nodal recurrences and no distant recurrences. Other incidents included one contralateral breast cancer and 2 second malignancies (lung). Ultra-short breast brachytherapy is feasible and has excellent toxicity and could be an alternative to standard 5-day, 10 fraction accelerated partial breast irradiation in eligible patients. Patients from this prospective trial will continue to be followed to evaluate long-term outcomes.

Single Ultra-High Dose Rate Proton Transmission Beam for Whole Breast FLASH-Irradiation: Quantification of FLASH-Dose and Relation with Beam Parameters.

Healthy tissue-sparing effects of FLASH (≥40 Gy/s, ≥4-8 Gy/fraction) radiotherapy (RT) make it potentially useful for whole breast irradiation (WBI), since there is often a lot of normal tissue within the planning target volume (PTV). We investigated WBI plan quality and determined FLASH-dose for various machine settings using ultra-high dose rate (UHDR) proton transmission beams (TBs). While five-fraction WBI is commonplace, a potential FLASH-effect might facilitate shorter treatments, so hypothetical 2- and 1-fraction schedules were also analyzed. Using one tangential 250 MeV TB delivering 5 × 5.7 Gy, 2 × 9.74 Gy or 1 × 14.32 Gy, we evaluated: (1) spots with equal monitor units (MUs) in a uniform square grid with variable spacing; (2) spot MUs optimized with a minimum MU-threshold; and (3) splitting the optimized TB into two sub-beams: one delivering spots above an MU-threshold, i.e., at UHDRs; the other delivering the remaining spots necessary to improve plan quality. Scenarios 1-3 were planned for a test case, and scenario 3 was also planned for three other patients. Dose rates were calculated using the pencil beam scanning dose rate and the sliding-window dose rate. Various machine parameters were considered: minimum spot irradiation time (minST): 2 ms/1 ms/0.5 ms; maximum nozzle current (maxN): 200 nA/400 nA/800 nA; two gantry-current (GC) techniques: energy-layer and spot-based. For the test case (PTV = 819 cc) we found: (1) a 7 mm grid achieved the best balance between plan quality and FLASH-dose for equal-MU spots; (2) near the target boundary, lower-MU spots are necessary for homogeneity but decrease FLASH-dose; (3) the non-split beam achieved >95% FLASH for favorable (not clinically available) machine parameters (SB GC, low minST, high maxN), but <5% for clinically available settings (EB GC, minST = 2 ms, maxN = 200 nA); and (4) splitting gave better plan quality and higher FLASH-dose (~50%) for available settings. The clinical cases achieved ~50% (PTV = 1047 cc) or >95% (PTV = 477/677 cc) FLASH after splitting. A single UHDR-TB for WBI can achieve acceptable plan quality. Current machine parameters limit FLASH-dose, which can be partially overcome using beam-splitting. WBI FLASH-RT is technically feasible.

Hypofractionated whole breast irradiation in association with hypofractionated or normofractionated boost to the tumor bed in early breast cancer: tolerance and efficacy analysis.

The boost to the tumor bed improves local control in breast cancer and it is an important part of the breast conserving therapy. However, information about the use of a hypofractionated boost is sparse, thus further studies are needed. We conducted a retrospective study with the aim of comparing hypofractionated boost (HB) and normofractionated boost (NB) on skin toxicity and local control. A total of 96 women with early breast cancer undergoing breast-conserving surgery and hypofractionated whole breast irradiation (WBI) were retrospectively analyzed divided into hypofractionated boost group and conventional fractionation boost group. Forty-nine patients were treated with NB with 16Gy in 8 fractions and 47 patients were treated with HB with 13.35Gy in 5 fractions. We examined acute and chronic toxicity with CTCAE version 5. The median follow-up was 49.5months (26-67). Median age was 57years (36-82). Sixty-six patients (68.7%) were younger than 60years at the time of boost and 30 (31.2%) were older than 60years who received the boost due to poor prognostic factors. No differences were found between the two groups in terms of patient, tumor or treatment characteristics. Grade 2 acute skin toxicity was 6.3% in the NB group and 4.2% in the HB group. Chronic skin induration was 4.2% in the NB group and 1% in the HB group. They did not show grade 3 skin toxicity. There were also no differences in acute or late skin toxicity between the two groups. No local recurrences were evidenced. Hypofractionated WBI associated with HB treatment is a viable option in the management of conservative breast therapy given the good tolerance and similar local control.

