Treatment Of Early-stage Breast Cancer Research Articles

Selecting postoperative adjuvant systemic therapy for early-stage breast cancer: An updated assessment and systematic review of leading commercially available gene expression assays.

Gene expression assays (GEAs) can guide treatment for early-stage breast cancer. Several large prospective randomized clinical trials, and numerous additional studies, now provide new information for selecting an appropriate GEA. This systematic review builds upon prior reviews, with a focus on five widely commercialized GEAs (Breast Cancer Index®, EndoPredict®, MammaPrint®, Oncotype DX®, and Prosigna®). The comprehensive dataset available provides a contemporary opportunity to assess each GEA's utility as a prognosticator and/or predictor of adjuvant therapy benefit.

Pooled analysis of NeoCARH and NeoCART trials: patient-reported outcomes in patients with early-stage breast cancer receiving platinum-based or anthracycline-based neoadjuvant chemotherapy.

Anthracycline-based or platinum-based neoadjuvant chemotherapy belongs to the standard treatment for early-stage breast cancer (EBC) that is either triple-negative or human epidermal growth factor receptor 2 positive (HER2 +). Currently, there is a paucity of data comparing their impact on health-related quality of life (HRQoL). Triple-negative or HER2 + EBC from our two prospective randomized controlled trials, neoCARH and neoCART, were divided into two groups based on the neoadjuvant chemotherapy regimens they received: anthracycline-based or platinum-based group. HRQoL was the exploratory endpoint in these two trials, which was assessed using the European Organization for Research and Treatment of Cancer Quality of Life-Core30 and Breast23 questionnaires. The primary variable of interest was the C30 summary score (C30-SumSc). Assessments were carried out at baseline, after neoadjuvant chemotherapy, and 1year and 2years after diagnosis. The mean questionnaires' compliance rate was 95.0%. After neoadjuvant chemotherapy, 210 patients had evaluable HRQoL data, the mean least square change from baseline for the platinum-based group was - 15.997 (95% confidence interval (CI): - 17.877 to - 14.117), and it was - 20.156 (95% CI: - 22.053 to - 18.258) for the anthracycline-based group (difference: 4.159, 95% CI: 1.462 to 6.855, P = 0.003, minimal important difference = 3). For the majority of the domains of interest assessed by the C30 and BR23 questionnaires, the platinum-based group demonstrated superior outcomes in comparison to the anthracycline-based group. Patients receiving platinum-based or anthracycline-based regimens both experienced worsened HRQoL after neoadjuvant chemotherapy; however, the former provided relatively better HRQoL compared with the latter. ClinicalTrials.gov: NCT03140553. Registered 4 May 2017 (neoCARH). NCT03154749. Registered 16 May 2017 (neoCART).

Abstract PO3-18-03: Preoperative single-dose camrelizumab and/or microwave ablation in women with early-stage breast cancer: A randomized window-of-opportunity trial

Abstract Immune checkpoint blockade (ICB) has shown low response rates for advanced breast cancer, and combinatorial strategies are needed to improve the effect of ICB. As an effective local therapy, microwave ablation (MWA) may be a trigger of antitumor immunity. This window-of-opportunity trial was conducted to determine the safety and feasibility of camrelizumab (anti-PD-1 antibody) combined with MWA in the treatment of early-stage breast cancer preoperatively. The peripheral immune response was also investigated. 60 participants were randomized to receive single-dose camrelizumab alone (n=20), microwave ablation (n=20), or both camrelizumab and microwave ablation (n=20), preoperatively. Camrelizumab and MWA were well tolerated alone and in combination. Different from that in single-dose camrelizumab or MWA group, participants showed stable quantity of blood cells after the combination therapy. After the combination therapy, peripheral CD8+T cells showed enhanced cytotoxic and effect-memory functions. Clonal expansional CD8+T cells showed different functions from emergent clones after the combination therapy, suggesting that the expansional clones may play a vital role in the enhanced biological functions of CD8+T cells. Enhanced interactions between clonal expansional CD8+T cells and monocytes was observed, suggesting monocytes contributed to enhanced functions of clonal expansional CD8+T cells. MHC I related pathways and interferon signaling pathways were activated in monocytes by the combination therapy. In conclusion, camrelizumab combined with MWA was feasible for the treatment of early-stage breast cancer. The peripheral CD8+T cells were activated after the combination therapy, dependent on monocytes with activated MHC I pathways. Citation Format: Wenbin Zhou, Hui Xie, Qiang Ding, Shui Wang. Preoperative single-dose camrelizumab and/or microwave ablation in women with early-stage breast cancer: A randomized window-of-opportunity trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-18-03.

Abstract PO2-22-04: Median Five-Year Follow-Up Results from the Multi-Institution Trial for the Treatment of Early-Stage Breast Cancer Using Intra-Operative Electronic Brachytherapy

