Drug Development: Neoadjuvant Opportunities in Breast Cancer

2013 ◽  
pp. 73-79
Author(s):  
Priya Rastogi ◽  
Charles E. Geyer ◽  
Eleftherios P. Mamounas ◽  
Angela DeMichele
Keyword(s):  
Breast Cancer ◽  
Clinical Trials ◽  
Cancer Biology ◽  
Residual Disease ◽  
Pathologic Complete Response ◽  
Predictive Biomarkers ◽  
Preoperative Therapy ◽  
New Agents ◽  
Her2 Breast Cancer ◽  
Improved Outcomes

Preoperative therapy allows for a higher rate of breast conserving surgery and has been shown equivalent to adjuvant therapy. Preoperative therapy provides an opportunity to obtain insights into breast cancer biology and to accelerate the evaluation of new therapies. Clinical trials have shown that women who achieve a pathologic complete response (pCR) have substantially improved outcomes compared with those who do not achieve a pCR. The U.S. Food and Drug Administration (FDA) meta-analysis demonstrated that the association of pCR and long-term outcomes is greater in women with aggressive breast cancer subtypes. In patients with HER2+ breast cancer, the addition of trastuzumab to chemotherapy in the neoadjuvant setting has doubled pCR and correlated with improved outcomes. Clinical trials will evaluate tailoring the use of radiation therapy in patients who have received neoadjuvant therapy. Trials have established neoadjuvant endocrine therapy as a valid treatment and research option for ER-rich breast cancer. The neoadjuvant setting allows for evaluation of endocrine therapies in combination with newer targeted therapies in the appropriate patient populations. The neoadjuvant setting provides opportunity to accelerate the evaluation of new agents, improve pCR rates, and identify predictive biomarkers for response. This setting provides the opportunity for screening new agents in combination with chemotherapy while obtaining serial biopsies to understand biology of response and resistance. Although current standard therapies provide substantial benefits for patients with a pCR, patients with residual disease are at substantial risk for disease recurrence. New agents are being evaluated in patients with high-risk residual disease following standard treatment regimens.

Comprehensive assessment of cancer stem cell like cells in prediction of pathologic complete response to preoperative dual anti–HER2 therapy for HER2–positive primary breast cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e12123-e12123
Author(s):  
Jose Rodrigo Espinosa Fernandez ◽  
Teruo Yamauchi ◽  
Chiyo K. Imamura ◽  
Hideko Yamauchi ◽  
Hiromitsu Jinno ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Tumor Cells ◽  
Prospective Trial ◽  
Pathologic Complete Response ◽  
Predictive Biomarkers ◽  
Preoperative Therapy ◽  
Her2 Positive ◽  
Her2 Breast Cancer ◽  
The Impact

e12123 Background: Chemotherapy for breast cancer destroys non–stem cells while sparing cancer stem cells (CSCs). In contrast, anti–HER2 therapy may eliminate resistant cells because HER2 may be a key driver of CSCs. CSC biomarkers have been found to be prognostic of poor outcome and predictive of resistance to therapy. However, there are no comprehensive studies of the impact of anti-HER2 therapies on CSC–related biomarkers. We conducted a prospective biomarker determination study of breast CSCs characterized by CD44v expression and increased aldehyde dehydrogenase 1 (ALDH1) enzymatic activity or expression. Methods: In a prospective trial (ClinicalTrials.gov: NCT01688609), 18 patients with operable primary HER2+ breast cancer (≥T2 excluding inflammatory, any N; median age of 54 yrs) were treated with preoperative anti–HER2 therapy following the NeoALTTO trial dual therapy arm regimen, with a goal of identifying novel predictive biomarkers for pCR. Proportions of tumor cells with CSC characteristics, defined as CD44v+ and ALDH1+, were estimated at baseline, at 6 weeks (after therapy with lapatinib/trastuzumab) and at 18 weeks (after therapy with lapatinib/trastuzumab and paclitaxel) to assess adaptive response. We determined changes in the quantity and characteristics of CSC–related biomarkers during preoperative therapy and correlated them to tumor response. Results: Out of 18 patients, 8 (44%) had a pCR; 5 of these 8 patients (62%) were positive for CD44v staining on tumor cells at baseline and none were positive on the 6–week biopsy. In contrast, 6 of the 10 patients without pCR exhibited persistent levels, or enrichment of CD44v proportion and expression at 6 and 18 weeks (p = 0.0128). ALDH1 expression and other biomarkers were not statistically significant predictors of pCR. Conclusions: Enrichment of CD44v+ tumor cells after double anti–HER2 therapy may predict poor response to dual anti–HER2 therapy with cytotoxic chemotherapy. A second biopsy after the start of preoperative therapy may reflect biological changes useful for the guidance and application of therapeutic strategies for patients with HER2+ breast cancer. Clinical trial information: NCT01688609.