Non-Surgical Definitive Treatment for Operable Breast Cancer: Current Status and Future Prospects.

This article reviews the results of various non-surgical curative treatments for operable breast cancer. Radiotherapy is considered the most important among such treatments, but conventional radiotherapy alone and concurrent chemoradiotherapy do not achieve high cure rates. As a radiosensitization strategy, intratumoral injection of hydrogen peroxide before radiation has been investigated, and high local control rates (75-97%) were reported. The authors treated 45 patients with whole-breast radiotherapy, followed by stereotactic or intensity-modulated radiotherapy boost, with or without a radiosensitization strategy employing either hydrogen peroxide injection or hyperthermia plus oral tegafur-gimeracil-oteracil potassium. Stages were 0-I in 23 patients, II in 19, and III in 3. Clinical and cosmetic outcomes were good, with 5-year overall, progression-free, and local recurrence-free survival rates of 97, 86, and 88%, respectively. Trials of carbon ion radiotherapy are ongoing, with promising interim results. Radiofrequency ablation, focused ultrasound, and other image-guided ablation treatments yielded complete ablation rates of 20-100% (mostly ≥70%), but long-term cure rates remain unclear. In these treatments, combination with radiotherapy seems necessary to treat the extensive intraductal components. Non-surgical treatment of breast cancer is evolving steadily, with radiotherapy playing a major role. In the future, proton therapy with the ultra-high-dose-rate FLASH mode is expected to further improve outcomes.

Voluntary versus mechanically-induced deep inspiration breath-hold for left breast cancer: A randomized controlled trial

Background and purposeDeep inspiration breath-hold (DIBH) protects critical organs-at-risk (OARs) for adjuvant breast radiotherapy. Guidance systems e.g. surface guided radiation therapy (SGRT) improve the positional breast reproducibility and stability during DIBH. In parallel, OARs sparing with DIBH is enhanced through different techniques e.g. prone position, continuous positive airway pressure (CPAP). By inducing repeated DIBH with the same level of positive pressure, mechanically-assisted and non-invasive ventilation (MANIV) could potentially combine these DIBH optimizations. Materials and MethodsWe conducted a randomized, open-label, multicenter and single-institution non-inferiority trial. Sixty-six patients eligible for adjuvant left whole-breast radiotherapy in supine position were equally assigned between mechanically-induced DIBH (MANIV-DIBH) and voluntary DIBH guided by SGRT (sDIBH). The co-primary endpoints were positional breast stability and reproducibility with a non-inferiority margin of 1 mm. Secondary endpoints were tolerance assessed daily via validated scales, treatment time, dose to OARs and their inter-fraction positional reproducibility. ResultsDifferences between both arms for positional breast reproducibility and stability occurred at a sub-millimetric level (p < 0.001 for non-inferiority). The left anterior descending artery near-max dose (14,6 ± 12,0 Gy vs. 7,7 ± 7,1 Gy, p = 0,018) and mean dose (5,0 ± 3,5 Gy vs. 3,0 ± 2,0 Gy, p = 0,009) were improved with MANIV-DIBH. The same applied for the V5Gy of the left ventricle (2,4 ± 4,1 % vs. 0,8 ± 1,6 %, p = 0,001) as well as for the left lung V20Gy (11,4 ± 2,8 % vs. 9,7 ± 2,7 %, p = 0,019) and V30Gy (8,0 ± 2,6 % vs. 6,5 ± 2,3 %, p = 0,0018). Better heart’s inter-fraction positional reproducibility was observed with MANIV-DIBH. Tolerance and treatment time were similar. ConclusionMechanical ventilation provides the same target irradiation accuracy as with SGRT while better protecting and repositioning OARs.

