Joyce O'Shaughnessy M.D.

Kaufman, P.A., Hurvitz, S.A., O’Shaughnessy, J., Mason, G., Yardley, D.A., Brufsky, A.M., Rugo, H.S., Cobleigh, M., Swain, S.M., Tripathy, D., Morris, A., Antao, V., Li, H. and Jahanzeb, M. (2021). “Baseline characteristics and first-line treatment patterns in patients with HER2-positive metastatic breast cancer in the SystHERs registry.” Breast Cancer Res Treat Feb 28. [Epub ahead of print].

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BACKGROUND: Systemic Therapies for HER2-Positive Metastatic Breast Cancer Study (SystHERs, NCT01615068) was a prospective, observational disease registry designed to identify treatment patterns and clinical outcomes in patients with HER2-positive metastatic breast cancer (MBC) in real-world treatment settings. METHODS: SystHERs enrolled patients aged ≥ 18 years with recently diagnosed HER2-positive MBC. Treatment regimens and clinical management were determined by the treating physician. In this analysis, patients were compared descriptively by first-line treatment, age, or race. Multivariate logistic regression was used to examine the associations between baseline variables and treatment selections. Clinical outcomes were assessed in patients treated with trastuzumab (Herceptin [H]) + pertuzumab (Perjeta [P]). RESULTS: Patients were enrolled from June 2012 to June 2016. As of February 22, 2018, 948 patients from 135 US treatment sites had received first-line treatment, including HP (n = 711), H without P (n = 175), or no H (n = 62) (with or without chemotherapy and/or hormonal therapy). Overall, 68.7% received HP + taxane and 9.3% received H without P + taxane. Patients aged < 50 years received HP (versus H without P) more commonly than those ≥ 70 years (odds ratio 4.20; 95% CI, 1.62-10.89). Chemotherapy was less common in patients ≥ 70 years (68.2%) versus those < 50 years (88.0%) or 50-69 years (87.4%). Patients treated with HP had median overall survival of 53.8 months and median progression-free survival of 15.8 months. CONCLUSIONS: Our analysis of real-world data shows that most patients with HER2-positive MBC received first-line treatment with HP + taxane. However, older patients were less likely to receive dual HER2-targeted therapy and chemotherapy.

Jackisch, C., Barcenas, C.H., Bartsch, R., Palma, J.D., Glück, S., Harbeck, N., Macedo, G., O’Shaughnessy, J., Pistilli, B., Ruiz-Borrego, M. and Rugo, H.S. (2021). “Optimal Strategies for Successful Initiation of Neratinib in Patients with HER2-Positive Breast Cancer.” Clin Breast Cancer Feb 6;S1526-8209(21)00043-4. [Epub ahead of print].

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Neratinib is an irreversible, pan-human epidermal growth factor inhibitor that has shown efficacy across human epidermal growth factor receptor 2 (HER2)-positive breast cancer settings. Neratinib is indicated for use as extended adjuvant therapy for HER2-positive early-stage breast cancer or, in combination with capecitabine, in the treatment of HER2-positive metastatic breast cancer. The primary tolerability concern with neratinib is diarrhea, and severe diarrhea early in treatment can lead to a substantial proportion of patients discontinuing neratinib, which may lead to reduced or nonexistent efficacy. In order to establish a set of treatment recommendations for use of neratinib, on May 12, 2020, an expert panel of oncologists and gastroenterologists met virtually to discuss the role of neratinib in the treatment of patients with HER2-positive breast cancer. The panel reviewed the current data on neratinib, including efficacy across settings and diarrhea management strategies. Based on these data and their clinical experience, the panelists developed a set of recommendations to guide selection of patients for neratinib, implement weekly dose escalation at initiation of therapy, and prophylactically manage diarrhea.

Filho, O.M., Stover, D.G., Asad, S., Ansell, P.J., Watson, M., Loibl, S., Geyer, C.E., Jr., Bae, J., Collier, K., Cherian, M., O’Shaughnessy, J., Untch, M., Rugo, H.S., Huober, J.B., Golshan, M., Sikov, W.M., von Minckwitz, G., Rastogi, P., Maag, D., Wolmark, N., Denkert, C. and Symmans, W.F. (2021). “Association of Immunophenotype With Pathologic Complete Response to Neoadjuvant Chemotherapy for Triple-Negative Breast Cancer: A Secondary Analysis of the BrighTNess Phase 3 Randomized Clinical Trial.” JAMA Oncol Feb 18;e207310. [Epub ahead of print].

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IMPORTANCE: Adding carboplatin to standard neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC) likely benefits a subset of patients; however, determinants of benefit are poorly understood. OBJECTIVE: To define the association of molecular subtype, tumor proliferation, and immunophenotype with benefit of carboplatin added to NAC for patients with stages II to III TNBC. DESIGN, SETTING, AND PARTICIPANTS: This was a prespecified secondary analysis of a phase 3, double-blind, randomized clinical trial (BrighTNess) that enrolled 634 women across 145 centers in 15 countries. Women with clinical stages II to III TNBC who had undergone pretreatment biopsy were eligible to participate. Whole transcriptome RNA sequencing was performed on the biopsy specimens. The prespecified end point was association of pathologic complete response (pCR) with gene expression-based molecular subtype, with secondary end points investigating established signatures (proliferation, immune) and exploratory analyses of immunophenotype. