Taxane-based Neoadjuvant Chemotherapy Research Articles

Construction and Validation of a Serum Albumin-to-Alkaline Phosphatase Ratio-Based Nomogram for Predicting Pathological Complete Response in Breast Cancer.

BackgroundBreast cancer patients who achieve pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) have favorable outcomes. Reliable predictors for pCR help to identify patients who will benefit most from NAC. The pretreatment serum albumin-to-alkaline phosphatase ratio (AAPR) has been shown to be a prognostic predictor in several malignancies, but its predictive value for pCR in breast cancer is still unknown. This study aims to investigate the predictive role of AAPR in breast cancer patients and develop an AAPR-based nomogram for pCR rate prediction.MethodsA total of 780 patients who received anthracycline and taxane-based NAC from January 2012 to March 2018 were retrospectively analyzed. Univariate and multivariate analyses were performed to assess the predictive value of AAPR and other clinicopathological factors. A nomogram was developed and calibrated based on multivariate logistic regression. A validation cohort of 234 patients was utilized to further validate the predictive performance of the model. The C-index, calibration plots and decision curve analysis (DCA) were used to evaluate the discrimination, calibration and clinical value of the model.ResultsPatients with a lower AAPR (<0.583) had a significantly reduced pCR rate (OR 2.228, 95% CI 1.246-3.986, p=0.007). Tumor size, clinical nodal status, histological grade, PR, Ki67 and AAPR were identified as independent predictors and included in the final model. The nomogram was used as a graphical representation of the model. The nomogram had satisfactory calibration and discrimination in both the training cohort and validation cohort (the C-index was 0.792 in the training cohort and 0.790 in the validation cohort). Furthermore, DCA indicated a clinical net benefit from the nomogram.ConclusionsPretreatment serum AAPR is a potentially valuable predictor for pCR in breast cancer patients who receive NAC. The AAPR-based nomogram is a noninvasive tool with favorable predictive accuracy for pCR, which helps to make individualized treatment strategy decisions.

English

BACKGROUND Locally advanced female breast cancer patients have the highest risk of recurrence and distant metastasis. Taxane-based neoadjuvant chemotherapy gives a more pathological response. The purpose of this study was to assess the pathological response rate of paclitaxel-based dose-dense and conventional neoadjuvant chemotherapy in locally advanced female breast cancer patients. METHODS In this observational study, a total of hundred locally advanced female breast cancer patients were randomly selected for neoadjuvant chemotherapy. Fifty patients received three weekly paclitaxel 200 mg/m2 (4 courses) and other fifty patients received weekly paclitaxel 80 mg/m2 (10 courses) along with three weekly doxorubicin 50 mg/m2(4 courses in both arms). Chemotherapy-induced clinical response in both arms was weekly assessed by tumour and lymph node size measurements, change in consistency and fixity. Pathological response of chemotherapy in each arm was assessed by taking the difference of mean tumour volumes and presence of chemotherapy-induced fibrosis and collections of histiocytes in lymph nodes. RESULTS There was statistically significant pathological reduction after neoadjuvant chemotherapy was seen in three weekly arms (68.18 cm3 to 37.22 cm3 P-value 0.000), in the weekly arm (68.42 cm3 to 18.04 cm3 P-value 0.000) and difference in reduction of tumour volume (more in weekly arm -50.38 cm3 versus 30.86 cm3, Pvalue 0.000). CONCLUSIONS Locally advanced female breast cancer patients receiving neoadjuvant chemotherapy with paclitaxel showed a better pathological response rate. It was more in the weekly paclitaxel arm. KEY WORDS Pathological Response Rate, Neoadjuvant Chemotherapy, Locally Advanced.

A pharmacophore-based classification better predicts the outcomes of HER2-negative breast cancer patients receiving the anthracycline- and/or taxane-based neoadjuvant chemotherapy.

AimsPrognosis of patients for human epidermal growth factor receptor 2 (HER2)‐negative breast cancer post neoadjuvant chemotherapy is not well understood. The aim of this study was to develop a novel pharmacophore‐based signature to better classify and predict the risk of HER2‐negative patients after anthracycline‐and/or taxane‐based neoadjuvant chemotherapy (NACT).Main methodsAnthracycline and taxane pharmacophore‐based genes were obtained from PharmMapper. Drug‐targeted genes (DTG) related clinical and bioinformatic analyses were undertaken in four GEO datasets.Key findingsWe used 12 genes from the pharmacophore to develop a DTG score (DTG‐S). The DTG‐S classification exhibited significant prognostic ability with respect to disease free survival (DFS) for HER2‐negative patients who receive at least one type of neoadjuvant chemotherapy that included anthracycline and/or taxane. DTG‐S associated with a high predictive ability for pathological complete response (pCR) as well as for prognosis of breast cancer. Using the DTG‐S classification in other prediction models may improve the reclassification accuracy for DFS. Combining the DTG‐S with other clinicopathological factors may further improve its predictive ability of patients’ outcomes. Gene ontology and KEGG pathway analysis showed that the biological processes of DTG‐S high group were associated with the cell cycle, cell migration, and cell signal transduction pathways. Targeted drug analysis shows that some CDK inhibitors and PI3K‐AKT pathway inhibitors may be useful for high DTG‐S patients.SignificanceThe DTG‐S classification adds prognostic and predictive information to classical parameters for HER2‐negative patients who receive anthracycline‐and/or taxane‐based NACT, which could improve the patients’ risk stratification and may help guide adjuvant treatment.

Paclitaxel versus docetaxel-based neoadjuvant chemotherapy and risk of lymphedema in breast cancer patients.

e12620 Background: Neoadjuvant chemotherapy (NAC) is commonly utilized in women with locally advanced breast cancer, usually followed by surgery and radiation therapy (RT). Many studies aimed to address the risk factors contributing to a higher incidence of lymphedema in patients with breast cancer. Our group previously reported the extent of surgery increases the risk of lymphedema. Adjuvant chemotherapy with taxane-based regimens are associated with an increased risk of lymphedema likely due an increase in interstitial extracellular fluid volume therefore resulting in fluid retention. This study aims to directly compare and characterize the risk of lymphedema in patients receiving paclitaxel versus docetaxel-based NAC. Methods: This is a retrospective study approved by our institutional review board. The study included women with breast cancer treated consecutively at our institution with taxane-based NAC followed by surgery and RT from 2006 to 2018. Patients and tumor characteristics including age, race, body mass index (BMI), clinical stage, hormone receptor, HER2 status, type of surgery, RT techniques, and type of NAC (Paclitaxel versus Docetaxel), and its association to risk of lymphedema were analyzed using univariable and multivariable binary logic regression tests. Lymphedema was assessed before RT and at follow up visits, and was identified by &gt;2.0-cm increase in arm circumference, or &gt;10% increase in limb volume, or new self-reported lymphedema symptoms. Results: A total of 263 patients treated with either paclitaxel or docetaxel-based NAC were identified and analyzed. At a median follow up of 28.4 months (range 3.5-158.7 months). 26.2% (69/263) of patients developed lymphedema. On a multivariable analysis, patients who underwent axillary lymph node dissection (ALND) had a significantly higher rate of lymphedema (42.6%) compared to those who had only a sentinel lymph node biopsy (SLNB, 10.5%, p&lt;0.05). Regardless of the type of surgery, there was no significant difference in rates of lymphedema between patients who received paclitaxel versus docetaxel-based NAC (28.7% vs 21.3%). However, among high-risk patients who underwent mastectomy with ALND, NAC with Paclitaxel was associated with a significantly higher rate of lymphedema compared to docetaxel (56.8% vs 22.7%, RR 2.50, p&lt;0.05). Conclusions: This represents one of the largest studies examining the impact of taxane-based NAC on the risk of lymphedema in women with breast cancer. In this study, paclitaxel-based NAC was associated with a significantly higher risk of lymphedema in women who underwent mastectomy and ALND compared to docetaxel based chemotherapy. A larger, balanced, prospective study is warranted to verify this previously unidentified lymphedema risk from paclitaxel and guide individualized NAC decision.

Phase III postneoadjuvant study evaluating sacituzumab govitecan, an antibody drug conjugate in primary HER2-negative breast cancer patients with high relapse risk after standard neoadjuvant treatment: SASCIA.

TPS602 Background: Women with triple-negative breast cancer (TNBC) having residual disease after neoadjuvant chemotherapy (NACT) as well as HR-positive/HER2-negative breast cancer (BC) with a CPS (clinical and post treatment pathological stage) +EG (estrogen receptor status and grade) score ≥ 3 or score 2 and nodal involvement after NACT (ypN+) are at high risk of recurrence. Sacituzumab govitecan is approved for the treatment of patients with metastatic TNBC who received at least two prior therapies for metastatic disease and has shown activity in heavily pretreated patients with metastatic HR-positive/HER2-negative BC. Therefore, sacituzumab govitecan may represent a new option against the resistant residual disease after standard NACT. Methods: SASCIA is a phase III, prospective, international, multi-center, randomized, open label, parallel group study in patients with HER2-negative BC with residual disease after NACT (NCT04595565). Eligible patients must have received taxane-based NACT for 16 weeks, including at least 6 weeks of a taxane. Patients should be at high risk of recurrence after treatment, defined as having centrally confirmed HER2-negative BC (IHC score 0-1 or FISH negative according to ASCO/CAP guideline) assessed preferably on tissue from postneoadjuvant residual invasive disease of the breast and either HR-negative (&lt;1% positive stained cells), with any residual invasive disease &gt; ypT1mi after NACT or HR-positive (≥1% positive stained cells), with a CPS+EG score ≥ 3 or CPS+EG score 2 and ypN+ using local ER and grade assessed on core biopsies taken before NACT. Radiotherapy should be delivered before the start of study treatment. Patients are randomized 1:1 to receive either sacituzumab govitecan 10 mg/kg body weight (days 1, 8 q3w for eight cycles) or treatment of physician´s choice (capecitabine 2000 mg/m² day 1-14 q21 or platinum-based chemotherapy i.e. carboplatin AUC 5 q3w or AUC 1.5 weekly for eight 3 weekly cycles or observation). Randomization is stratified by HR status (HR-positive vs negative) and nodal involvement after NACT (ypN+ vs ypN0). In patients with HR-positive BC, endocrine-based therapy will be administered according to local guidelines. The primary endpoint is invasive disease-free survival (iDFS). Secondary endpoints include comparison of overall survival (OS, key secondary endpoint), distant disease-free survival, locoregional recurrences-free interval, safety, compliance, iDFS and OS according to stratified and - predefined subgroups, patient reported outcome, and quality of life between treatment arms. As of February 2 2021, 7/1200 patients have been randomized in Germany. International study groups will join soon. Clinical trial information: NCT04595565.