scholarly journals Current trends in the treatment of HR+/HER2+ breast cancer

2021 ◽  
Vol 17 (13) ◽  
pp. 1665-1681
Author(s):  
Charlene Kay ◽  
Carlos Martínez-Pérez ◽  
James Meehan ◽  
Mark Gray ◽  
Victoria Webber ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Trials ◽  
Trastuzumab Emtansine ◽  
Breast Cancers ◽  
Newly Diagnosed ◽  
Luminal A ◽  
New Agents ◽  
Her2 Breast Cancer ◽  
Current Trends

Treatment for HR+/HER2+ patients has been debated, as some tumors within this luminal HER2+ subtype behave like luminal A cancers, whereas others behave like non-luminal HER2+ breast cancers. Recent research and clinical trials have revealed that a combination of hormone and targeted anti-HER2 approaches without chemotherapy provides long-term disease control for at least some HR+/HER2+ patients. Novel anti-HER2 therapies, including neratinib and trastuzumab emtansine, and new agents that are effective in HR+ cancers, including the next generation of oral selective estrogen receptor downregulators/degraders and CDK4/6 inhibitors such as palbociclib, are now being evaluated in combination. This review discusses current trials and results from previous studies that will provide the basis for current recommendations on how to treat newly diagnosed patients with HR+/HER2+ disease.

Recent Updates in the Management of Triple Negative Breast Cancer

2016 ◽  
Vol 12 (01) ◽  
pp. 36
Author(s):  
Tara Sanft ◽  
Meena S Moran ◽  
◽  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Residual Disease ◽  
Treatment Options ◽  
New Agents ◽  
Locoregional Treatment ◽  
Disease Biology ◽  
Improved Outcomes ◽  
Druggable Targets

Triple negative breast cancer is the most aggressive subtype of breast cancer, characterized by a lack of targeted therapy. Neoadjuvant chemotherapy is used to understand disease biology; patients who attain a complete pathologic response have improved outcomes compared to those who have residual disease. Locoregional treatment options remain similar to other types of breast cancer. Further research to identify druggable targets is ongoing and new agents appear to be on the horizon.

Impact of neoadjuvant HER2-directed therapy on HER2 status in breast cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e12130-e12130
Author(s):  
Nicholas Manguso ◽  
Jeffrey Johnson ◽  
Reva Kakkar Basho ◽  
Heather L. McArthur ◽  
Hisashi Tanaka ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Neoadjuvant Therapy ◽  
Residual Disease ◽  
Pathologic Complete Response ◽  
Residual Tumor ◽  
Her2 Status ◽  
Her2 Positive ◽  
Her2 Breast Cancer ◽  
Copy Numbers ◽  
Pre Treatment

e12130 Background: Neoadjuvant chemotherapy (NAC) with HER2-directed therapy has become standard-of-care for most women with potentially curable HER2-positive (HER2+) breast cancer and is associated with a high pathologic complete response (pCR) rate. The HER2 status of residual disease after NAC is not well characterized and could potentially inform clinical decisions about additional systemic therapy. We describe tumoral HER2 status before and after NAC with HER2-directed therapy. Methods: An institutional database was screened to identify patients with stage 1-3 HER2+ breast cancer by fluorescence in situ hybridization (FISH) and/or immunohistochemistry (IHC) who received NAC with HER2-directed therapy followed by resection between 2011 and 2015. Clinicopathologic data was collected. Change in HER2 status by FISH and IHC following treatment was described. Results: 99 patients were identified. Median age was 49 years (range 26-85). Pre-treatment median HER2/CEP17 copy number ratio (CNR) for all tumors was 6.3 (range 1.9-20.7) by FISH and 84 (84.8%) tumors were IHC 3+. 44 (44.4%) patients achieved a pCR. Of the 55 patients with residual disease, 35 had sufficient residual tumor to evaluate HER2 status and 14/35 (40%) were HER2- by FISH and IHC (table). Tumors converting from HER2+ to HER2- had lower pre-treatment median HER2 copy numbers (11.9, range 4.6-22) compared to tumors that remained HER2+ (18.3, range 5.1-48.6; p=0.04) after neoadjuvant therapy. Additionally, pre-treatment median HER2/CEP17 CNR was lower among tumors that converted from HER2+ to HER2- (3.0, range 2.2-8.2) compared to those remaining HER2+ (6.8, range 2-15.7; p=0.02). Conclusions: While pCR rates are high with NAC and HER2-directed therapy, many patients still have residual tumor. In this cohort, 40% of patients with evaluable residual disease after NAC had HER2+ tumors that became HER2-. HER2 conversion was associated with lower pre-treatment HER2 copy numbers and HER2/CEP17 CNR. Conversion from HER2+ to HER2- in patients undergoing neoadjuvant therapy may have clinical significance and biological implications. [Table: see text]

Escalating and De-escalating Therapy for Early-Stage HER2-Positive Breast Cancer

2020 ◽  
pp. 3-13
Author(s):  
Danielle File ◽  
Giuseppe Curigliano ◽  
Lisa A. Carey
Keyword(s):  
Breast Cancer ◽  
Residual Disease ◽  
Early Stage ◽  
Clinical Stage ◽  
Pathologic Complete Response ◽  
Complete Response ◽  
Intrinsic Subtype ◽  
Her2 Positive ◽  
Drug Conjugates ◽  
Her2 Breast Cancer

Untreated, HER2+ disease is the most aggressive breast cancer phenotype; however, the development of multiple highly effective HER2-targeting drugs has transformed treatment and survival. These drugs include the anti-HER2 monoclonal antibodies trastuzumab and pertuzumab; small molecule inhibitors lapatinib, neratinib, and tucatinib; and antibody-drug conjugates trastuzumab emtansine (T-DM1) and now trastuzumab deroxtecan. More complex regimens using these drugs continue to improve outcomes, but the incremental benefits of these advances are often modest. Improved outcomes came from the addition of HER2-targeted therapies to conventional chemotherapy, beginning with trastuzumab, then pertuzumab added to trastuzumab, or with neratinib given for the year after trastuzumab. Neoadjuvant, or preoperative, administration of chemotherapy plus HER2-targeting allows surgical deescalation and tailoring treatment by pathologic complete response (pCR) to therapy. Patients with pCR after conventional therapy have excellent outcomes; what we now know is that the poorer outcomes associated with residual disease can be ameliorated with adjuvant T-DM1. However, as we have developed more complex, effective, and expensive therapy to maximize outcomes, it is also true that we are overtreating many patients. In stage I HER2+ breast cancer, there are excellent outcomes with paclitaxel plus trastuzumab or T-DM1 alone. Higher clinical stage HER2+ disease is still treated aggressively, although intrinsic subtype or activated immune tumor microenvironment may identify those with augmented treatment response or better outcome. It is likely that future strategies to escalate and de-escalate treatment with less chemotherapy, fewer anti-HER2 drugs, or shorter duration will depend upon integrated clinical and genomic modeling.

Association between treatment duration and overall survival in early-stage HER2+ breast cancer patients receiving extended adjuvant therapy with neratinib in the ExteNET trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 540-540
Author(s):  
Beverly Moy ◽  
Masato Takahashi ◽  
Shoichiro Ohtani ◽  
Ewa Chmielowska ◽  
Naohito Yamamoto ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Adjuvant Therapy ◽  
Residual Disease ◽  
Early Stage ◽  
Pathologic Complete Response ◽  
Disease Free Survival ◽  
Cox Proportional Hazards ◽  
Breast Cancer Patients ◽  
Her2 Breast Cancer

540 Background: Completion of planned treatment has been shown to improve clinical outcomes. In the ExteNET trial (NCT00878709), where diarrhea prophylaxis was not mandated, 17% of patients (pts) discontinued neratinib early due to diarrhea. This compares with 3.3% of pts from the CONTROL trial (NCT02400476) who used a neratinib dose-escalation strategy. Prior analyses have shown improved invasive disease-free survival (iDFS) in pts who completed planned duration of neratinib therapy in ExteNET (Table). Here we assess outcomes, including overall survival (OS), for pts who completed planned therapy in 3 groups from ExteNET: intent-to-treat (ITT) population; pts with hormone receptor-positive (HR+) disease who initiated neratinib within 1y after prior trastuzumab (HR+/≤1y, the population neratinib is approved for in the EU); and HR+/≤1y with residual disease post-neoadjuvant therapy (no pathologic complete response [pCR]). Methods: Pts with early-stage HER2+ breast cancer received oral neratinib 240 mg/d or placebo after trastuzumab-based (neo)adjuvant therapy. Pts who completed neratinib therapy (defined as ≥11m or cessation of neratinib if recurrence occurred prior to 11m) were compared with placebo (all randomized pts). iDFS and OS were analyzed using Kaplan-Meier methods; hazard ratios (HR) with 95% confidence intervals (CI) were estimated using Cox proportional-hazards models. Data cutoff: July 2019. Results: There were 2840 pts in the ITT population. The table shows iDFS and OS in the overall population and in pts who completed planned duration of neratinib therapy. Completion of planned neratinib was associated with improvements in iDFS and OS in all groups evaluated. Conclusions: These descriptive findings suggest that pts who receive the recommended duration of treatment of 1y with neratinib may have improved outcomes. Clinical trial information: NCT00878709. [Table: see text]

scholarly journals Top 3 abstracts concerning hormone-receptor-positive early breast cancer