Abstract Background: An IRB-approved single arm prospective multi-institution trial was designed to determine the efficacy and outcome of single fraction 20 Gy intra-operative radiation therapy (IORT) using disposable balloon electronic brachytherapy at the time of breast conserving surgery for early-stage breast cancer (women at least 40 years old, infiltrating ductal carcinoma [IDC] or ductal carcinoma in situ [DCIS], single lesion no larger than 3 cm, pN0). Ipsilateral breast tumor recurrences (IBTR) at median 5-year follow-up, the primary protocol endpoint of the trial, would be analyzed with outcomes compared to reported whole breast radiation therapy (WBRT) results. Methods: Between May 2012–July 2018,1199 enrolled breast cancer patients at twenty-six national and international institutions were successfully treated per protocol with lumpectomy plus single 20 Gy fraction IORT using disposable balloon electronic brachytherapy. Data collection and retrospective chart review included demographics, treatment, histopathology, toxicity, IBTR (defined as recurrence in the lumpectomy cavity/index quadrant), and survival. Results: All subjects were successfully treated with a single 20 Gy fraction of IORT. IORT cohort characteristics of the treated subjects are summarized in Table 1. Sixty-six (5.5%) patients received subsequent unplanned risk-adjusted WBRT. At median 5.0-year follow-up (range 0.5 – 9 years), there were 42 (3.50%) IBTR. The original mean tumor size of patients with IBTR was 13.6mm (range 0.03 - 30mm). The mean time to IBTR was 47.6 months (range 12 – 98 months). There were 30 IBTR in patients originally diagnosed with IDC, and 12 IBTR among patients originally diagnosed with DCIS. Three patients originally diagnosed with IDC recurred as DCIS, while 4 patients with DCIS recurred as IDC. The remainder recurred with the same pathology as their original diagnoses. Sorting by 2017 ASTRO accelerated partial breast irradiation (APBI) criteria, there were 25 IBTR in patients categorized immediately following lumpectomy plus IORT as Suitable, 12 IBTR among patients categorized immediately following lumpectomy plus IORT as Cautionary, and 5 IBTR in patients categorized immediately following lumpectomy plus IORT as Unsuitable. Nine (0.75%) patients experienced new ipsilateral primary breast cancers, with 8 classified as Suitable and one as Cautionary using post-lumpectomy plus IORT ASTRO APBI criteria. Seventeen (1.4%) patients experienced acute serious adverse events (SAEs). These included 5 wound infections, 4 hematomas, 2 skin ulcerations, 2 cellulitis, 2 seromas, 1 skin necrosis, and 1 wound dehiscence. All SAEs resolved within 6 months of IORT. One patient died of breast cancer metastases at 3-year follow-up. One patient who was diagnosed with IBTR at 3-year follow-up died 3 years later from dementia. There were 45 unrelated patient deaths. Conclusions: At median 5.0-year follow-up, the 1199 early-stage breast cancer patients successfully treated in this multi-institution trial with a single 20 Gy fraction of IORT to the lumpectomy cavity at the time of partial mastectomy experienced an IBTR of 3.50%. This recurrence rate is acceptable when compared to the 0.9% - 2.5% IBTR reported for WBRT, given the benefits of IORT (convenience, decreased exposure to XRT, better cosmetic outcome, patient preference). Table 1. IORT cohort characteristics Citation Format: Barbara Schwartzberg, AM Nisar Syed, Ajay Bhatnagar, Sophia Rahman, Veronica Jones, Albert Chang, Todd Cockerham, Virginia Osborn, Robert Cohen, Charles Hodge, Christina Lopez-Penalver, Bapsi Chakravarthy, William Dooley, Chika Madu, Atsuko Okabe, Maen Farha, Andrea Madrigrano, Christopher Morrison, Geoffrey Neuner, Craig Wengler, Steven David, Katayoon Toosie, Bryon Stephens. Median Five-Year Follow-Up Results from the Multi-Institution Trial for the Treatment of Early-Stage Breast Cancer Using Intra-Operative Electronic Brachytherapy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-22-04.

Abstract PO4-18-04: An exploratory study of Trastuzumab Deruxtecan neoadjuvant therapy in HER2-positive or HER2-low early or locally advanced breast cancer after a poor response to neoadjuvant chemotherapy

Abstract Background The current standard of care for neoadjuvant treatment of HER2-positive early-stage breast cancer consists of dual HER2-blockade with trastuzumab (H) plus pertuzumab (P) and polychemotherapy with a pathological complete response (pCR) rate of 31%~50%. Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate composed of an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor. T-DXd significantly prolonged progression-free and overall survival vs trastuzumab emtansine in HER2-positive unresectable and/or metastatic breast cancer (mBC) previously treated with H and taxane in DESTINY-Breast03 study. HER2-low breast cancer is currently treated as HER2-negative (HER2-low and HER2-zero) breast cancer, with patients stratified according to hormone-receptor (HR) status. In DESTINY-Breast04 study, T-DXd resulted in significantly longer progression-free and overall survival than the physician’s choice of chemotherapy in HER2-low mBC. Given the efficacy of T-DXd monotherapy in HER2-positive or HER2-low mBC, we conduct an exploratory study to evaluate the efficacy and safety of T-DXd in HER2-positive or HER2-low early or locally advanced breast cancer after a poor response to neoadjuvant chemotherapy, and to identify sensitive biomarkers for T-DXd neoadjuvant therapy. Methods Eligible patients were women aged 18 years to 75 years with clinical stage cT2–cT4/cN0–cN3/cM0 (stage II–III) invasive breast cancer (>2 cm in size) confirmed as HER2-positive (immunohistochemistry [IHC] 3+) or HER2-low (IHC2+ or IHC1+/situ hybridization-negative). Patients are required to have an Eastern Cooperative Oncology Group performance status of 0 or 1, and baseline left ventricular ejection fraction of at least 55% (as measured by echocardiogram). Patients are also required to have adequate organ function and bone marrow function. Patients with HER2-positive breast cancer should receive taxane (paclitaxel or nab-paclitaxel) or docetaxel, carboplatin, and H plus P for 2 cycles. Patients with HER2-low and HR-positive breast cancer should receive taxane (paclitaxel or nab-paclitaxel) or docetaxel, and cisplatin or carboplatin for 2 cycles. Patients with HER2-low and HR-negative breast cancer should receive taxane (paclitaxel or nab-paclitaxel) or docetaxel, and anthracycline (epirubicin, pirarubicin or liposomal doxorubicin) for 2 cycles. For patients who have responses of stable disease assessed by magnetic resonance imaging will receive T-DXd neoadjuvant therapy. T-DXd will be administered intravenously every 3 weeks at a dose of 5.4 mg per kilogram of body weight for 4 cycles. Peripheral blood and biopsy tissue will be collected before neoadjuvant chemotherapy and T-DXd neoadjuvant therapy, and peripheral blood and surgical tissue will be collected after the surgery. Lipid metabolites in peripheral blood and mass spectrometry-based protein quantification in tissue will be detected to find sensitive biomarkers for T-DXd neoadjuvant therapy. The primary endpoint is pCR rate (ypT0/Tis ypN0) and identify sensitive biomarkers for T-DXd neoadjuvant therapy. Secondary endpoints include objective response rate, breast-conserving rate and invasive disease-free survival. Citation Format: Jin Zhang, Zhendong Shi, Jingjing Liu. An exploratory study of Trastuzumab Deruxtecan neoadjuvant therapy in HER2-positive or HER2-low early or locally advanced breast cancer after a poor response to neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-18-04.

Abstract PO2-11-10: Can chemotherapy-induced peripheral neuropathy be predicted? Implications for future prevention and treatment of this side-effect

Abstract Background: The pain and sensory abnormalities associated with chemotherapy-induced peripheral neuropathy (CIPN) may persist for months or even years after chemotherapy. CIPN has a negative impact on routine activities, functions, and behaviors in the domestic, work, and social lives of cancer patients, adversely affecting the quality of their survivorship. CIPN is a major adverse effect of taxanes and other agents, possibly requiring dose-reduction or early termination of treatment. Taxane-based regimens are first-line treatment in both early-stage and metastatic breast cancer and therefore place numerous women at risk for developing CIPN. Regrettably, taxane-induced neurotoxicity can be arduous to predict, and there are no preventive or curative treatments currently available. Our work aims to assess a predictive tool for identification of patients at high risk of developing neuropathy and the progression of symptoms towards chronic CIPN. We hypothesized that oxidative stress might be a triggering event for the development of CIPN and that changes in glutathione recycling can identify patients at high risk for developing prolonged and severe CIPN. This hypothesis is based on reports in the literature proposing that CIPN is triggered by damage to the myelin sheath, which protects nerves from damage, by drug-induced free radicals in and around the nerves. Damage to myelin, a lipid- and protein rich sheath, by lipid peroxidation can result in loss of signal transmission, false signaling, or signal overload. Prolonged exposure to elevated levels of free radicals might result in structural changes to the nerves. Methods: Cancer patients seeking treatment at the Lankenau Medical Center Cancer center were asked to participate in our Institutional Review Board approved study of adverse effects. In this on-going study, the cohort (Ntotal =352) includes 104 breast cancer patients that are predominantly Caucasian with 14.9% African American. The median age is 56 (range 26 – 82) and 60.9% were treated with a taxane-based regimen. Nearly half the breast cancer group were diagnosed with Stage I disease. All consented patients donated a tube of blood prior to each treatment and filled out the Rotterdam Symptom Checklist (RSCL). Blood samples were analyzed for glutathione recycling using the ChemoTox assay (MNT™ Test, MYNARI Biomedical) and lipid peroxidation using a thiobarbituric acid reactive substances (TBARS) test (Cayman Chemical). All samples were analyzed in duplicate, and results analyzed using GraphPad Prism 8.4.3. Results: Preliminary results from the first 83 breast cancer patients showed African American patients reported a higher rate of NCCN grade 2 and 3 CIPN while Caucasians reported a higher rate of severe, long-lasting CIPN. Our results showed that patients who reported CIPN at later cycles had diminished glutathione recycling capacity already after the first treatment. Drop in recycling capacity had an inverse relationship with lipid peroxidation and grade of CIPN. Both decreased recycling capacity and increase in lipid oxidation were apparent already after the first treatment in patients that reported CIPN after cycle 6-8 or after completion of treatment Discussion: There are many proposed mechanisms for the development of CIPN. One mechanism that is shared by both most agents is damage induced by free radicals released following chemotherapy. We show that patients with reduced ability to neutralize free radicals have elevated and prolonged lipid peroxidation. Both processes precede the development of CIPN by several treatment cycles. Therefore, this test could identify patients that might benefit from other regimens rather than a taxane-based therapy. The test could also aid in the identification of patients for preventive therapy once such agents become available. Citation Format: Alisha Maity, Nolan Metz, Kathryn Fleck, Zonera Ali, Aarthi Shevade, Arezoo Ghaneie, Margaretha Wallon. Can chemotherapy-induced peripheral neuropathy be predicted? Implications for future prevention and treatment of this side-effect [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-11-10.

Abstract PO2-20-07: A case report of a severe cutaneous adverse event in triple negative breast cancer treated with chemoimmunotherapy

