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Background: Inflammatory breast cancer (IBC) is associated with a poor prognosis. While many stage III IBC patients (pts) experience a sufficient response to first-line (1L) neoadjuvant chemotherapy (NAC) to permit subsequent surgical therapy, the prognostic significance of requiring additional NAC to enable resectability is unknown. We sought to describe the pathologic complete response (pCR) rates, breast cancer-free survival (BCFS) and overall survival (OS) among pts requiring 1 vs >1 lines of NAC prior to surgery. Methods: Upon IRB approval, pts with stage III IBC from 2 academic institutions (Dana-Farber Cancer Institute and MD Anderson Cancer Center) who received 1L or 2-3 lines (2-3L) of NAC prior to surgery were identified. Standard NAC regimens containing different drugs, such as AC-T or TCHP, were considered as 1L. Pts with locoregional progression or metastatic disease prior to surgery were excluded. Hormone receptor (HR), HER2 status, grade, and pCR, defined as no residual invasive cancer in the breast and the axilla, were evaluated. BCFS, defined as time from surgery to locoregional and/or distant recurrence, and OS, defined as time from surgery to death, were evaluated by the Kaplan-Meier method. Multivariable Cox models stratified by institution and containing the covariates pCR and tumor subtype were utilized to estimate the HR of 2-3L vs. 1L of therapy. Results: 808 eligible pts diagnosed between 1997 and 2020 were identified. 733 (91%) had 1L and 75 (9%) had 2-3L of NAC, and the median age was 50 years. 295 (37%) had HER2+, 282 (35%) HR+HER2-, 211 (26%) had HR-HER2- disease and for 20 (2%) pts, the receptor status was unknown. The median time from diagnosis to surgery was 6 months. Grade III disease, triple-negative and HER2-positive disease were more prevalent in pts receiving 2-3L of therapy (table). pCR was achieved in 178 (24%) pts receiving 1L of NAC, and in 14 (19%) pts receiving 2-3L of NAC. At 68 months of median follow-up, 417 (52%) pts experienced a recurrence with 376 in the 1L group and 41 in the 2-3L group. The 5-year BCFS was shorter for the 2-3L group compared to the 1L group (33% v 46%, HR=1.37; 95% CI:0.99-1.91). However, in 192 pts with a pCR, BCFS was similar, regardless of the number of NAC lines. There were 38 recurrences among 178 1L pts, and 3 recurrences among 14 2-3L pts, resulting in BCFS of 76% and 83% in 1L and 2-3L pts, respectively. Overall, there were 308 deaths, 276 deaths among 1L pts and 32 among 2-3L pts. The 5-yr OS estimate in 1L versus 2-3L pts was 60% versus 53% (HR=1.32, 95% CI: 0.91-1.93). Conclusion: Among pts with stage III IBC, pCR was observed among 24% who had 1L and 19% of pts who required 2-3L of NAC. BCFS and OS were comparable among pts with pCR after 1L and 2-3L. Our results suggest the need to continue to optimize current treatment strategies in IBC to improve pCR rates across all disease subtypes regardless of the number of lines of NAC required. Citation Format: Faina Nakhlis, Samuel Niman, Naoto T. Ueno, Elizabeth Troll, Sean Ryan, Eren Yeh, Laura Warren, Jennifer Bellon, Beth Harrison, Toshiaki Iwase, H. T. Carisa Le-Petross, Sadia Saleem, Mediget Teshome, Gary J. Whitman, Wendy Woodward, Beth Overmoyer, Sara Tolaney, Meredith Regan, Filipa Lynce, Rachel M. Layman. Long-term Outcomes After 1 or 2-3 Lines of Neoadjuvant Therapy in Stage III Inflammatory 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 P4-07-14.

Background: Breast conserving surgery (BCS) is typically followed by adjuvant radiotherapy (RT) based on several landmark trials demonstrating improvements in disease control and survival. Since completion of these historical trials, the advent of molecular subtyping has revealed that breast cancer is not a single disease entity, but rather a class of cancers with differential risk profiles. We evaluated whether RT could be safely omitted following BCS for patients with the most favorable subtype as defined by the Prosigna PAM50 assay. Methods: We conducted a multicenter prospective single-arm cohort study with IRB approval and an FDA investigational device exemption (IDE). Eligible patients were women 50 to 75 years of age (inclusive) who had undergone BCS revealing tumors ≤2cm in size, that were estrogen or progesterone receptor positive (HR+), HER2 negative, grade 1-2, node negative (N0), with negative excision margins (no ink on tumor). Intent to take endocrine therapy was required. Upon registration, tumors were submitted for central Prosigna testing and those with Risk of Recurrence (ROR) score ≤40 were deemed eligible for the investigational omission of RT. The primary endpoint was the 5-year locoregional recurrence rate (LRR). Anticipating a total of 345 RT-omitting patients to enroll over 3.5 years, the study was designed with 90% power to exclude a 5-year LRR of 5% using a one-sample exponential test with one-sided type I error of 0.025. Results: From 2016 to 2020, 671 patients were registered from 13 centers, inclusive of affiliated regional network sites. Of these, 382 patients had a ROR Score ≤40 and opted to forego RT, comprising the main intention-to-treat (ITT) study population. Median age was 65 years (range 50 to 75), and median tumor size was 0.9 cm (range 0.1 to 2.0 cm). At a median follow-up of 26.9 months, 12 events were observed: 4 patients had ipsilateral in-breast recurrences, 7 had contralateral breast cancers, and 1 developed an unrelated melanoma. There were no regional-nodal or distant recurrences. The 2-year cumulative rate of LRR was 0.3% (95% CI: 0 – 1.0%). Of the 4 ipsilateral breast recurrences, 2 were in the same quadrant as the original primary tumor. Conclusion: In this preliminary report of the PRECISION trial, patients 50-75 years of age undergoing BCS and endocrine therapy for pT1N0 HR+ HER2-negative breast cancer with ROR score ≤40 had exceedingly low rates of LRR in the absence of adjuvant RT at a median follow-up of 26.9 months. Additional follow-up is required to determine whether these favorable results are durable. Citation Format: Lior Z. Braunstein, Julia Wong, Deborah A. Dillon, Yu-Hui Chen, Paul Catalano, Oren Cahlon, Mahmoud B. El-Tamer, Rachel Jimenez, Atif Khan, Carmen Perez, Rinaa Punglia, Ron Shiloh, Laura Warren, David Wazer, Jean Wright, Elizabeth Buckley, Tari King, Simon Powell, Eric Winer, Jennifer Bellon. Preliminary report of the PRECISION Trial (Profiling Early Breast Cancer for Radiotherapy Omission): A Phase II Study of Breast-Conserving Surgery Without Adjuvant Radiotherapy for Favorable-Risk 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 OT1-12-02.

Background: Inflammatory breast cancer (IBC) is unresectable at presentation, thus neoadjuvant systemic therapy (NAS) is the primary treatment for this aggressive disease. Eribulin (E) (Eisai Co., Ltd) is a synthetic analog of Halichondroin B that suppresses microtubule growth. Its properties of inducing a mesenchymal-to-epithelial transition and normalizing the vasculature of mammary tumors are particularly relevant to IBC. Pre-clinical data revealed changes in dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) parameters after exposure to E, thought to reflect tumor vasculature remodeling. We sought to examine the efficacy of E-containing NAS specifically for patients (pts) with HER2- IBC. We also characterized changes in breast DCE-MRI and diffusion weighted MRI (DWI) between baseline and 1 week (wk) after NAS. Methods: Pts with newly diagnosed HER2- IBC received 4 cycles of E 1.4 mg/m2 day (D)1, D8 every 21 D followed by 4 cycles of dose-dense (dd) doxorubicin (A) 60 mg/m2 + cyclophosphamide (C) 600mg/m2 every 2 wk followed by modified radical mastectomy (MRM) + postmastectomy radiation (PMRT) on a phase II prospective study (Cohort A). Primary endpoint was pathologic complete response (pCR) defined as no invasive disease in breast + axillary lymph nodes. Based on a Simon 2-stage design, if ≥ 2 of 16 pts had pCR then enrollment would continue to 25, with the regimen worthy of study if pCR ≥ 0.30 and not if pCR ≤ 0.10 (α=0.10, β=0.10). A second cohort was opened, changing the NAS sequence to ddAC followed by E (Cohort B). All pts had 2 research breast biopsies (rbx) for genomic analysis at baseline and 1 wk after first dose of NAS. An imaging study evaluated breast DCE-MRI and DWI at baseline and 1 wk after first dose of NAS. Tofts 2-compartment pharmacokinetic (PK) model calculated Ktrans, Ve, Kep, and iAUC from DCE. ADC was calculated from DWI. The change in Ktrans, Ve, Kep, iAUC, and ADC between baseline and wk 1 was evaluated using a signed-rank test. The magnitude of these changes was compared between Cohort A and Cohort B using a Wilcoxon rank-sum test. All testing was two-tailed and exact p-values were used; p-value < 0.05 were considered statistically significant. Results: 22 pts were enrolled, 16 pts in Cohort A and 6 pts in Cohort B before the study was closed due to slow accrual. Median age was 58 years, 3 pts (13.6%) had triple negative disease. 