DCIS: When is accelerated partial breast irradiation an option? A meta-analysis on outcomes and eligibility

BackgroundThe natural history of DCIS may not be progression to invasive breast cancer (IBC). Accelerated partial breast irradiation (APBI) has emerged as an alternative to whole breast radiotherapy (WBRT). The purpose of this study was to assess the impact of APBI on DCIS patients. Materials and methodsEligible studies from 2012 to 2022 were identified in PubMed, Cochrane Library, ClinicalTrials, and ICTRP. A meta-analysis was done comparing recurrence rates, breast-related mortality rates, and adverse events of APBI versus WBRT. A subgroup analysis of 2017 ASTRO Guidelines “Suitable” and “Unsuitable” groups was performed. Forest plots and quantitative analysis were done. ResultsSix studies were eligible (3 on APBI versus WBRT, 3 on APBI suitability). All had a low risk of bias and publication bias. The cumulative incidence was the following for APBI and WBRT respectively: IBTR was 5.7% and 6.3% with odds ratio of 1.09, 95% CI [0.84, 1.42], mortality rate was 4.9% and 5.05%, and adverse events was 48.87% and 69.63%. All had no statistical significance between groups. Adverse events were found to favor the APBI arm. Recurrence rate was significantly less in the Suitable group with an odds ratio 2.69, 95% CI [1.56, 4.67], favoring it over the Unsuitable group. ConclusionAPBI was comparable to WBRT in terms of recurrence rate, breast cancer-related mortality rate, and adverse events. APBI was not inferior to WBRT and showed better safety in terms of skin toxicity. Patients classified as suitable for APBI had significantly lesser recurrence rate.

Impact of de-escalating systemic therapy guided by 21-gene assay on locoregional recurrence after partial-breast irradiation

PURPOSEPartial-breast irradiation (PBI) has been performed as alternative to whole-breast irradiation (WBI) in breast-conserving therapy (BCT). Recently, the 21-gene recurrence score (RS) was introduced to determine the adjuvant therapy for estrogen receptor (ER)-positive, and human epidermal growth factor receptor 2 (HER2)-negative diseases. However, the impact of RS-based systemic therapy on locoregional recurrence (LRR) following BCT with PBI remains uninvestigated. METHODS AND MATERIALSPatients with ER-positive, HER2-negative, and node-negative breast cancer who underwent BCT with PBI were examined during May 2012–March 2022. In addition to immunohistochemistry (IHC), RS was available to decide on adjuvant therapy. RESULTSIn total, 431 patients were evaluated with a median followup of 48.6 months. The 4-year LRR-free survival rates were 97.3% and 96.4% in the IHC and RS cohorts, respectively (p = 0.50). Ki67 of >20% was significantly associated with LRR in the multivariate analysis (HR 4.39, p < 0.05). For patients with Ki67 > 20%, 29 of 71 (40.8%) and 46 of 59 (78.0%) patients received only endocrine therapy in the IHC and RS cohorts, respectively (p < 0.0001). For patients with Ki67 >20% who received only endocrine therapy, the 4-year LRR-free survival rates were 91.8% in the IHC cohort and 94.6% in the RS cohort (p = 0.29) CONCLUSIONSAlthough the introduction of RS increased the number of patients receiving endocrine therapy alone for Ki67 >20% of disease by two times, the LRR-free survival after BCT with PBI could be maintained. However, further studies from multiple institutions with longer followup data are required.

Abstract PD3-05: Early results of the French multicenter, randomized SHARE trial comparing whole breast irradiation versus accelerated partial breast irradiation in postmenopausal women with early-stage breast cancer