A novel treatment protocol with 6 cycles of neoadjuvant chemotherapy followed by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) in stage III primary ovarian cancer

BackgroundFew prospective studies investigated neoadjuvant chemotherapy (NAC), interval cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in advanced ovarian cancer. We report the results of a phase II study where 6 rather than 3 cycles of NAC, followed by CRS and HIPEC, were adopted (HIPEC_ovaio, EudraCT number 2007-005674-31). Materials and methodsBetween 2007 and 2014, 56 patients with stage III primary ovarian cancer and peritoneal carcinomatosis were assigned to 6 cycles of platinum and taxane-based NAC. Of these, two had progression, 8 underwent palliative surgery, and 46 had CRS and HIPEC. ResultsA complete pathological response was observed in 9 patients. Of 46 patients who completed the treatment protocol, 29 had no macroscopic residual tumor. Postoperative grade III morbidity rate was 28.2%; no grade IV complications or mortality events were observed. Five-year overall survival (OS) of the entire series was 36 ± 7% (median: 36, 95% CI: 26–45 months). In 46 patients treated by CRS and HIPEC, 5-year OS was 42 ± 8% (median: 53, 95% CI: 29–76 months), and 5-year progression-free survival was 26 ± 7% (median: 23, 95% CI: 19–27 months). Completeness of cytoreduction, peritoneal cancer index and FIGO stage resulted as significant prognostic factors. ConclusionsA novel protocol consisting of 6 cycles of NAC, followed by CRS and HIPEC, is associated with notable improvement in peritoneal carcinomatosis, limited postoperative morbidity risk and high survival rates in responders, and could deserve further investigations in randomized clinical trials.

Adjuvant and Neoadjuvant Treatment of Triple-Negative Breast Cancer With Chemotherapy.

Triple-negative breast cancer (TNBC) accounts for 15% to 20% of all invasive breast carcinomas and is defined by the lack of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. Although TNBC is characterized by high rates of disease recurrence and worse survival, it is significantly more sensitive to chemotherapy as compared with other breast cancer subtypes. Accordingly, despite great efforts in the genomic characterization of TNBC, chemotherapy still represents the cornerstone of treatment. For the majority of patients with early-stage TNBC, sequential anthracycline- and taxane-based neoadjuvant chemotherapy (NACT) represents the standard therapeutic approach, with pathological complete response that strongly correlates with long-term survival outcomes. However, some issues about the optimal neoadjuvant regimen, as well as the effective role of chemotherapy in patients with residual disease after NACT, are still debated. Herein, we will review the current evidences that guide the use of (neo)adjuvant chemotherapy in patients with early-stage TNBC. Furthermore, we will discuss current controversies, including the incorporation of platinum compounds to the neoadjuvant backbone and the optimal treatment for patients with residual disease after NACT. Lastly, we will outline potential future directions that can guide treatment escalation and de-escalation, as well as the development of new therapies. In our view, the application of multi-omics technologies, liquid biopsy assays, and machine learning algorithms are strongly warranted to pave the way toward personalized anticancer treatment for early-stage TNBC.

Efficacy and safety of cyclophosphamide in anthracycline- and taxane-based neoadjuvant chemotherapy in breast cancer: a meta-analysis.

Our study aimed to compare the efficacy and safety of anthracycline plus taxane (AT)-based neoadjuvant chemotherapy (NAC) with or without cyclophosphamide in the treatment of breast cancer. We searched PubMed, Embase, Web of Science and the Cochrane Library for randomized controlled studies comparing the efficacy and safety of AT-based NAC with or without cyclophosphamide in breast cancer patients. Four eligible studies with 2,302 individuals were ultimately included in the quantitative analysis. After applying the AT-based NAC regimen, the overall rates of pathologic complete response (pCR) and breast conserving surgery in all included subjects were 26.5% and 70.6%, respectively. The rates of pCR [risk ratio (RR): 1.35; 95% CI: 0.75, 2.45; P=0.32], breast-conserving surgery (RR: 1.07; 95% CI: 0.97, 1.19; P=0.17) and clinical response (RR: 1.08; 95% CI: 0.97, 1.19; P=0.15) in patients in the cyclophosphamide group were similar to those in the control group. However, participants in the cyclophosphamide group had a lower no clinical response rate than those in the control group (RR: 0.72; 95% CI: 0.60, 0.87; P<0.001). Subjects in the cyclophosphamide group had significantly lower rates of infection (RR: 0.57; 95% CI: 0.41, 0.79; P<0.001) and diarrhea (RR: 0.46; 95% CI: 0.30, 0.68; P<0.001) and higher rates of thrombocytopenia (RR: 3.38; 95% CI: 1.96, 5.84; P<0.001), sensory/motor neuropathy (RR: 1.57; 95% CI: 1.03, 2.39; P=0.03) and nausea/vomiting (RR: 1.51; 95% CI: 1.11, 2.06; P=0.009) than those in the control group. The AT-based NAC regimen with or without cyclophosphamide had similar clinical outcomes in breast cancer patients. The addition of cyclophosphamide might increase the risks of thrombocytopenia, sensory/motor neuropathy and nausea/vomiting.