Abstract Introduction Cutaneous adverse events related to immune checkpoint inhibitors (ICI) are common and most are mild. However, numerous case reports have documented severe ICI-related skin-toxicities such as Stevens-Johnsons Syndrome (SJS) most commonly among patients with melanoma and lung cancer as immunotherapy has now become a mainstay of treatment in these tumors. The use of ICIs in breast cancer treatment has only recently become standard of care for treatment of metastatic and high risk early-stage triple negative breast cancer with the publication of two landmark clinical trials, KEYNOTE-355 and KEYNOTE-522, respectively. While these trials report low rates of severe skin reactions, little is known about ICI-related severe skin toxicities in patients with breast cancer. Case description A 58-year-old female with clinical stage IIB (cT2N0M0) triple negative breast cancer was undergoing neoadjuvant treatment with pembrolizumab, an anti-programmed death (PD-1) monoclonal antibody, coupled with a chemotherapy back-bone of 12 weekly treatments of carboplatin and paclitaxel followed by 4 cycles of doxorubicin and cyclophosphamide. She developed an erythematous and itchy rash on the right breast and axilla approximately 61 days into her treatment course after having received her fourth dose of pembrolizumab. Over the next 10 days, she developed progression of the rash with painful red papules coalescing into reticulated plaques and dusky blistering of the skin involving the right arm, axilla, abdomen, inguinal folds, thigh, and back, totaling < 10% total body surface area. Notably, the rash did not have mucosal involvement. She was hospitalized for close monitoring and treatment. A punch biopsy of the rash revealed interface dermatitis with areas of full thickness skin necrosis consistent with erythema multiforme, SJS, toxic epidermal necrolysis (TEN), or a fixed drug eruption. Her skin continued to slough in the distribution of rash and a diagnosis of SJS was made. The patient had no response to initial treatment with high dose steroids. Cyclosporine was added, resulting in rapid improvement of her rash. The patient’s neoadjuvant treatment was stopped given the grade 3 SJS she experienced. Despite this truncated neoadjuvant treatment, she had excellent clinical response as her tumor was no longer palpable. She proceeded with a partial mastectomy and sentinel lymph node biopsy. Pathology revealed a pathological complete response. She did not receive any further systemic therapy in the adjuvant setting. Three months later, she was evaluated in clinic without evidence of SJS on physical exam. She was rapidly tapered off cyclosporine over one week without recurrence of her rash. Discussion Severe cutaneous adverse events related to ICIs remains an emerging area of study. In SJS, drug-specific CD8+ T lymphocytes utilize granulysin to mediate keratinocyte apoptosis. It is hypothesized that the blocking of the PD-1/PD-L1 interaction by ICIs results in the disruption of T-cell homeostasis leading to self-directed cytotoxic and inflammatory reactions and ultimately epidermal detachment. In contrast, Molina et al 2020 postulate that such ICI-related skin reactions may represent a separate clinical entity from SJS. In their case report of seven patients, they propose the term “progressive immunotherapy-related mucocutaneous eruption” (PIRME), which the authors suggest is characterized by delayed symptom onset, mild initial presentation, rare ocular involvement, benign clinical course, and favorable treatment response. Further characterization of ICI-related cutaneous adverse events is needed to understand the disease course, optimal treatment, and importantly, implications for re-challenging patients with immunotherapy. Clinicians taking care of breast cancer patients treated with ICIs need to be educated to recognize the associated skin toxicities as patients can rapidly worsen without appropriate treatment. Citation Format: Annie Zhang, Mara Beveridge, Bahar Moftakhar. A case report of a severe cutaneous adverse event in triple negative breast cancer treated with chemoimmunotherapy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-20-07.

Abstract PO2-22-10: Surgical outcomes after neoadjuvant chemotherapy with and without immunotherapy in patients with triple negative breast cancer

Abstract Background: The KEYNOTE-522 trial demonstrated that the addition of neoadjuvant pembrolizumab to neoadjuvant chemotherapy (NAC) for the treatment of early-stage triple negative breast cancer (TNBC) significantly improves rates of both pathologic complete response (pCR) and event-free survival. The impact of adding immunotherapy to NAC on surgical outcomes, however, is unknown. The purpose of this study is to compare 90-day surgical complication rates and timing to subsequent adjuvant therapy of patients undergoing neoadjuvant chemotherapy for stage I-III TNBC with and without immunotherapy. Methods: Patients treated at University of California, Los Angeles with neoadjuvant therapy for TNBC between 2018-2022 were identified retrospectively. Patient comorbidities, tumor characteristics, type of surgery, 90-day postoperative minor and major complications, timing to adjuvant therapy, and oncologic outcomes were reviewed and analyzed. Major complications were defined as those requiring reoperation or hospitalization. Results: A total of 44 patients were included, 15 patients received neoadjuvant chemotherapy with immunotherapy (NAC-I) and 29 patients received neoadjuvant chemotherapy alone (NAC). There was no difference in patient comorbidities between the groups. Compared to the NAC group, significantly more patients in the NAC-I group had stage II or III tumors (58.6% vs. 86.7%, respectively, p=0.028). 73% of patients in the NAC-I group underwent mastectomy compared to only 44% of patients in the NAC group (p=0.111). In total, 23 patients underwent reconstruction with mastectomy, 6 patients underwent immediate DIEP flap (4 in NAC-I group and 2 in NAC group) and 17 underwent immediate tissue expander (7 in NAC-I and 10 in NAC group). 80% of patients in the NAC-I experienced a pCR compared to only 44% in the NAC group (p=0.026). A total of 15 patients (34.1%) experienced surgical complications and there was no significant difference in the complication rate between the groups (p= 0.552). Five patients (33%) in the NAC-I group experienced minor complications of seroma requiring aspiration (n=4), cellulitis requiring antibiotics (n=1), or wound dehiscence requiring local wound care (n=2). No patients in the NAC-I group had major complications. Ten patients (33%) in the NAC group experienced complications, including 6 minor complications and 4 major complications including postoperative bleeding or flap necrosis requiring unplanned return to surgery or hyperbaric oxygen treatment. On multivariable regression analysis, controlling for patient characteristics, tumor stage, and preoperative immunotherapy, only younger age was a statistically significant variable associated with increased risk of surgical complications (p=0.012). Median time to adjuvant therapy, including radiation and/or systemic therapy, was similar between NAC-I and NAC groups, at 32 and 36 days, respectively (p=0.37). In the NAC-I group, 14 patients (93.3%) had adjuvant systemic therapy including pembrolizumab alone (n=12), pembrolizumab with olaparib (n=1) or capecitabine alone (n=1). In the NAC group, 11 patients (37.9%) underwent adjuvant systemic treatment including chemotherapy with either capecitabine (n=1), pembrolizumab (n=1), or olaparib (n=2); or single agent capecitabine (n=6) or olaparib (n=1). Conclusions: Despite patients in the NAC-I group having more advanced stage tumors and undergoing more extensive surgery and reconstruction compared to those in the NAC alone group, a significantly higher rate of surgical complications was not observed in the NAC-I group and there was no significant difference in time to adjuvant therapy between the two groups. Similar to results from the KEYNOTE-522 trial, more patients in the NAC-I group experienced a pCR compared to NAC alone. Larger studies are needed to continue to assess and optimize the surgical safety of neoadjuvant immunotherapy with chemotherapy in patients with TNBC. Citation Format: Anouchka Coste Holt, Maurice Berkowitz, Nicholas McAndrew, Courtney Smith, Jennifer Baker, Nimmi Kapoor. Surgical outcomes after neoadjuvant chemotherapy with and without immunotherapy in patients with triple negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-22-10.

