Purpose/Objective(s): To analyze 66 patients with inoperable breast cancer who failed  to neoadjuvant chemotherapy and were rescued with radiotherapy prior to surgery.Materials/Methods: From a total  of  10.199  registered  breast cancer  patients,  3.365  new  cases  of  advanced  disease  were  treated  and  their  charts  revised. 1.641  patients  received neoadjuvant  chemotherapy (NeoCh) and  229  failed  it.  In  66  cases,  they received neoadjuvant  radiotherapy (NeoRT).  Endpoints  were  resectability  and  response  rate. Chi-square test was used  for comparison among groups. NeoRT was delivered in a conventional course of 50 Gy @ 25 fractions or 40 Gy @ 16 fractions to breast, supraclavicular fossae and  axila,  with  tangential  and  non-pair irregular  opposed  fields,  and  6  MV photons energy. If inoperable, they received a 10 Gy boost on the breast area. Surgery was intended to be done four weeks after RT.Results: From a total of 66 patients analyzed, the median age was 55 years, and 97% of patients were  staged  as IIIB.  Invasive ductal carcinoma was the most frequent hystopathological diagnose. Regarding NeoCh, 43 (65.15%) received FAC; 16 (24.2%)  FAC  plus  Docetaxel  and  6  (10%)  CMF.  Tamoxifen  was  used  in  8 (12%) cases. After  NeoCh,  34  (52%)  showed  stable  disease  (SD);  24 (36%), progression disease (PD) and 8 (12%), partial response (PR). After NeoRT, 33 (50%) showed SD; 24 (36%), PR and 4 (6%) had clinical complete response (CR). 5 cases (8%) showed PD. 32 patients  (48.5%)  were  eligible  to  mastectomy. In  pathological  study,  4 (12,5%)  had  pathological  CR  and  20  (61%)  showed  PR,  with a response rate of 73,5% and median volume of surgical specimen of 2,68 cm3. Axillary  dissection  was  performed  in  all  patients,  and  the  mean  number excised and positive nodes were respectively 11 (5-22) and 2 (0-18). In the  hypofractionated  group (13 cases), 4 (31%) patients  were considered operable. In the  conventional  group  (49 cases), 28 (57%) had their tumor respected. 4 patients received an additional whole breast boost of  10 Gy @ 5  fractions . Median time  of  RT was,  respectively,  26 and 37 days in the hypofractionated and in the conventional group (including boosted  patients).  Patients  who  remained  inoperable  after  RT, showed 91% of distant metastasis. With a median  follow  up  of  84 months, 7 operated  patients  (21.8%) are alive without evidence of disease and no patients at the inoperable group; last follow-up: Dec/2014. Regarding  operated  and  non-operated  patients, 3 years OS, were respectively 75% and 50% (p Conclusion: NeoRT in  patients  with  poor  response  to NeoCh, who  remained  inoperable, is a feasible treatment approach.  It has allowed almost half of them to become eligible to surgery, with significant benefit on OS when compared to those that remained inoperable. Although,  further studies should  be  done  before  this  protocol  becomes  standard of  are for advanced breast cancer patients.

Purpose/Objective(s): The expected local recurrence rate in 5 year follow-up after breast conserving therapy and whole breast irradiation is 7,6%. Adding a boost of the index region results in a reduced recurrence rate of 4,3%. The boost irradiation as an intraoperative procedure showed a further decrease of local recurrence rates down to 1,75% . We adapted this approach to patients after neoadjuvant chemotherapy (NACT) and are reporting the DFS after a median of 4 years of follow up. To our knowledge this is the first time that data concerning intraoperative radiotherapy with a 50 kV X-ray source after neoadjuvant chemotherapy are presented.Materials/Methods: Between April 2010 and November 2011 we treated 61 patients after NACT (+/- Trastuzumab according to HER2-status) with an intraoperative boost of 20 Gy with a 50 kV X-ray source followed by an external radiation with 50 Gy. The patient characteristics were as follows and represent the high risk cohort typical for a cohort of patients treated with NACT: median age 54,9 years, 24 pts premenopausal / 37 pts postmenopausal, 31 pts G2 / 30 pts G3, 39 pts ER positive / 22 pts ER negative, 29 pts PR positive / 32 pts PR negative, 24 pts HER2 positive / 37 pts HER2 negative, 36 pts T1 / 24 pts T2 / 1 pt T3, 28 pts node negative / 33 pts node positive. 19 patients reached a pCR. 17 patients needed more than one operation. No patient was lost to follow up and at the time of data closure the median follow up was 49,56 months.Results: At a median follow up of 49,55 months the DFS was 86,89%, the DDFS 93,44%. 18 of the 19 patients were disease free in the group of patients who reached a pCR (DFS 94,74%). In the group of 42 patients who had residual tumor after NACT, 35 were disease free (DFS 83,33%).Conclusion: A DFS of 86,89% compares favorably to the DFS expected for patients after NACT. The higher DFS in the pCR-group was expected due to the fact that a pCR after NACT +/- Trastuzumab is predictive for DFS. Still the DFS in the non pCR-group compares favorably to the known data for patients not reaching a pCR. Our data are the first on IORT as a boost after neoadjuvant chemotherapy and show a favorable outcome of the patients in this high risk group. They strongly encourage the design of prospective trials in this indication.

Purpose/Objective(s): Breast conserving therapy has become the standard option for patients with early stage breast cancer. Still, there are some patients in need for mastectomy due to multicentric disease or diffuse microcalcifications. If mastectomy is to be performed, keeping the nipple areola complex (NAC) is still controversial. Studies have shown that preservation of the NAC provided higher patient’s satisfaction and less psychological impact after mastectomy. Previous studies have used nipple sparing approach using intraoperative radiation (RT) to the NAC. This study is to report preliminary data of a prospective phase I trial using nipple sparing mastectomy with immediate reconstruction, followed by prophylactic NAC RT at weeks 5 to 8 postoperative.Materials/Methods: From 2009 to 2014, 10 patients with 11 breast cancers primary (one patient had bilateral disease) were enrolled in the study.  The first 6 patients were treated to the NAC using 25 Gy in 10 fractions, BID, 6 hours apart, over 5 consecutive days, using electrons (dose level II; dose escalation/de-escalation design). The next 3 patients received dose level III, 30 Gy in 10 fractions, using same regimen. Radiation was delivered 5 to 8 weeks postoperative. Patient’s cosmesis was assessed by the patient and physicians during 1, 3, 6, and 12 months after completion of protocol therapy. Patient’s satisfaction was also evaluated at same interval.Results: Nine out of ten patients were able to complete treatment per protocol. At the last follow up, patient’s evaluation of cosmesis was excellent in 78% (7/9), good in 11% (1/9), and poor in 11% (1/9). Overall patient satisfaction with nipple sparing protocol was Good/Excellent in all patients during the time interval of evaluations. Physician’s evaluation of NAC cosmesis was excellent in 34% (3/9), good 66% (6/9). In regard toxicity, only one patient developed grade 3 infection and loss of NAC postoperative; this patient did not receive NAC RT. Of the 9 evaluable patients in the protocol, there was no NAC loss or need for treatment interruption. There was no grade 4, 5 toxicity in patients treated with NAC RT. The most common toxicity was acute radiation dermatitis and NAC pain, mostly grade 2, which completely resolved in subsequent follow up.Conclusion: The preliminary results of this nipple sparing protocol for early stage breast cancer showed a high level of patient’s satisfaction and self-reported good/excellent cosmesis in the majority of patients treated. Toxicity appeared to be acceptable so far, mostly related to acute radiation dermatitis, grade 2. There was no NAC loss with the use of prophylactic NAC RT. Final results will be presented at completion of the trial.

Purpose/Objective(s): VMAT has been reported to offer improved dosimetric sparing of the ipsilateral lung, total lung and heart compared to 3D conformal planning while covering IMNs. However OARs in the supraclavicular region often receive higher doses compared to 3D conformal planning. We aim to compare VMAT versus a combination of 3D and VMAT to improve sparing of OARs in this region without compromising target coverage or the dosimetric advantage that is already offered on using VMAT alone.Materials/Methods: 10 patients previously treated with VMAT at our institution were re-planned with 3D conformal planning in the supraclavicular region and VMAT inferiorly to the chestwall. VMAT planning consisted of 2 complementary arcs within a 230° arc range with 6 MV. The supraclavicular region was planned either with a single off-cord AP field or with off-cord AP/PA and field in field employing 6 MV and/or 16 MV depending on the depth of nodal coverage. Coverage criteria were PTV D95 = 50 Gy, V95 = 98% and PTV D05 = 115%. Doses to the esophagus, trachea, larynx, brachial plexus, thyroid and cord were noted in addition to the heart, lungs and contralateral breast.Results: Combining 3D with VMAT significantly reduced the maximum dose to the esophagus, trachea and spinal cord by 15 Gy, 11 Gy and 12 Gy and also significantly reduced mean dose to the thyroid, larynx and trachea by 15 Gy, 12 Gy and 18 Gy respectively (Table 1). No significant differences were seen in the mean dose to the heart, ipsilateral lung, total lung and contralateral