Outcome of radiotherapy for clinically overt metastasis to the internal mammary lymph node in patients receiving neoadjuvant chemotherapy and breast cancer surgery

PurposeThis study was aimed to assess the outcome of radiotherapy and determine prognostic factors for survival in breast cancer patients with clinically overt metastasis to the internal mammary lymph node (IMN+). MethodsWe retrospectively reviewed the medical records of 193 patients with IMN + breast cancer who received neoadjuvant chemotherapy (NAC), breast surgery without internal mammary lymph node (IMN) dissection, and postoperative radiotherapy at 9 hospitals between 2009 and 2013. Breast-conserving surgery or mastectomy was performed after taxane-based NAC. Radiotherapy was administered to the whole breast/chest wall and regional nodes. IMN-covering radiotherapy was performed in 92.2% of patients with median dose of 58.4 Gy (range, 44.9–69.1 Gy). The overall survival (OS), disease-free survival (DFS), and IMN failure-free survival (IMNFFS) were analyzed. ResultsAfter median follow-up of 71 months, 9 patients (4.7%) developed IMN failure and simultaneous distant metastasis. The 5-year DFS, OS, and IMNFFS was 68.6%, 81.8%, and 95.3%, respectively. Non-triple-negative breast cancer, Ki-67 ≤ 10%, pathological complete response (CR) in tumor and axillary node, and radiologic CR of IMN after NAC were significant factors for predicting higher DFS; however, IMN radiation dose was not significant determinants for DFS. The 5-year DFS of patients with IMN-dose ≤ 50.0 Gy and those with >50.0 Gy was 86.7% and 76.7%, respectively (p = 0.41). ConclusionsA multimodality strategy including NAC, breast surgery, and IMN-covering radiotherapy was effective for patients with overt IMN + breast cancer. Even without an IMN dissection, most patients were IMN failure-free with an IMN-focusing radiotherapy.

135 Poster - Omission of axillary dissection after neoadjuvant chemotherapy for node-positive primary breast cancer

Background: Anthracycline and taxane-based neoadjuvant chemotherapy (NAC) has been shown to downstage axillary lymph nodes in approximately 40% of node-positive patients. However, the feasibility of sentinel lymph node biopsy (SLNB) following NAC for initially node-positive patients is unclear because of high false-negative rates reported in previous trials. The aim of this study was to evaluate whether axillary lymph node dissection (ALND) could be safely omitted for patients with clinically node-positive breast cancer treated with NAC.

Abstract PO-007: Breast cancer management during COVID-19 outbreak: Learned lessons

Abstract Purpose: From the first case of COVID-19 infection in Wuhan (China), the infection spread westward around all the world, causing a pandemic. Madrid has been one of the more impacted cities worldwide due to this infection. BC (breast cancer) remains a major public health problem due to its high incidence, prevalence, and mortality. Surgical treatmentss were cancelled and postponed within the worse weeks of the pandemic in our BC Unit, located inside San Carlos Clinical Hospital in Madrid. We aimed to ensure the safety while maintaining the highest health care quality assisting our BC patients during the COVID-19 outbreak. Patients and Methods: All consecutive patients newly diagnosed with BC, patients undergoing neoadjuvant therapy approaching to definitive for surgery, and patients whose surgical treatments were canceled, since March 15th to April 21st, were included in our analysis. Our multidisciplinary team triaged these BC patients and patient treatments were rescheduled including primary genomic platforms and harmonizing the antitumor systemic treatment. Telemedicine was used to evaluate the eventual side effects and to avoid unnecessary hospital visits, minimizing the exposure to COVID-19 risk infection. Results: Surgical treatment was delayed in seven diagnosed cases of CDIS (ductal carcinoma in situ). Six patients with invasive triple-negative BC stage I-III underwent docetaxel plus CBDCA neoadjuvant systemic treatment. Two additional CBDCA-monotherapy cycles were scheduled in two patients in this TNBC group because the surgery had to be postponed. Both patients achieved a pCR. Ten patients with HER+ 2+ BC either ER+ or ER- early (stages I-III) BC received antiHER2-based neoadjuvant chemotherapy (taxanes plus trastuzumab and pertuzumab). Double neoadjuvant antiHER2 moAB followed beyond the 12-18 weeks until a safer time to perform surgery was obtained. Eight out of 13 luminal breast cancer patients underwent the 21 gene recurrence score (RS) assay at the time of the diagnosis. High RS (&amp;gt;25) was found in 2 patients, so they received taxane-based neoadjuvant chemotherapy. Patients with low RS (&amp;lt;25) received neoadjuvant endocrine therapy (w/o LH/RH analogs if needed). The full cohort of our patients agreed on the perceived quality of care. Conclusion: Our patients received oncology primary treatments according to the molecular tumor subtypes until the surgery was safe. The role of interdisciplinary committee and the molecular platforms in neoadjuvant scenario allowed us to ensure safety and quality of care during the COVID outbreak. These strategies could be useful if a second viral wave appears. Citation Format: Juana María Brenes Sánchez, Amanda López Picado, José Ángel García Sáenz, María Eugenia Olivares Crespo, Rosa María De La Plata Merlo, María Herrera De La Muela. Breast cancer management during COVID-19 outbreak: Learned lessons [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2020 Jul 20-22. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(18_Suppl):Abstract nr PO-007.

FDA Approval Summary: Ado-Trastuzumab Emtansine for the Adjuvant Treatment of HER2-positive Early Breast Cancer.

On May 3, 2019, the FDA granted regular approval to ado-trastuzumab emtansine (KADCYLA), for the adjuvant treatment of patients with HER2-positive early-breast cancer (EBC) who have residual invasive disease after neoadjuvant taxane-based chemotherapy and trastuzumab-based treatment. Approval was based on data from the KATHERINE trial, which randomized patients to receive ado-trastuzumab emtansine or trastuzumab. At 3 years, the event-free rate for invasive disease-free survival in the ado-trastuzumab emtansine arm was 88.3% [95% confidence interval (CI), 85.8-90.7] compared with 77.0% (95% CI, 73.8-80.7) in the trastuzumab arm, (HR, 0.50; 95% CI, 0.39-0.64; P < 0.0001). Results from secondary endpoints, subgroup analyses, and sensitivity analyses generally supported the primary efficacy endpoint results. Common adverse reactions (>25% and higher incidence in ado-trastuzumab emtansine arm) with ado-trastuzumab emtansine were fatigue, nausea, increased transaminases, musculoskeletal pain, hemorrhage, thrombocytopenia, headache, peripheral neuropathy, and arthralgia. Ado-trastuzumab emtansine is the first drug approved for the treatment of patients with residual disease after neoadjuvant treatment and surgery. This article summarizes the FDA review and the data supporting the approval of ado-trastuzumab emtansine as a component of treatment for patients with HER2-positive EBC with residual disease.