Abstract PO3-03-12: Factors associated with response to neoadjuvant chemoimmunotherapy in triple-negative breast cancer

Abstract Background: The addition of pembrolizumab (pembro) to neoadjuvant chemotherapy (NAC) became a standard-of-care for the treatment of early-stage triple negative breast cancer (TNBC) after the phase III KEYNOTE-522 trial demonstrated improved pathologic complete response (pCR) rates and event free survival with the combination. To date, clinical predictors of response to pembro with NAC are lacking. We sought to identify real-world clinical characteristics and treatment variables associated with response to NAC with pembro. Methods: We performed a single institution, retrospective study of early-stage TNBC patients diagnosed between February 1st, 2020 and December 1st, 2022 who were treated with NAC and pembro. Patients who had not undergone definitive surgery were excluded. Demographic information, clinical and pathologic characteristics, and treatment data were collected. pCR was defined as ypT0/Tis and ypN0. Univariate and multivariate analysis was performed using logistic regression to identify factors associated with pCR. This study was approved by an Institutional Review Board. Results: Of the 94 patients analyzed, 93 were female and 1 was male. The median age was 55 years (IQR 47 – 61.8) and median body mass index (BMI) was 30 (24.1-33.6). Self-reported racial/ethnic groups included 37 non-Hispanic White (39.4%), 33 Hispanic (35.1%), 13 Asian (13.8%), 7 Black (7.4%), and 4 other/unknown (4.3%). 8 (8.5%) and 2 (2.1%) of patients had deleterious germline BRCA1+ and BRCA2+ mutations, respectively. The majority of patients had invasive ductal histology (90.4%), clinical T2 stage (68.1%), and node negative (55.3%) disease. 61 (64.9%) patients completed the planned 8 cycles of NAC, while 42 (44.7%) completed the planned 8 cycles of neoadjuvant pembro. A pCR (ypT0/Tis ypN0) was achieved in 60 (63.8%) of the 94 patients. Among those who achieved a pCR, 32 (53.3%) completed the prescribed course of NAC and pembro in combination, whereas 9 (47.1%) of the 34 patients with residual disease did not. In univariate analyses, patients under 55 years at time of diagnosis (vs. age >55 years), higher ki-67, those completing the prescribed course of NAC, those completing the prescribed course of pembro, the months from start of NAC to surgery, and the months from start of pembro to surgery were associated with pCR. The duration from start of NAC or pembro to surgery overlapped considerably with the response explained by completion of NAC or pembro, respectively. Although pCR estimates were lower for Hispanic (60.6%) and non-Hispanic White patients (Black: 57.1%, Asian: 53.8%, and Other: 50%) when compared to non-Hispanic White patients (73.0%), the results were not statistically significant. In multivariate analyses, patients under 55 years at time of diagnosis (OR 3.06, 95% CI:1.18-8.0, p=0.02) and those completing the full course of pembro (OR 2.86, 95%CI: 1.08-7.58, p=0.034) had improved rates of pCR. BMI, race, BRCA1/2 status, histology, clinical T and N stage, grade, time between start/end of NAC and IO to surgery were not significantly associated with pCR on multivariate analysis. Conclusion: In our experience, younger TNBC patients were more likely to achieve a pCR with NAC with pembro. Moreover, the completion of the planned course of pembro prior to surgery was also associated with improved pCR rates. These findings suggest that adherence to neoadjuvant pembro prior to surgery may be more important than the completion of the NAC. Further research to identify the optimal exposure of NAC with pembro is needed to refine treatment recommendations in this high-risk population. Citation Format: Alexis LeVee, Megan Wong, Sarah Flores, Nora Ruel, Heather McArthur, James Waisman, Joanne Mortimer. Factors associated with response to neoadjuvant chemoimmunotherapy in triple-negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-03-12.

Hyaluronic acid-based injectable formulation developed to mitigate metastasis and radiation-induced skin fibrosis in breast cancer treatment

The standard treatment for early-stage breast cancer involves breast-conserving surgery followed by adjuvant radiotherapy. However, approximately 20 % of patients experience distant metastasis, and adjuvant radiotherapy often leads to radiation-induced skin fibrosis (RISF). In this study, we develop an on-site injectable formulation composed of selenocystamine (SeCA) and hyaluronic acid (HyA), referred to as SeCA cross-linked HyA (SCH) agent, and investigate its potential to mitigate metastasis and prevent RISF associated with breast cancer therapy. SCH agents are synthesized using the nanoprecipitation method to modulate cell-cell tight junctions and tissue inflammation. The toxicity assessments reveal that SCH agents with a higher Se content (Se payload 17.4 μg/mL) are well tolerated by L929 cells compared to SeCA (Se payload 3.2 μg/mL). In vitro, SCH agents significantly enhance cell–cell tight junctions and effectively mitigate migration and invasion of breast cancer cells (4T1). In vivo, SCH agents mitigate distant lung metastasis. Furthermore, in animal models, SCH agents reduce RISF and promote wound repair. These findings highlight the potential of SCH agents as a novel therapeutic formulation for effectively mitigating metastasis and reducing RISF. This holds great promise for improving clinical outcomes in breast cancer patients undergoing adjuvant radiotherapy.