13 pts (59%) were postmenopausal. All but 1 had stage III disease. All 22 pts completed NAS followed by MRM + PMRT. 19 pts completed full course of NAS, 1 pt received E followed by 3 cycles of AC and 2 pts received 3 cycles of E in addition to 4 cycles of AC. In Cohort A, 1/16 pts had pCR (6.3%; 80% CI 0,22.2%). At a median follow up of 51 months, 3 pts had distant disease recurrence with 1 death; no local-regional recurrence. 7 pts experienced grade (gd) 3 or 4 adverse event (AE); most common were neutropenia and aminotransferase increase. 10 pts participated in the DCE-MRI and DWI substudy: 5 from Cohort A, 5 from Cohort B. Decrease in value from baseline to wk 1 was detected in Ktrans (median -49), Ve (-128), and iAUC (-57). The magnitude of changes was not different when comparing Cohort A to Cohort B. There was no significant change in Kep or ADC. Given the small size of each group, a lack of statistical significance should not be interpreted as suggestive of no effect. Evaluation of changes in angiogenesis- and EMT-related gene expression in rbx + residual disease is ongoing.Conclusion: A regimen of E + ddAC is tolerable NAS for HER2- IBC. All pts underwent curative surgery despite low pCR rate, commonly observed in ER+ IBC. There were changes in some DCE-MRI parameters after exposure to chemotherapy but may not be specific to E. Studies specifically designed for IBC are needed to enhance the understanding of this disease. Clinical trial: NCT02623972 Citation Format: Filipa Lynce, Eren D. Yeh, Meredith M. Regan, Lei Qin, Camden P. Bay, Ian Krop, Beth T Harrison, Faina Nakhlis, Jennifer Bellon, Beth Overmoyer. A phase 2 study of neoadjuvant systemic therapy with eribulin followed by doxorubicin and cyclophosphamide for HER2-negative inflammatory breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-12-18.

Background: Radiation therapy (RT) following breast conserving surgery (BCS) is known to improve locoregional and distant control in women with invasive breast cancer; however, RT does pose significant cost and potential risk, including concern for cardiopulmonary toxicity and secondary malignancy. Randomized trials show that the omission of RT among older women with otherwise favorable-risk breast cancer does not affect overall survival (OS) at 10 years, and modestly increases the risk of local recurrence (LR). Nevertheless, there is little prospective support for RT omission in younger women. Moreover, risk stratification in the randomized prospective studies to date relies on limited methods with potentially low fidelity at distinguishing luminal subtypes. Enhanced molecular profiling techniques could better discern tumor biology and, in turn, more precisely assess risk. PAM-50 is an expression profile of 50 genes used to classify breast cancer intrinsic subtype with consequent prognostic implications. The goal of this study is to identify low-risk breast cancer patients with luminal A subtype who may feasibly omit RT from their therapeutic regimen. Methods: This is a phase II prospective cohort study (NCT02653755) designed to assess the safety of treatment de-escalation (omission of RT) in women with favorable-risk invasive breast cancer following BCS. Eligibility criteria include female patients with invasive breast cancer, age 50-75, with tumors less than or equal to 2cm, negative surgical margins, ER+ or PR+ and HER2- disease, grade 1 or 2, no lymph node involvement, and no plans for chemotherapy or biologic therapy, who are eligible for and willing to receive endocrine therapy. Tumor samples from eligible patients will undergo PAM-50 transcriptional profiling using the Nanostring Prosigna assay. A low Risk of Recurrence (ROR) score, corresponding to the luminal A subtype, will permit patients to forego radiotherapy should they so choose. The primary endpoint is 5-year risk of local or regional recurrence of invasive or in situ breast carcinoma within the ipsilateral breast or regional lymph nodes. Study enrollment began in May 2016. Citation Format: Mira A. Patel, Deborah A. Dillon, Giulia Digiovanni, Yu-Hui Chen, Paul Catalano, Carmen Perez, David Wazer, Jean Wright, Rachel Jimenez, Eric Winer, Julia Wong, Jennifer Bellon, Lior Z. Braunstein. PRECISION (Profiling early breast cancer for radiotherapy omission): A phase II study of breast-conserving surgery without adjuvant radiotherapy for favorable-risk breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT271.