Comparaison des performances prédictives du TEP-TDM et du nomogramme CGFL/Curie pour prédire la réponse histologique complète après chimiothérapie néo-adjuvante des cancers du sein HER2-positifs

ObjectivesThe aim of this study was to compare the value of 18F-fluorodesoxyglucose positron emission tomography (18F-FDG PET/CT) with CGFL/Curie nomogram to predict a pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) in women with human epidermal growth factor 2 (HER2)-positive breast cancer treated by trastuzumab. MethodsFifty-one women with HER2-positive breast cancer treated with trastuzumab plus taxane-based NAC were retrospectively included from January 2005 to December 2015. For 18F-FDG PET/CT, the analyzed predictor was the maximum standardized uptake value of the primary tumor and axillary nodes after the first course of NAC (PET2.SUVmax). pCR was defined by no residual infiltrative tumor but in situ tumor was accepted. Accuracy of CGFL/Curie nomogram and PET2.SUVmax was evaluated measuring sensitivity (Se), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV). Combined prediction was evaluated testing predictor's associations. ResultsFor CGFL/Curie nomogram's performances, Se, Sp, PPV and NPV were respectively: 76% (95%CI: 58–90%), 57% (95%CI: 43–66%), 55% (95%CI: 42–65), 77% (95%CI: 59–90%). For PET2.SUVmax's performances, Se, Sp, PPV and NPV were respectively: 67% (95%CI: 48–81%), 77% (95%CI: 64–97%), 67% (95%CI: 48–82%), 77% (95%CI: 64–87%). ROC curves for these predictors were similar; the areas under the curve were 0.6 (95%CI: 0.56–0.64) for PET2.SUVmax and 0.55 (95%CI: 0.50–0.59) for CGFL/Curie nomogram. Combined prediction was efficient with Se at 80%, VPN at 76%, Sp at 78% and VPP at 81%. ConclusionsCGFL/Curie nomogram and PET2.SUVmax were two efficient predictors of pCR in patients with HER2-positive breast cancer. Combined prediction has an improved accuracy.

A 3-gene biomarker signature to predict response to taxane-based neoadjuvant chemotherapy in breast cancer.

Breast cancer is the most common cancer in women worldwide, affecting one in eight women in their lifetime. Taxane-based chemotherapy is routinely used in the treatment of breast cancer. The purpose of this study was to develop and validate a predictive biomarker to improve the benefit/risk ratio for that cytotoxic chemotherapy. We explicitly strived for a biomarker that enables secure translation into clinical practice. We used genome-wide gene expression data of the Hatzis et al. discovery cohort of 310 patients for biomarker development and three independent cohorts with a total of 567 breast cancer patients for validation. We were able to develop a biomarker signature that consists of just the three gene products ELF5, SCUBE2 and NFIB, measured on RNA level. Compared to Hatzis et al., we achieved a significant improvement in predicting responders and non-responders in the Hatzis et al. validation cohort with an area under the receiver operating characteristics curve of 0.73 [95% CI, 69%—77%]. Moreover, we could confirm the performance of our biomarker on two further independent validation cohorts. The overall performance on all three validation cohorts expressed as area under the receiver operating characteristics curve was 0.75 [95% CI, 70%—80%]. At the clinically relevant classifier’s operation point to optimize the exclusion of non-responders, the biomarker correctly predicts three out of four patients not responding to neoadjuvant taxane-based chemotherapy, independent of the breast cancer subtype. At the same time, the response rate in the group of predicted responders increased to 42% compared to 23% response rate in all patients of the validation cohorts.

Abstract P2-16-03: Neoadjuvant treatment of triple negative breast cancer patients with docetaxel and carboplatin to assess anti-tumor activity