Abstract Purpose: The aim of current analyses is to report toxicity and cosmetic outcomes at 3 and up to 9 years of follow-up of post-menopausal patients randomized to receive either standard external beam whole breast radiotherapy (WBI), including hypofractionated options, versus accelerated partial breast irradiation (APBI). Methods and materials: From December 2010 to July 2015, 1006 patients were enrolled in 34 French centers (503 in each arm). Among the whole population, 28 patients who did not meet the final selection criteria or withdrew consent were excluded leading to a modified intention to treat analysis dataset of 978 patients (WBI: n=488; APBI: n=490). Median age (65y) and tumor stage pT1 (99%) rates were similar in both arms. Patients had conservative surgery with clip placement in the tumor bed. Clear margins (&amp;gt; 2mm) were observed in 99% of the patients. In both arms, 96-97% of the patients had negative sentinel lymph node biopsy (SLNB; median number: 4 in WBI arm and 5 in APBI), luminal BC. Ductal histology was observed 82%. Only 2% and 1% of patients had grade III and pN(i+) disease. The median time interval between surgery and radiotherapy was 57d in WBI vs 62d in APBI. WBI schedules consisted of: 50Gy in 25fr + 16Gy boost (n=212) or 40Gy in 15fr (n=156) or 42.5Gy in 16fr (n=120), while APBI arm consisted of 38.5Gy or 40Gy in 10fr. Overall, 94 patients from the APBI arm finally received standard WBI. For statistical considerations, SHARE trial, sponsored by UNICANCER (NCT01247233) is a non-inferiority randomized controlled trial comparing APBI versus WBI in terms of local control as primary objective. Secondary endpoints were severe toxicity (NCI-CTCAE v4 grade ≥ 2), and cosmetic results, evaluated by doctors and by patients, over the entire follow-up. For both outcomes, we estimated the cumulative incidences (CI) using Kalbfleish and Prentice method, considering disease relapse, secondary cancer or death as competing events. Treatment effect (APBI vs WBI) was estimated by cause-specific Hazard Ratios (cs-HR) from Cox models adjusted on stratification factors. Results: Median follow-up was 5.8y (range, 0.13-9.5). The number of deaths was 27, and the number of local relapses was 8. Among the 978 patients, 582 and 396 had finally WBI and APBI, respectively. The rates of post-operative hematoma, edema and infection were low: 8-9%, 2%, 3-2%, respectively. When considering any type of severe toxicity, we observed a significant reduction rate in APBI compared to WBI: cs-HR=0.73 (95% confidence interval: 0.61-0.88); p=0.001, and 3-year cumulative incidence (CI) of severe toxicity at 45% (41-49) in WBI vs 36% (32-40) in APBI arm. The difference was also in favor of APBI when considering breast skin toxicity alone: cs-HR=0.55 (0.44-0.70), p&amp;lt; 0.001 and 3-year CI at 36% (32-40) in WBI vs 21% (18-25) in APBI arm. Conversely, for breast other toxicities, WBI was found less toxic than APBI: cs-HR= 2.10 (1.51-2.91), p&amp;lt; 0.001, and 3-year CI at 8% (5-10) vs 15% (12-19), respectively. When considering cosmetic results according to the investigator, we observed no significant difference between the two arms: cs-HR=1.04 (0.81-1.33), p=0.26 and 3-year probability of remaining with good to excellent cosmetic results at 77% (73-81) in WBI arm and 78% (74-81) in APBI arm. Findings were similar when considering results according to the patient: cs-HR=1.07 (0.85-1.37), p=0.23, and 3-year probability at 74% (70-78) and 75% (70-79), respectively. Conclusions Historically SHARE is the first APBI trial that included hypofractionated schedules in the standard arm. We reported increased risk of severe toxicity and skin breast toxicity in standard arm as compared with APBI arm without any difference in terms of cosmetic results. Longer follow-up is needed. Citation Format: Yazid Belkacemi, Isabelle Gabelle-Flandin, Marie-Cécile Le Deley, Adeline Petit, Philippe Guilbert, Julien Geffrelot, Christian Carrie, Eleonor Rivin Del Campo, Chantal Hanzen, Claire Charra-Brunaud, Isabelle Lecouillard, Nicolas Magne, Agnès Tallet, Nicolas Leduc, Blaha Belgadi, Philippe Fourneret, Alexandre Coutte, Esther Capelo, Franck Darloy, Muriel Garcia Ramirez, Philippe Dudouet, Pierre Clavere, Jean-Philippe Suchaud, Guillaume Auzac, Thomas Lacornerie, Jérôme Lemonnier, Céline Bourgier, Eric Lartigau. Early results of the French multicenter, randomized SHARE trial comparing whole breast irradiation versus accelerated partial breast irradiation in postmenopausal women with early-stage breast cancer. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD3-05.