Evaluation of the impact of breast-conserving surgery on cancer outcomes of multiple (multifocal or multicentric) ipsilateral breast cancer

Background Breast conservative therapy (BCT) includes conservative breast surgery (CBS) with adjuvant radiotherapy and is now considered a standard treatment for early-stage breast cancer to achieve survival with acceptable aesthetic outcomes. Management of multiple ipsilateral breast cancer (MIBC) is a challenge, since the choice of optimal surgical procedures is controversial. Recently, many breast surgeons have advocated CBS is technically feasible to safely excise MIBC in selected cases. Aim This study aimed to evaluate the outcome of MIBC patients who received CBS with special attention on local control and recurrence. Patient and method This retrospective study was carried out on 90 patients at Al Azhar University Hospital and Ain Shams University Hospitals between January 2021 and January 2023. Results The majority of patients 85 (94.4%) had two foci of disease while five (5.5%) patients had three foci. The distance between the lesions ranges between 0.5 and 6.5 cm. The most common type of CBS was wide local excision en bloc resection of all lesions with normal tissue in between was done in 85 (94.4%) patients and five (5.5%) patients had two separate incisions leaving normal tissue in between. Clear margins were reported in 79 (87.7%) patients. 15 (5.5%) patients had different pathological lesion types (heterogeneous). One patient had a recurrence and another had distant metastases. Conclusion With good patient selection, there is no difference between CBS and mastectomy in the management of MIBC. CBS is oncological safe provided that an adequate excision with clear margins followed by whole-breast radiation therapy and adjuvant systemic therapy.

Cost-benefit ratio of modern medical education using micro-costing: amodel calculation using the example of an innovative breast brachytherapy workshop.

Radiation oncology is an essential component of therapeutic oncology and necessitates well-trained personnel. Multicatheter brachytherapy (MCBT) is one radiotherapeutic option for early-stage breast cancer treatment. However, specialized hands-on training for MCBT is not currently included in the curriculum for residents. Arecently developed hands-on brachytherapy workshop has demonstrated promising results in enhancing knowledge and practical skills. Nevertheless, these simulation-based teaching formats necessitate more time and financial resources. Our analyses include computational models for the implementation and delivery of this workshop and can serve as abasis for similar educational initiatives. This study aimed to assess the cost-effectiveness of apreviously developed and evaluated breast brachytherapy simulation workshop. Using amicro-costing approach, we estimated costs at adetailed level by considering supplies, soft- and hardware, and personnel time for each task. This method also allows for acomprehensive evaluation of the costs associated with implementing new medical techniques. The workshop costs were divided into two categories: development and workshop execution. The cost analysis was conducted on aper-participant basis, and the impact on knowledge improvement was measured using aquestionnaire. The total workshop costs were determined by considering the initial workshop setup expenses including the development and conceptualization of the course with all involved collaborators, as well as the costs incurred for each individual course. The workshop was found to be financially efficient, with aper-participant cost of € 39, considering the industrial sponsorship provided for brachytherapy equipment. In addition, we assessed the workshop's efficacy by analyzing participant feedback using Likert scale evaluations. The findings indicated anotable enhancement in both theoretical and practical skills among the participants. Moreover, the cost-to-benefit ratio (CBFR) analysis demonstrated aCBFR of € 13.53 for each Likert point increment. The hands-on brachytherapy workshop proved to be avaluable and approximately cost-effective educational program, leading to asignificant enhancement in the knowledge and skills of the participants. Without the support of industrial sponsorship, the costs would have been unattainable.

Preoperative single-dose camrelizumab and/or microwave ablation in women with early-stage breast cancer: A window-of-opportunity trial

Immune checkpoint blockade has shown low responserates for advanced breast cancer, and combination strategiesareneeded. Microwave ablation (MWA) may be a triggerofantitumor immunity. This window-of-opportunity trial (ClinicalTrials.gov: NCT04805736) was conducted to determine the safetyand feasibility of preoperative camrelizumab (an anti-PD-1 antibody) combined with MWA in the treatment of early-stage breast cancer. Sixty participants were randomized to preoperatively receive single-dose camrelizumab alone (n= 20), MWA alone (n= 20), or camrelizumab+MWA (n= 20). A random number table was used to allocate interventions. The primary outcome was the safety and feasibility of MWA combined with camrelizumab. Camrelizumab and MWA were well tolerated alone and in combination without delays in prescheduled surgery. No treatment-related grade III/IV adverse events were observed. Different from in the single-dose camrelizumab or MWA group, participants showed stable counts of blood cells after combination therapy. After combination therapy, peripheral CD8+ Tcells showed enhanced cytotoxic and effect-memory functions. Clonal expansional CD8+ Tcells showed higher cytotoxic activity and effector memory- and tumor-specific signatures than emergent clones after combination therapy. Enhanced interactions between clonal expansional CD8+ Tcells and monocytes were observed, suggesting that monocytes contributed to the enhanced functions of clonal expansional CD8+ Tcells. Major histocompatibility complex (MHC) class I-related pathways and interferon signaling pathways were activated in monocytes by combination therapy. Camrelizumab combined with MWA was feasible for early-stage breast cancer. Peripheral CD8+ Tcells were activated after combination therapy, dependent on monocytes with activated MHC class I pathways. This study was supported by the Natural Science Foundation of Jiangsu Province (BK20230017).

Omission of radiation therapy after breast conserving surgery for older women at low-risk of local recurrence: One option among many

This editorial discusses the evolving landscape of early-stage breast cancer treatment, emphasizing the need to tailor therapies based on disease biology and genomic approaches. The focus is on the reconsideration of postoperative radiation therapy (RT) for older patients with low-risk, hormone receptor-positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) breast cancer. Recent trials show modest long-term local recurrence rates with the omission of RT after BCS in certain cases, challenging the traditional approach. The commentary calls for continued research on predictive tests for treatment response and advocates for a multidisciplinary approach to decision-making, considering factors like quality of life. The nuanced risk/benefit ratio of RT in older patients is explored, emphasizing the importance of comprehensive assessment for optimal therapy.