Abstract Background: Anthracycline- and taxane-based neoadjuvant chemotherapy (NAT) in triple negative breast cancer (TNBC) patients yields a pathological complete response (pCR) rate of approximately 45%. Anthracyclines can lead to long-term toxicities including congestive heart failure and leukemia. TNBC patients achieving pCR have excellent long-term outcomes irrespective of NAT regimen. This study was designed to evaluate the efficacy of a non-anthracycline NAT regimen with carboplatin and docetaxel in TNBC. Correlative studies include detecting and tracking plasma circulating tumor DNA (ctDNA) to determine if it will predict clinical outcomes, and whole exome sequencing (WES) on tissue samples to decipher the genomic architecture of those who achieve pCR versus those who do not. Methods: This is a joint analysis of two identical multicenter trials. Eligible patients with AJCC 7 clinical stages II and III TNBC received docetaxel 75mg/m2 and carboplatin AUC 6 every 3 weeks X 6 cycles. Following NAT, all patients underwent definitive surgery. The primary endpoint is pCR (no invasive tumor in the breast and axilla). Secondary objectives include evaluating ctDNA as a prognostic biomarker that may be used in identifying TNBC patients at a high risk of disease relapse, and evaluating differences in the genomic architecture between pCR and non-pCR patients. Patients have a research biopsy at baseline, cycle 1 day 3 (optional), and at definitive surgery for those with residual disease. Plasma for ctDNA is collected at baseline, cycle 1 day 3, at definitive surgery, and every 6 months for 5 years. Results: Between 2014 and 2019, 103 patients have been registered. Median age is 53 years (range 25-74), 27.2%: African-American, 77.7%: clinical stage II. Ninety-nine have completed NAT and have had surgery. In the intent to treat population, the preliminary pCR rate is 46.5% (95% CI 36.9% - 56.2%). Nine (8.7%) have developed recurrent disease, and 7 (6.8%) have died. Preliminary ctDNA results from 6 patients (4 non-pCR, 2 pCR) show that ctDNA is detectable in 67%. We identified 627 somatic variants by exome analysis. Of these, 10 variants overlapped with the Swift panel (Accel-Amplicon™ 56G Oncology Panel v2) used for ctDNA sequencing and variant detection. TP53 variants were identified in all 6 patients’ tumor tissue samples. At least one TP53 variant was identified in 4 patients’ baseline pre-chemotherapy ctDNA. Both pCR patients had either no detectable ctDNA TP53 mutations, or clearance of ctDNA following chemotherapy. Three non-PCR patients had persistent TP53 mutations in ctDNA during the treatment course. WES and ctDNA analysis on all patients is currently ongoing. Conclusions: We report a very encouraging pCR rate of 46.5% in TNBC patients with carboplatin and docetaxel NAT. This rate is similar to observed rates with anthracycline- and taxane-based NAT and may represent an option for treatment for TNBC patients. Correlative genomic and ctDNA studies are ongoing. Clinical trial information: NCT02124902 &amp; NCT02547987. Citation Format: FOLUSO O ADEMUYIWA, Mothaffar F Rimawi, Tracy Summa, Jingqin Luo, Tao Wang, Rama Suresh, Lindsay Peterson, Michael Naughton, Ashley Frith, Leonel Hernandez-Aya, Katherine Weilbaecher, Cynthia Ma, Aadel A Chaudhuri, Yang-Yang Feng, Zachary L Skidmore, Obi L Griffith, Malachi Griffith, Matthew Ellis. Neoadjuvant treatment of triple negative breast cancer patients with docetaxel and carboplatin to assess anti-tumor activity [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-16-03.

Abstract P2-16-28: Younger age at diagnosis as a prognostic factor in Latin American triple negative breast cancer treated with neoadjuvant chemotherapy

Abstract Background: Triple negative breast cancer (TNBC) typically affects younger women and is associated with an aggressive natural history and worse prognosis. Anthracycline and taxane-based neoadjuvant chemotherapy (NACT) is a standard treatment option for locally advanced TNBC. Althtough baseline and post-NACT clinical and pathologic data provide important prognostic information, the prognostic value of age remains controversial. We aim to evaluate the prognostic impact of age in the outcomes of Latin-American TNBC patients (pts) treated with NACT in a real world scenario.Methods: We performed a retrospective analysis of TNBC pts treated with NACT and surgery between 2011 and 2018 in an academic cancer center. Pts were divided into 2 groups: (A) those younger 40 years old (y) or less and (B) those who were older than 40y ate the time of diagnosis. Electronic records were reviewed for data on clinical and demographic characteristics, treatment and outcomes. Overall survival (OS) was calculated from the date of diagnosis to date of death or last data record and disease-free survival (DFS) was calculated from the date of diagnosis until the date of recurrence. The Kaplan-Meier method was used for survival analysis and the log-rank test to compare survival curves. Prognostic factors were evaluated using Cox regression.Results: We analyzed a cohort of 441 TNBC pts treated with anthracycline and taxane-based NACT followed by surgical resection. For the overall TNBC population, median age was 53.7 years (range: 24-84y), 70.3% had clinical T3-T4 tumor and 68.9% had positive axillary nodes. Groups A and B were comprised of 63 pts (14,3%) and 377 pts (85.5%), respectively. Mean age was 36.0 y for and 56.7 y for Groups A and B, respectively. Baseline characteristics were balanced between groups A and B, including the proportion of T3-T4 tumors (81.0 vs 68.4%, p = 0.052), and rates of clinically positive lymph nodes (76.2 vs 67.9%, p = 0.238). Complete pathological response rates were 20.6% and 30.7% (p = 0.134), for groups A and B, respectively. In the multivariate analysis, clinical T1-2 tumors (HR 0.49, 95%CI 0.28 - 0.84), clinical N0 staging (HR 0.50, 95%CI 0.29 - 0.87), and complete pathological response (HR 0.17, 95%CI 0.08 - 0.38) were associated with better prognosis, while younger age was significantly and independently associated with worse prognosis (HR 1.98, 95%CI 1.20 - 3.27).Conclusion: In Latin American patients with TNBC treated with NACT followed by surgery, the younger age at diagnosis was independently associated with worse prognosis. The inclusion of this under-represented subgroup of patients in future trials is essential to characterize their singularities allowing the development of personalized therapeutic strategies in this group of patients with poor prognosis. Citation Format: Maria FernandaVicentini Neffa, Guilherme Nader Marta, Abraao FerreiraLopes Dornellas, Alessandro Leal, Laura Testa. Younger age at diagnosis as a prognostic factor in Latin American triple negative breast cancer treated with neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-16-28.