breast or in the maximum dose to the brachial plexus. A statistically significant increase in the V20 Gy to the ipsilateral lung and total lung was observed but was = 2%.Conclusion: 3D conformal planning in the supraclavicular region while restricting VMAT to the chestwall helps reduce dose to additional OARs without compromising doses to the heart, lungs and contralateral breast when VMAT alone is used. OARVMAT3D + VMAT   Esophagus Max (Gy)45.65*    (SE 2.32)30.8*  (SE 4.54) Esophagus Mean (Gy) 9.16*    (SE 0.64) 6.54*  (SE 0.54)Trachea Max (Gy)43.97*    (SE 1.51)33.24*  (SE 5.44) Trachea Mean (Gy)26.53*    (SE 1.65)8.52*  (SE 1.38)Cord Max (Gy)28.25*      (SE 1.64)15.93*   (SE 3.46) Thyroid Mean (Gy)29.61*    (SE 2.91)14.36*  (SE 3.25)Larynx Mean (Gy)14.24*     (SE 2.15)2.26*  (SE 0.64) Brachial Plexus Max (Gy)56.03    (SE 1.2)55.95  (SE 1.83)Heart Mean (Gy)5.54    (SE 0.71)5.49  (SE 0.7) Ipsilateral Lung Mean (Gy)15.31    (SE 0.27)16.01  (SE 0.24)Ipsilateral Lung V20Gy (%)24.69*      (SE 0.72)26.85*    (SE 0.62) Total Lung Mean (Gy)9.78    (SE 0.24)9.97  (SE 0.23)Total Lung V20Gy (%)13.04*      (SE 0.61)14.06*    (SE 0.49) Contralateral Lung Mean (Gy)3.6*    (SE 0.37)3.23*  (SE 0.32)Contralateral Breast Mean (Gy)4.13      (SE 0.2)4.05      (SE 0.23)SE= standard error*p <0.05

Purpose/Objective(s): This retrospective study explores the impact of SBRT as an aggressive local treatment on the disease evolution and survival of patients with oligometastatic breast cancer treated for lung and liver metastases.Materials/Methods: 24 lung lesions in 11 patients and 39 liver lesions in 24 patients (total of 63 lesions) were irradiated using SBRT between Feb.’07-Nov.‘14. All 35 patients treated (KPS =70) were oligometastatic which according to our criteria implied the presence of = 5 in lung- or in liver-only metastases, or = 3 if presented in > 1 site. 7 patients (20%) were with single metastases while 28 (80%) with multiple. 11 patients were irradiated for lung lesions while 24 for liver lesions. Histology was ductal ADK in 81% of patients, lobular in 10%, mixed in 2% and other histologies or no data in 7%. The median diameter of the lung lesions was 1 cm (range 0.5-5) and of the liver metastases 3.5 cm (range 1-9.1). Planning Target Volume was created by adding a 3 mm margin to the Gross Tumor Volume. SBRT was delivered with VMAT by 6 MV LINAC and planned by TPS with Montecarlo algorithm. All lesions were treated in Breath-hold with different dose levels depending on tumor site and size. Almost all lung lesions (83.3%) were irradiated with 26 Gy in a single fraction prescribed to the 70% isodose (BED10 to isocenter = 175). Liver lesions were treated mainly (72%) with 37.5 Gy in 3 fractions prescribed to the 67% isodose (BED10 to isocenter = 161). Set-up and isocenter were assessed by CBCT. All patients treated for liver lesions underwent Gold fiducials insertion 1 week before CT simulation. The response was evaluated after 60 days by CT and PET, and every 3 months subsequently. Toxicity was assessed by CTCAE score.Results: Considering all treated lesions, both lung and liver, only 5 (7.9%) “in field” recurrences were observed, all occurred in liver during the first year from SBRT so the local control rate at 1 year was 92.1%; Dividing irradiated lesions by anatomic site 1 year local control rate for lung lesions was 100% while for liver-group 87.2%. At 1 and 2 years Overall Survival (OS) rates were 86% and 69% (91% and 70% in lung-group vs. 83% and 50% in liver-group), and Progression Free Survival rates were 37% and 20%, respectively (median F.U. 19.9 months, range 2,2-60). No predictive factors of local failure were found. No toxicity > G2 (4 patients) was recorded.Conclusion: SBRT for Lung and Liver metastases in Breast oligometastatic patients is a safe and well tolerated treatment. High local control rate (only 5 recurrences in field) confirms the ablative role of SBRT using high BED doses (> 100). The low number of relapses does not allow statistical analysis on predictive factors of local failure but high local control rate in the subset of patients with primary breast cancer indicates an trend for better local control respect to other primitive tumors (92.1% at 1 year that appears stable over the time).