Abstract B077: Subtype-specific signaling dynamics during treatment in non-responding breast cancer patients in the neoadjuvant I-SPY2 TRIAL: are there clues on how to overcome resistance?

Abstract Background: Despite ever-improving treatments (Tx) for early-stage aggressive breast cancer – e.g., neoadjuvant platinum and immune agents (IO) for TN and dual-anti-HER2 for HER2+ - many patients don’t respond, and insight into resistance mechanisms and how to overcome them are lacking. To look for clues, we performed serial gene expression profiling of non-responding patients to assess which tumor features change during treatment, and to identify dynamics most associated with distant recurrence. Methods: Non-response was defined as moderate or extensive residual cancer burden after Tx. 167 non-responders [76 HR+HER2-, 72 TN, 19 HER2+] with mRNA at one or more on-treatment time points (148 pretreatment (T0), 122 on-treatment (T1), and 120 surgical (T3)) were considered. Normalized data were scored for 112 published signatures representing immune, proliferation, ER/PR, HER2-related, ECM, and development; and for 50 Cancer Hallmarks (MSigDB). Signatures were assessed for early (T1-T0), late (T3-T1) and overall (T3-T0) changes during Tx using Wilcoxon tests, adjusted using the Benjamini-Hochberg method (BH p<0.05). 110/167 (66%) pts have distant recurrence free survival (DRFS) data, with median follow-up of ~4.5yr. Associations with DRFS were assessed using Cox Proportional Hazards modeling, also adjusted (BH log rank test p<0.05). Results: Signaling dynamics during Tx differed by receptor subtype. Within HR+HER2-, in addition to a decrease in ESR1_PGR, early decreases in proliferation and interferon (but not T/B-cell) signatures were observed; along with late increases in TGFB, IL8 and IL2, and Mast-cell. In TN, late decreases in T/B-cell, and Tumor-Immune signaling were observed, including those predicting IO sensitivity (STAT1_sig, DendriticCell and Chemokine12). Among the few signaling changes in common between subtypes were early increases in xenobiotic metabolism and late increases in hypoxia. Associations with DRFS were subtype-specific as well. In HR+HER2-, high levels of proliferation at T3 associate with decreased DRFS, and late increases in macrophage and Th1-related immune signatures associated with improved DRFS. Paradoxically, though high Mast-cell at T0 were previously shown to associate with non-pCR, high levels at T3 and increases late in Tx associate with improved DRFS. In TN, there were few significant associations with DRFS. Finally, we assessed the overlap between signatures that change during treatment and those that associate with DRFS, and to our surprise found no significant association. Conclusion: We observed subtype-specific changes in signatures over Tx in non-responders, however these changes do not generally predict an association with DRFS. Early targeting of xenobiosis; or TGFB, IL2 or IL8 in HR+HER2-, may be promising for overcoming resistance; but likely not a Mast-cell inhibitor, where high levels predict both resistance and survival. Citation Format: Denise M. Wolf, Christina Yau, Mark Jesus M. Magbanua, Rosalyn Sayaman, Julia Wulfkhule, Rosa I. Gallagher, Lamorna Brown-Swigart, Michael J. Campbell, Amrita Basu, Gillian L. Hirst, Jane Perlmutter, Angela DeMichele, Doug Yee, Lajos Pusztai, Paula R. Pohlmann, Amy S. Clark, Hope S. Rugo, Emanuel F. Petricoin, Laura J. Esserman, Laura van ‘t Veer. Subtype-specific signaling dynamics during treatment in non-responding breast cancer patients in the neoadjuvant I-SPY2 TRIAL: are there clues on how to overcome resistance? [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B077.

Ultrasound-based radiomics nomogram for predicting axillary lymph node metastasis in early-stage breast cancer.

We aimed at assessing the predictive ability of ultrasound-based radiomics combined with clinical characteristics for axillary lymph node (ALN) status in early-stage breast cancer patients and to compare performance in different peritumoral regions. A total of 755 patients (527 in the primary cohort and 228 in the external validation cohort) were enrolled in this study. Ultrasound images for all patients were acquired and radiomics analysis performed for intratumoral and different peritumoral regions. The MRMR and LASSO regression analyses were performed on extracted features from the primary cohort to construct a radiomics signature formula combined with clinical characteristics. Pearson's coefficient and the variance inflation factor (VIF) were performed to check the correlation and the multicollinearity among the final predictors. The best performing model was selected to develop a nomogram, which was established by performing binary logistic regression and acquiring cut-off values based on the corresponding nomogram scores of the masses. Among all the radiomics models, the "Mass + Margin3mm" model exhibited the best performance. The areas under the curves (AUC) of the nomogram in the primary and external validation cohorts were 0.906 (95% confidence intervals [CI] 0.882-0.930) and 0.922 (95% CI 0.894-0.960), respectively. They both showed good calibrations. The nomogram exhibited a good ability to discriminate between positive and negative lymph nodes (AUC: 0.853 (95% CI 0.816-0.889) in primary cohort, 0.870 (95% CI 0.818-0.922) in validation cohort), and between low-volume and high-volume lymph nodes (AUC: 0.832 (95% CI 0.781-0.884) in primary cohort, 0.911 (95% CI 0.858-0.964) in validation cohort). The established nomogram is a prospective clinical prediction tool for non-invasive assessment of ALN status. It has the ability to enhance the accuracy of early-stage breast cancer treatment.