Abstract P4-02-16: Prognostic and Predictive Capacity of Tumor Infiltrating Lymphocytes in the MA.20 regional radiotherapy trial

Abstract Background: The benefit of regional nodal irradiation (RNI) in patients with low burden metastatic axillary disease was established in MA.20 showing that patients randomized to receive adjuvant whole breast irradiation (WBI) plus RNI experienced a significantly better disease free survival (DFS) and distant disease free survival (DDFS) compared to those who received WBI alone and this advantage was maintained in the hormone receptor negative subgroup. Stromal tumor infiltrating lymphocytes (sTILs) have shown prognostic and predictive value in HER2 positive and triple negative breast cancers. To date, clinical importance of immune infiltrates as prognostic and predictive biomarkers in the context of benefit from RNI has not been shown. Methods: 1064 full-face hematoxylin and eosin (H&amp;E) stained sections and formalin fixed paraffin embedded primary tumor blocks assembled into 16 tissue microarrays (TMAs) in quadruplicates linked with clinical data were accessible from the original 1832 patients in the MA.20 trial for this retrospective-prospective translational study conducted according to the REMARK guidelines. sTILs were assessed on scanned images of H&amp;E sections according to the International Immuno-Oncology Working Group method, and on TMAs by CD8 immunohistochemistry (IHC) using a validated assay. Biomarkers were scored by pathologists blinded to the clinical data and analyzed as continuous and categorical variables using prespecified median cutpoints. The median follow-up was 9.5 years. Cox proportional regression modelling was used after adjusting for clinicopathological factors and treatments. Hazard ratios (HR) with 95% confidence intervals (CI) were reported for the primary endpoint of DFS and secondary endpoint of DDFS. Predictive value was assessed by the interaction test between the treatment arm and the biomarkers in the full cohort and an IHC defined non-luminal A subgroup. Results: 1035 cases were evaluable for sTILs on H&amp;E sections. Of these 52.6% (n=544) cases with ≥10% sTILs displayed a significant correlation with age &amp;lt; 50 years, grade III, tumor size &amp;gt;2cm, hormone receptor negative status, and non-luminal A subgroup (p &amp;lt; 0.05). Of the 857 evaluable cases on TMAs, CD8+sTILs (≥16) were observed in 49.8% (n=427) cases and showed a significant association with grade III, ER negativity and non-luminal A status (p &amp;lt; 0.05). For the full cohort, H&amp;E sTILs assessed as a continuous parameter, were not prognostic for DFS (HR 0.993; 95% CI 0.984-1.003; p=0.18) but provided prognostic information for DDFS (HR 0.988; 95% CI 0.977-0.999; p=0.04) in multivariate analyses. H&amp;E sTILs did not show predictive value as a continuous variable. Similarly, using the prespecified cutpoint (≥10%), H&amp;E sTILs were neither prognostic nor predictive. Increasing level of CD8+sTILs was associated with significantly improved DFS (HR 0.99; 95% CI 0.983-0.998; p=0.02) and DDFS (HR 0.98; 95% CI 0.97-0.99; p=0.002) in multivariate analyses. For the full cohort, CD8+sTILs as a continuous variable, showed a significant improvement in DDFS for patients randomized to WBI and RNI (HR 0.979; 95%CI 0.959-0.999; p(interaction) =0.04) compared to WBI alone and a trend (HR 0.977; 95%CI 0.954-1.001; p(interaction) =0.06) for better outcome was observed for the non-luminal A subgroup. CD8+sTILs at the prespecified cutpoint (≥16) were not prognostic or predictive. Conclusions: Pre-treatment tumoral infiltration with stromal lymphocytes provided positive prognostic information for DFS (CD8+sTILs) and DDFS (H&amp;E sTILs and CD8+sTILs) when examined as a continuous variable but failed to do so at prespecified cutpoints. While CD8+sTILs as a continuous variable predicted benefit from RNI, significant prediction results were not seen for prespecified cutpoint or related biomarker H&amp;E sTIL. These results require further validation. Citation Format: Nazia Riaz, Bingshu Chen, Anita Bane, Dongxia Gao, Elisabeth Stovgaard, Zuzana Kos, Samuel Leung, Elahe Shenasa, Wendy Parulekar, Shelley Chambers, Torsten Nielson, Timothy J. Whelan. Prognostic and Predictive Capacity of Tumor Infiltrating Lymphocytes in the MA.20 regional radiotherapy trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-02-16.