Purpose/Objective(s): A new concept of “oligo-recurrence (OR)” indicates one to several distant metastases/recurrences in one or several organs which can be treated with local therapy, while the primary site of the cancer was once controlled. A previous study demonstrated that first failure detected as the state of OR (e.g. isolated loco-regional recurrence (LRR) or isolated pulmonary metastasis) could be salvaged by local therapy. However, a subset of once salvaged patients with OR could have a second failure which is also detected as the state of OR. We have often experienced this situation in patients with breast cancer and have defined that as “2nd OR.” The purpose of this study was to assess the efficacy and toxicity of salvage radiotherapy (RT) for the 2nd OR of breast cancer.Materials/Methods: All the 23 patients satisfied the following requirements of our definition for 2nd OR: (i) disease-free status after initial therapy for clinically localized breast cancer had been once confirmed; (ii) first failure was detected as OR (1st OR), and disease control of the 1st OR after salvage local therapy was confirmed, while simultaneously there were no other distant metastases/recurrences; (iii) second failure was also detected as OR (2nd OR) which was treated with salvage RT. The sites of the 2nd OR were LRR in 9 patients and distant metastasis in 14 patients. The total radiation dose of the salvage RT ranged from 40–76 Gy (median, 60 Gy), the daily dose was 2.0–3.0 Gy (median, 2.0 Gy). Efficacy and toxicity of the salvage RT for the 2nd OR were retrospectively evaluated, and the predictors of a long-term survival were analyzed.Results: Twenty-one (91%) patients had an objective response. The median overall survival and progression-free survival times were 40 and 20 months after salvage RT for the 2nd OR, respectively. The three-year local (in-field) control rates were 84%. The toxicities were mild; acute toxicities = Grade 3 were seen in one patient with Grade 3 dermatitis, and no late toxicity = Grade 2 was observed, except for one patient who had a Grade 3 lymphatic edema of the arm. The first sites of disease progression after the salvage RT for the 2nd OR were out-field alone in 11 patients (48%) and both in-field and out-field in 4 patients (17%); none of the patients had first sites in local (in-field) alone. The univariate analyses indicated that age (Conclusion: Salvage RT for the 2nd OR was able to achieve a better local control rate and longer progression-free survival time without inducing severe toxicity, and therefore may be a potentially effective modality for inducing long-term survival in select patients.

Purpose/Objective(s): The Clinical Evaluation of Pertuzumab and Trastuzumab (CLEOPATRA) study showed a benefit in overall survival with the addition of pertuzumab (P) to docetaxel (T) and trastuzumab (H) (THP) compared to TH as first-line treatment for patients with HER2-positive metastatic breast cancer. With median follow-up of 50 months, median overall survival for the THP and TH groups were 56.5 and 40.8 months, respectively [Swain, NEJM 2015]. Based on these results, we performed a cost-effectiveness analysis to determine the impact of pertuzumab on the treatment of HER2-positive metastatic breast cancer.Materials/Methods: Cost-effectiveness was evaluated from a societal perspective. A four-state Markov model was constructed to evaluate the cost-effectiveness of TH with or without P. Health states included: stable disease, progression of disease, hospice, and death. The model was run over 10 years with cycle length of 1 week. Transition probabilities were based on the results of the CLEOPATRA study. Costs were based upon 2014 Medicare reimbursement rates and manufacturers’ Average Sales Price. Interventions were evaluated with a willingness-to-pay threshold (WTP) of $100,000 per quality-adjusted life years (QALY) gained. One-way and multi-way sensitivity analyses were performed to explore the effects of specific assumptions.Results: Our modeled overall survival and progression-free survival intervals compared well with the results of the CLEOPATRA study. Modeled median survival was 171 weeks (39.5 months) and 253 weeks (58.3 months) for TH and THP group, respectively. The addition of P resulted in an additional 0.73 QALY at an increased cost of $426,039 compared with TH, resulting in an incremental cost-effectiveness ratio (ICER) of $582,141 per QALY. Two-way sensitivity analysis showed that in the scenario where baseline costs (including cost of trastuzumab) were half of predicted, THP would not become cost-effective until discounted by 96% of the current Medicare Average Sales Price.Conclusion: The addition of pertuzumab to docetaxel and trastuzumab in metastatic HER2(+) breast is unlikely to be cost-effective at a WTP threshold of $100,000 per QALY gained. This finding is attributed to 1) the expense of pertuzumab, and 2) that patients treated with pertuzumab have prolonged progression-free survival, and, therefore, accrue higher costs for prolonged treatment with both pertuzumab and trastuzumab. Additional results from the adjuvant trials of pertuzumab will be important to characterize the overall cost-benefit of this agent in both metastatic and early stage HER2-positive breast cancer.