Abstract P4-02-07: Validity of omission of axillary lymph node dissection after neoadjuvant chemotherapy for node-positive primary breast cancer

Abstract Background: Anthracycline and taxane-based neoadjuvant chemotherapy (NAC) has been shown to downstage axillary lymph nodes in approximately 40% of patients. However, the feasibility of sentinel lymph node biopsy (SLNB) following NAC for initially node-positive patients is unclear because of high false-negative rates reported in previous trials. The aim of this study was to evaluate whether axillary lymph node dissection (ALND) could be safely omitted for patients with clinically node-positive breast cancer treated with NAC. Patients and methods: We identified 128 patients with clinically node-positive breast cancer who received NAC from March 2006 to March 2017. A correlation between axillary pathologic response and clinicopathological factors was analyzed. Preoperative clinical assessment of lymph-node status was performed by palpation and diagnostic imaging such as ultrasound and MRI. Lymphatic mapping was performed using a combined method of blue dye and radioisotope. Results: The median age was 56.5 (range: 29-79) years and the mean tumor size was 3.6 ± 2.37cm. Of 128 patients, 72 (56.2%) patients had luminal, 32 (31.3%) had HER2-positive, and 24 (18.8%) had triple-negative disease. Sequential anthracycline and taxane were administered for 115 (89.8%) patients, and 25 (78.1%) patients with HER2-positive disease received concomitant trastuzumab preoperatively. Overall, 53 (41.4%) patients achieved axillary pathologic complete response (ypN0). The ypN0 status was significantly correlated with clinical complete response (cCR) in breast (67.9%, p=0.004), ER-negative disease (59.5%, p=0.004) and HER2-positive disease (56.3%, p=0.049). Multivariate analysis demonstrated that cCR in breast (p=0.015) and ER negativity (p=0.006) were significant predictive factors for ypN0. In 14 ER-negative patients achieving cCR in breast, ypN0 was found in 12 (85.7%) patients. Among 85 patients who converted to clinically node-negative, ALND was omitted in 16 patients (18.8%) after SLNB. Of these 16 patients, irradiation to whole-breast and axilla was performed in 14 (87.5%) and 5 (31.3%) patients, respectively. After a median follow-up of 53.2 months, no axillary recurrence was observed in entire patients and 5-year disease-free survival was not significantly different between patients with or without ALND (85.5% vs. 87.5%, p=0.965). Conclusions: As ER-negativity and cCR were correlated with high eradication rate of initially positive lymph nodes, these patients might be good candidates of omission of ALND after NAC. Citation Format: Akiko Matsumoto, Yasuko Umemoto, Daisuke Tsukahara, Hiromitsu Jinno. Validity of omission of axillary lymph node dissection after neoadjuvant chemotherapy for node-positive primary breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-02-07.

Abstract P2-16-14: HER2-positive breast cancer: Combined 18F-FDG PET and CGFL/Curie nomogram to predict pathologic complete response after preoperative chemotherapy with trastuzumab

Abstract Background The aim of this study was to compare the value of 18F-fluorodesoxyglucose positron emission tomography (18F-FDG PET/CT) with CGFL/Curie nomogram to predict a pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) in women with human epidermal growth factor 2 (HER2)-positive breast cancer treated by trastuzumab. Methods Fifty-one women with HER2-positive breast cancer treated with trastuzumab plus taxane-based NAC, were retrospectively included from January 2005 to December 2015. For 18F-FDG PET/CT, the analyzed predictor was the maximum standardized uptake value of the primary tumor and axillary nodes after the first course of NAC (PET2.SUVmax). pCR was defined by no residual infiltrative tumor but in situ tumor was accepted. Accuracy of CGFL/Curie nomogram and PET2.SUVmax was evaluated measuring sensitivity (Se), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV). For each predictor, receiver operating characteristic (ROC) curve was created. To evaluate the correlation between predictors, the Spearman coefficient was calculated. Combined prediction was evaluated testing predictor’s associations. Results For CGFL/Curie nomogram’s performances, Se, Sp, PPV and NPV were respectively: 76% (CI95%: 58-90%), 57% (CI95%: 43-66%), 55% (CI95%: 42-65), 77% (CI95%: 59-90%). For PET2.SUVmax’s performances, Se, Sp, PPV and NPV were respectively: 67% (CI95%: 48-81%), 77% (CI95%: 64-97%), 67% (CI95%: 48-82%), 77% (CI95%: 64-87%). ROC curves for these predictors were similar; the areas under the curve were 0.6 (CI95%: 0.56-0.64) for PET2.SUVmax and 0.55 (CI95%: 0.50-0.59) for CGFL/Curie nomogram. Spearman coefficient was 0.23. Combined prediction was more efficient with Se at 80%, VPN at 76%, Sp at 78% and VPP at 81 %. Conclusions CGFL/Curie nomogram and PET2.SUVmax were two efficient predictors of pCR in patients with HER2-positive breast cancer. Combined prediction has an improved accuracy. Citation Format: Laura Vincent, Clémentine Jankowski, Marion Cortet, Laurent Arnould, Sylvain Ladoire, Bruno Coudert, Isabelle Desmoulins, Céline Charron-Barra, Françoise Beltjens, Roman Rouzier, Fabien Reyal, Olivier Humbert, Alexandre Cochet, Charles Coutant. HER2-positive breast cancer: Combined 18F-FDG PET and CGFL/Curie nomogram to predict pathologic complete response after preoperative chemotherapy with trastuzumab [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-16-14.