Abstract ED6-2: RT: How short can it be

Abstract Adjuvant whole-breast radiotherapy for breast cancer has traditionally been delivered over the course of 5 weeks. In the past decades, there has been a paradigm shift towards moderate hypofractionation with 15-16 fractions over 3 weeks based on randomized controlled trials demonstrating comparable oncological safety, decreased acute toxicity and similar long-term toxicity compared to conventional fractionation. More recently, ultra-hypofractionated whole-breast radiotherapy delivered with 5 fractions over 1 week or 5 weeks has been introduced into the clinic. Furthermore, the increasing use of partial-breast irradiation with a de-escalation of the target volume to the region of the lumpectomy cavity has further allowed acceleration of radiotherapy delivery for patients with breast cancer. This lecture will summarize recent advances and data on hypofractionation for breast cancer. Citation Format: David Krug. RT: How short can it be [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr ED6-2.

Abstract P1-09-03: Impact of BRCA1/2 pathogenic variants on ipsilateral breast tumor recurrence and prognosis following breast-conserving surgery

Abstract Background The risk of ipsilateral breast tumor recurrence (IBTR) and the prognostic outcome of breast-conserving surgery (BCS) for germline BRCA1/2 pathogenic variant (BRCA1/2+) carriers remain controversial. We examined differences in IBTR and prognosis between BRCA1/2+ carriers and non-carriers following BCS for breast cancer. Methods Clinical and pathological data were collected by retrospectively reviewing charts of consecutive patients with stage 0-III breast cancer who underwent genetic testing for germline BRCA1/2 and BCS between 1996 and 2020. Patients with variants of breast cancer-associated genes other than BRCA1/2 were excluded. We compared the incidence of IBTR and prognosis, including overall survival (OS), breast cancer-specific survival (BCSS), and distant recurrence-free survival (DRFS), between BRCA1/2+ carriers and non-carriers. Results We analyzed 551 patients (587 breasts with cancer), including 30 BRCA1+ carriers (32 breasts) and 31 BRCA2+ carriers (32 breasts). The median follow-up was 5.8 years (7.2 and 5.3 years for carriers and non-carriers, respectively). The median age at breast cancer diagnosis was 43 and 46 years for carriers and non-carriers, respectively, indicating younger onset of cancer in carriers (age ≤ 40 years; 46.9% for carriers vs. 27.5% for non-carriers, p = 0.001). In carriers, breast cancer more frequently expressed estrogen receptor-negative (56.2% for BRCA1+ carriers and 15.6% for BRCA2+ carriers vs. 22.0% for non-carriers, p = 0.013), progesterone receptor-negative (62.5% for BRCA1+ carriers and 31.3% for BRCA2+ carriers vs. 29.5%, p = 0.005), nuclear grade III (45.3% for carriers vs. 29.5% for non-carriers, p = 0.010), or a higher Ki-67 index (Ki-67 index &amp;gt; 20) (89.5% vs. 61.8%, p = 0.001) than non-carriers. Moreover, carriers underwent chemotherapy more frequently than non-carriers (62.5% vs. 42.4%, p = 0.002). Cancer stage, tumor size, HER2 status, presence of lymphovascular invasion, and the rate of positive or close surgical margins did not statistically differ between the examined groups. No statistical differences were detected in the number of patients who underwent whole-breast radiotherapy following BCS: 59 breasts in carriers and 503 in non-carriers (92.2% vs. 96.4%). During follow-up, we noted that 9 breasts of BRCA1/2+ carriers (5 [15.6%] for BRCA1+ and 4 [12.5%] for BRCA2+) and 35 breasts (6.7%) of non-carriers developed IBTR (p = 0.035). In an analysis excluding patients who did not undergo radiotherapy, the rate of IBTR remained significantly higher in BRCA1/2+ carriers (p = 0.034) than that in non-carriers. The median time to IBTR was 10.2 years in carriers (10.2 years for BRCA1+ and 8.5 years for BRCA2+) and 3.5 years in non-carriers. Carriers were more likely than non-carriers to exhibit distinct subtypes of recurrent tumors in the ipsilateral breast (66.7% for carriers vs. 19.4% for non-carriers, p = 0.006), occurring in a different quadrant from the primary tumor (50.0% vs. 27.3%, p = 0.215). No significant differences in OS (p = 0.068), BCSS (p = 0.109), or DRFS (p = 0.359) were noted between carriers and non-carriers. Conclusion BRCA1/2+ carriers exhibited a higher risk of IBTR after BCS and a longer time to IBTR than non-carriers. One limitation of the present study is a longer follow-up period for carriers than for non-carriers, as carriers typically underwent long-term observation at our institution; hence, further data accumulation is warranted for validating these findings. Subtypes and quadrants of IBTR were frequently distinct in carriers, indicating the increased incidence of new primary breast cancer. Although the prognosis did not differ between carriers and non-carriers, our results suggest the necessity for long-term intensive breast surveillance of BRCA1/2+ carriers after BCS. Citation Format: Sakiko Kondo, Kumiko Kida, Misato Suzuki, Chika Fukano, Atsushi Yoshida, Naoki Hayashi, Junko Takei, Michiko Yamanaka, Hideko Yamauchi. Impact of BRCA1/2 pathogenic variants on ipsilateral breast tumor recurrence and prognosis following breast-conserving surgery [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-09-03.