Combined modality treatment of early breast cancer. Literature review

The object of the study was to conduct a systematic literature review on combined modality treatment for early-stage breast cancer using postoperative and intraoperative radiation therapy, and consider new treatment approaches for early breast cancer.Material and Methods. The search for sources relevant to the review topic was carried out in the Medline, Cochrane Library, and Elibrary systems. A total of 905 studies on combination treatments for early breast cancer were identified, of which 43 were included in the review.Results. Data analysis showed that the rate of local relapses in early breast cancer was lower in patients who underwent breast-conserving surgery in combination with adjuvant radiation therapy than in patients without adjuvant radiation therapy. Research is ongoing on radiotherapy deintensification using intraoperative radiation therapy for patients at low risk of recurrence. Ongoing clinical trials support the omission of radiotherapy after breast-conserving surgery for elderly women with hormone receptor-positive early-stage breast cancer, who receive adjuvant endocrine therapy. Understanding the characteristics of the tumor process will allow us to personalize the treatment of patients with early breast cancer, reduce the risk of local relapses, and avoid unnecessary treatment-related complications.Conclusion. To improve survival in breast cancer patients is only possible by maximizing the tumor control. The effectiveness of adjuvant radiation therapy, which is an integral component in the combined modality treatment of early breast cancer, has been proven. However, third-generation studies discuss the feasibility of identifying a low-risk group of patients with a favorable clinical prognosis, who receive adequate endocrine therapy, and additional radiation do not provide a significant survival benefit.

Inflammatory breast cancer: As surgical oncologists, what can we do?

Breast cancer surgery is the primary treatment for early-stage breast cancer. However, inflammatory breast cancer (IBC), with its specific presentation characterized by skin invasion, is unfit for primary surgery. According to the different guidelines, the management of IBC is trimodal with the coordination of oncologists, surgeons, and radiation therapists. Advances in breast cancer imaging and the development of more targeted therapies make new challenges for this aggressive cancer. This chapter aims to provide an update on the role of surgery in IBC. Radical surgery is still considered the standard surgical treatment in IBC. Some authors suggest a conservative surgery in patients with a clinical response to chemotherapy without affecting survival. For lymph node surgery, the sentinel lymph node biopsy (SLNB) is not feasible in IBC patients, according to the existing studies. However, prospective studies on SLNB are needed to verify its reliability after chemotherapy for a specific group of patients. In the metastatic IBC, surgery can be considered if there is a good response after chemotherapy or for uncontrolled symptoms. Existing studies showed that surgery may impact survival for these patients. Prospective studies are mandatory to optimize IBC management, considering factors such as tumor's molecular profile.

Predicting Neoadjuvant Treatment Response in Triple-Negative Breast Cancer Using Machine Learning.

Neoadjuvant chemotherapy (NAC) is the standard treatment for early-stage triple negative breast cancer (TNBC). The primary endpoint of NAC is a pathological complete response (pCR). NAC results in pCR in only 30-40% of TNBC patients. Tumor-infiltrating lymphocytes (TILs), Ki67 and phosphohistone H3 (pH3) are a few known biomarkers to predict NAC response. Currently, systematic evaluation of the combined value of these biomarkers in predicting NAC response is lacking. In this study, the predictive value of markers derived from H&E and IHC stained biopsy tissue was comprehensively evaluated using a supervised machine learning (ML)-based approach. Identifying predictive biomarkers could help guide therapeutic decisions by enabling precise stratification of TNBC patients into responders and partial or non-responders. Serial sections from core needle biopsies (n = 76) were stained with H&E and immunohistochemically for the Ki67 and pH3 markers, followed by whole-slide image (WSI) generation. The serial section stains in H&E stain, Ki67 and pH3 markers formed WSI triplets for each patient. The resulting WSI triplets were co-registered with H&E WSIs serving as the reference. Separate mask region-based CNN (MRCNN) models were trained with annotated H&E, Ki67 and pH3 images for detecting tumor cells, stromal and intratumoral TILs (sTILs and tTILs), Ki67+, and pH3+ cells. Top image patches with a high density of cells of interest were identified as hotspots. Best classifiers for NAC response prediction were identified by training multiple ML models and evaluating their performance by accuracy, area under curve, and confusion matrix analyses. Highest prediction accuracy was achieved when hotspot regions were identified by tTIL counts and each hotspot was represented by measures of tTILs, sTILs, tumor cells, Ki67+, and pH3+ features. Regardless of the hotspot selection metric, a complementary use of multiple histological features (tTILs, sTILs) and molecular biomarkers (Ki67 and pH3) resulted in top ranked performance at the patient level. Overall, our results emphasize that prediction models for NAC response should be based on biomarkers in combination rather than in isolation. Our study provides compelling evidence to support the use of ML-based models to predict NAC response in patients with TNBC.

Women's Preferences for Hypofractionated Radiation Therapy for Treatment of Early-Stage Breast Cancer: A Discrete Choice Experiment

IntroductionThe primary treatment recommended for early-stage breast cancer is breast conserving surgery followed by external beam radiation therapy of the whole breast. Previously radiation therapy for early-stage breast cancer was given using more fractions over longer durations. Guidelines support treatments with fewer fractions over a shorter time (hypofractionated radiation therapy-HFRT). This study aimed to understand women's preferences for different features of treatments for early-stage breast cancer. MethodsA discrete choice experiment (DCE) with 12 choice tasks was conducted, describing the treatments by: extent of surgery, duration of radiation treatment, need to relocate for treatment, local side effects, changes in breast appearance, costs, and difficulty with daily activities during and after treatment. Participants were women with breast cancer and from the general population. Mixed logit analyses were conducted and trade-offs between attributes estimated. Results420 respondents completed the DCE. The relative importance of attributes varied by respondent characteristics; the most influential attribute for younger women was type of surgery (breast conserving surgery); type of surgery did not influence older women's preferences. Shorter treatment duration, avoiding relocation, fewer local side effects, and less difficulty with daily activities all positively influenced treatment preference. Younger women were willing to accept 32-40 days of radiation treatment before a treatment that included mastectomy was potentially acceptable. Conclusionattributes of treatment such as duration, need for relocation, side effects and impacts on normal daily activities during and after treatment significantly influenced women's preference for treatment, including surgery. Our findings have the potential for real impact for patients and services including supporting one on one clinical discussions, supporting program and patient resource development, and by informing service funding, organisation and delivery.