Abstract OT1-01-04: A randomized phase 2 study of peri-operative ipilimumab, nivolumab and cryoablation versus standard care in women with residual, early stage/resectable, triple negative breast cancer after standard-of-care neoadjuvant chemotherapy

Abstract Background: Local tumor destruction with cryoablation (cryo) induces inflammation and releases antigens that can activate tumor-specific immune responses. Pre-clinically, cryo with checkpoint inhibition augmented tumor-specific immune responses and prevented recurrence. Clinically, we established that peri-operative (peri-op) cryo with ipilimumab (ipi) +/- nivolumab (nivo) was not only safe in patients (pts) with operable, early stage breast cancer (ESBC) but also generated robust intra-tumoral and systemic immune responses. In this randomized phase 2 study, we evaluate the disease specific impact of peri-op ipi/nivo/cryo versus standard care in women with residual triple negative breast cancer (TNBC) after neoadjuvant chemotherapy (NAC), a subset at high risk of early relapse. Methods: Eligible pts are ≥18y, with ER &amp;lt;10%, PR &amp;lt;10%, HER2 negative (per ASCO/CAP definition), ≥ 1.0 cm, residual operable disease after taxane-based NAC. Approximately 160 pts will be randomized to one of two arms: breast surgery (control arm) or ipi/nivo/cryo followed by breast surgery and adjuvant nivo (intervention arm). Pts in the intervention arm will undergo percutaneous, image-guided cryo with concurrent research core biopsy 7-10 days prior to surgery and will receive ipi (1mg/kg IV) with nivo (240mg IV) 1 to 5 days prior to cryo. After surgery, pts will receive 3 additional doses of nivo at 240mg IV Q2 weeks. Adjuvant capecitabine is recommended for all patients per local standard-of-care. Patients will be stratified by NAC platinum administration, NAC anthracycline administration, and clinical nodal status (positive versus negative). The primary endpoint is 3-year Event Free Survival (EFS). Secondary endpoints include Invasive Disease-Free Survival (IDFS), Distant Disease-Free Survival (DDFS), overall survival (OS) and safety. Exploratory correlative studies will be performed on tumor and serum to characterize the immunologic impact of the intervention and to explore predictors of efficacy and toxicity. Citation Format: Heather McArthur, Elizabeth Comen, Yolanda Bryce, Stephen B Solomon, Jorge Leal, Micaela Rodine, Christina DiLauro Abaya, Sujita Patil, David Page, Larry Norton. A randomized phase 2 study of peri-operative ipilimumab, nivolumab and cryoablation versus standard care in women with residual, early stage/resectable, triple negative breast cancer after standard-of-care neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT1-01-04.

Abstract P1-01-02: Early changes in diffuse optical tomography predicts pathologic complete response to neoadjuvant chemotherapy in triple-negative breast cancer

Abstract Background: Optical based imaging modalities have shown promise for monitoring tumor response to neoadjuvant chemotherapy (NAC) in patients with breast cancer (BC). Patients with triple negative BC (TNBC) who achieve a pathologic complete response (pCR) have improved disease free and overall survival after NAC. In this study, we evaluated whether early changes in diffuse optical tomography breast imaging system (DOTBIS) parameters can predict a pCR. In particular, we studied total hemoglobin concentration (ctHbT) in the tumor region. Methods: This is a retrospective evaluation of 105 stage II-III BC patients enrolled in a prospective cohort study between 2011 and 2019. All patients received standard taxane-based chemotherapy in the neoadjuvant setting and pCR was defined as no invasive tumor cells from the breast and axillary tissue at surgery (ypT0 ypN0). Residual Cancer Burden (RCB) score was also calculated. By imaging the whole breast volume using low intensity near infrared light, we measured tissue concentration of oxy-hemoglobin (ctO2Hb) and deoxy-hemoglobin (ctHHb). After tumor volume segmentation, the mean ctHbT (ctO2Hb+ ctHHb) extracted from the region of interest was normalized by the non-tumor region ctHbT mean value. We conducted an independent-samples t-test to determine if there was a difference in changes in the normalized ctHbT levels at week 4 (w4) between patients with a pCR and non-pCR. A Pearson's correlation assessed for correlation between RCB score and changes in the normalized ctHbT level at w4 compared to baseline. Results: In total, 77 patients had complete data for the analysis. Of these, TNBC accounted for 18% (14/77) of BC cases. DOTBIS data was acquired at baseline for all patients. Twelve patients received weekly paclitaxel x 12, followed by dose-dense adriamycin/cyclophosphamide every 2 weeks x 4, and two received docetaxel/cyclophosphamide every 3 weeks x 6. Ten of 14 TNBC patients were imaged after four weeks of taxane-based NAC (w4). Of the 14 TNBC patients, 6 (43%) achieved pCR. Two patients were classified as RCB-I, 5 as RCB-II, and 1 non-pCR patient without an available RCB. After comparing normalized ctHbT levels at w4 to baseline, NAC was associated with an overall decrease of 28% for the pCR group (n=5) as opposed to an increase of 67% for non-pCR (n=5). The normalized ratio between ctHbT levels measured at w4 and baseline was statistically lower in the pCR group (0.72 ± 0.28) than non-pCR (1.67 ± 0.83) (95% CI, 0.17 to 2.09), p = .043. Changes in the normalized ctHbT levels after 4 weeks of NAC were strongly correlated to RCB score (r = .833, p = .005). Conclusions: This study demonstrates that changes as early as 4 weeks in DOTBIS-measured ctHbT levels in patients with TNBC receiving NAC correlate strongly with pathologic response. If further validated on a larger set, these data could potentially be used to optimize treatment outcomes or improve personalized therapeutic strategies. Citation Format: Mirella L Altoe, Kevin Kalinsky, Hua Guo, Hanina Hibshoosh, Mariella Tejada, Katherine D Crew, Melissa K Accordino, Meghna S Trivedi, Alessandro Marone, Hyun K Kim, Andreas H Hielscher, Dawn L Hershman. Early changes in diffuse optical tomography predicts pathologic complete response to neoadjuvant chemotherapy in triple-negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-01-02.