Low doses to the heart in daily practice for treating left-sided breast cancer using accelerated partial-breast irradiation by multicatheter brachytherapy and deep-inspiration breath-hold using a SIB

PurposeThe aim of this study was to analyze the heart dose for left-sided breast cancer that can be achieved during daily practice in patients treated with multicatheter brachytherapy (MCBT) accelerated partial-breast irradiation (APBI) and deep-inspiration breath-hold (DIBH) whole-breast irradiation (WBI) using a simultaneous integrated tumor bed boost (SIB)—two different concepts which nonetheless share some patient overlap.Materials and methodsWe analyzed the nominal average dose (Dmean) to the heart as well as the biologically effective dose (BED) and the equivalent dose in 2‑Gy fractions (EQD2) for an α/β of 3 in 30 MCBT-APBI patients and 22 patients treated with DIBH plus SIB. For further dosimetric comparison, we contoured the breast planning target volume (PTV) in each of the brachytherapy planning CTs according to the ESTRO guidelines and computed tangential field plans. Mean dose (Dmean), EQD2 Dmean, and BED Dmean for three dosing schemes were calculated: 50 Gy/25 fractions and two hypofractionated regimens, i.e., 40.05 Gy/15 fractions and 26 Gy/5 fractions. Furthermore, we calculated tangential field plans without a boost for the 22 cases treated with SIB with the standard dosing scheme of 40.05 Gy/15 fractions.ResultsMCBT and DIBH radiation therapy both show low-dose exposure of the heart. As expected, hypofractionation leads to sparing of the heart dose. Although MCBT plans were not optimized regarding dose to the heart, Dmean differed significantly between MCBT and DIBH (1.28 Gy vs. 1.91 Gy, p < 0.001) in favor of MCBT, even if the Dmean in each group was very low. In MCBT radiation, the PTV–heart distance is significantly associated with the dose to the heart (p < 0.001), but it is not in DIBH radiotherapy using SIB.ConclusionIn daily practice, both DIBH radiation therapy as well as MCBT show a very low heart exposure and may thus reduce long term cardiac morbidity as compared to currently available long-term clinical data of patients treated with conventional tangential field plans in free breathing. Our analysis confirms particularly good cardiac sparing with MCBT-APBI, so that this technique should be offered to patients with left-sided breast cancer if the tumor-associated eligibility criteria are fulfilled.