Background: Radiation therapy (RT) following breast conserving surgery (BCS) is well-known to improve outcomes for invasive breast cancer. However, RT can be resource-intensive, disruptive, and confers a small risk of long-term adverse effects. In addition, reports have suggested that not all patients stand to benefit equally from RT, with certain features portending an excellent prognosis regardless of the adjuvant treatment approach. Specifically, favorable luminal A cancers exhibit a 10-year locoregional recurrence (LRR) rate of 2% following BCS and RT. However, distinguishing luminal A cancers from their less-favorable luminal B counterparts remains a challenge. This trial employs molecular profiling to identify favorable-risk, early-stage breast cancer patients who may safely omit RT following BCS. Methods: To identify a low-risk, luminal A cohort, we are employing well-characterized clinicopathologic parameters in addition to molecular profiling. Eligible patients are 50-75 years of age and must have invasive breast cancer ≤2 cm (T1), that is estrogen or progesterone receptor positive, low- or intermediate-grade, without HER2 amplification, and with negative margins (no ink on tumor) following BCS. Following resection, tumor samples undergo prediction analysis of microarray 50 (PAM50) profiling via the NanoString Prosigna assay to characterize intrinsic biologic subtype. Patients with tumors classified as luminal A (low risk of recurrence score) are eligible for the omission of RT. The trial is a single-arm prospective cohort study designed to assess the viability of RT omission in this favorable population. The primary endpoint is LRR at 5 years; a rate of Results: PRECISION opened to accrual in April 2016 and, as of October 2017 has registered 57 patients to undergo molecular risk profiling. Of these, 2 (3.5%) withdrew consent prior to receiving their PAM50 results and 11 (19.3%) were ineligible based on their risk-of-recurrence score, leaving 43 patients eligible for the omission of RT. Of these, 4 (7.0%) ultimately chose to undergo RT, while 39 (68.4%) opted to omit RT on the investigational arm of the study. Conclusions: The omission of RT is of interest to low-risk breast cancer patients. The safety and feasibility of this approach is currently being studied. Citation Format: Lior Zvi Braunstein, Ashley Iannone, Alphonse G. Taghian, Julia Wong, Jennifer Bellon, Jay R. Harris. PRECISION (Profiling Early Breast Cancer for radiotherapy Omission): An ongoing phase II study of breast-conserving surgery without adjuvant radiotherapy for favorable-risk breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3692.

Axillary node dissection (ALND) is the standard of care for patients who have a positive sentinel lymph node (SLN) on sentinel lymph node biopsy (SLNB). We sought to identify a low-risk patient population with positive SLN that may not need cALND. We analyzed SLNB for breast cancer at our institutions between 1999 and 2007. We identified 130 patients who had a positive SLN but did not undergo completion ALND. We evaluated clinical data, adjuvant treatment patterns and intermediate locoregional and distant events. The median patient age was 50; 19% had N0(i+) disease, 53% had micrometastatic (N1mi) disease, and 28% had macrometastasis. Eighty-eight percent of patients underwent radiation therapy; 66 patients (51%) had documented nodal radiation (of these 50 were treated with three fields and 14 with high tangents. Local recurrence in the breast occurred in two patients (2%) and nine patients (7%) developed distant metastases; there were no axillary/nodal recurrences. In this highly selected group of patients who had a positive SLNB but did not undergo cALND, we observed no axillary recurrences.

When we think of Saccharomyces cerevisiae, fermentation immediately comes to mind, but this is not the only trait that makes this yeast the organism of choice for bread, beer and wine production. The winemaking industry, for example, requires robust strains, capable of converting sugar to ethanol in challenging conditions; high osmotic stress and low pH in the initial grape must, followed by high ethanol concentration at the later stages of fermentation. Winemakers also look for ways of using fermentation to introduce aroma and flavour diversity to their wines as a means of improving style and for product differentiation. Choice of wine yeast from the plethora of strains available to winemakers is one way of achieving this, particularly with the new breed of interspecific hybrid yeast strains currently being generated.