2021 ◽  
Author(s):  
Simon Peter Gampenrieder ◽  
Gabriel Rinnerthaler ◽  
Richard Greil
Keyword(s):  
Breast Cancer ◽  
Adjuvant Chemotherapy ◽  
Endocrine Therapy ◽  
Early Breast Cancer ◽  
Hormone Receptor ◽  
Menopausal Status ◽  
Pathologic Complete Response ◽  
Oncotype Dx ◽  
Hormone Receptor Positive ◽  
Her2 Breast Cancer

SummaryThe three top abstracts at the 2020 virtual San Antonio Breast Cancer Symposium regarding hormone-receptor-positive early breast cancer, from our point of view, were the long-awaited results from PenelopeB and RxPONDER as well as the data from the ADAPT trial of the West German Study Group. PenelopeB failed to show any benefit by adjuvant palbociclib when added to standard endocrine therapy in patients without pathologic complete response after neoadjuvant chemotherapy. RxPONDER demonstrated that postmenopausal patients with early hormone receptor positive (HR+)/human epidermal growth factor receptor 2 negative (HER2−) breast cancer, 1–3 positive lymph nodes and an Oncotype DX Recurrence Score of less than 26 can safely be treated with endocrine therapy alone. In contrast, in premenopausal women with positive nodes, adjuvant chemotherapy plays still a role even in case of low genomic risk. Whether the benefit by chemotherapy is mainly an indirect endocrine effect and if ovarian function suppression would be similarly effective, is still a matter of debate. The HR+/HER2− part of the ADAPT umbrella trial investigated the role of a Ki-67 response to a short endocrine therapy before surgery in addition to Oncotype DX—performed on the pretreatment biopsy—to identify low-risk patients who can safely forgo adjuvant chemotherapy irrespective of menopausal status.

scholarly journals Recommendations for standardized pathological characterization of residual disease for neoadjuvant clinical trials of breast cancer by the BIG-NABCG collaboration

2015 ◽  
Vol 26 (7) ◽  
pp. 1280-1291 ◽  
Author(s):  
V. Bossuyt ◽  
E. Provenzano ◽  
W.F. Symmans ◽  
J.C. Boughey ◽  
C. Coles ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Trials ◽  
Residual Disease

Independent validation of simbiosys tumorscope to predict response to neoadjuvant chemotherapy (NACT) in early breast cancer (EBC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 582-582
Author(s):  
Gong He ◽  
Frederick Howard ◽  
Tushar Pandey ◽  
Hiroyuki Abe ◽  
Rita Nanda
Keyword(s):  
Breast Cancer ◽  
Sensitivity And Specificity ◽  
Cancer Biology ◽  
Tumor Volume ◽  
Performance Metrics ◽  
External Validation ◽  
Pathologic Complete Response ◽  
Disease Free Survival ◽  
Biophysical Model ◽  
Lymph Node Status

582 Background: Despite substantial advances in the understanding of breast cancer biology, the decision to use NACT for EBC is based on tumor size, lymph node status, and subtype. Even with aggressive therapy, the majority of women will not achieve a pathologic complete response (pCR). Investigational treatment regimens, including immunotherapy, can increase pCR rates, but are associated with irreversible immune-related toxicities. Being able to accurately predict pCR could identify candidates for intensification or de-escalation of NACT, allowing for personalized medicine. SimBioSys TumorScope (TS) is a biophysical model that utilizes baseline MRI, receptor status, and planned treatment regimen to simulate response to NACT over time. TS has demonstrated accurate prediction of pCR in prior studies. Here, we describe an independent external validation of TS. Methods: We conducted a retrospective study of University of Chicago patients (pts) who received NACT for EBC from Jan 2010 - March 2020. Pts must have had a pretreatment breast MRI. Tumors were analyzed using TS by investigators who were blinded to response data. TS predicted pCR was predefined as a residual tumor volume < 0.01 cm3 or a 99.9% or greater reduction in tumor volume. Performance metrics of TS were calculated. Results: 144 tumors from 141 pts were analyzed. Average age was 52 yrs; 65% had stage II and 19% had stage III disease. Sensitivity and specificity of TS for predicting pCR were 90.4% and 92.4%, respectively. Of the 7 patients who were predicted to achieve a pCR but did not, 5 had a tumor cellularity < 5%. With a median follow-up of 4.7 yrs, the 4-yr distant disease free survival (DDFS) was 100% for patients predicted to achieve pCR, versus 81.5% for those predicted to have residual disease. Results were generally robust for all subgroups analyzed (Table). Conclusions: TS accurately predicts pCR and DDFS from baseline MRI and clinicopathologic data. Given the high sensitivity and specificity of this assay across breast cancer subtypes, TS can be used to aid in escalation/de-escalation strategies for EBC.[Table: see text]

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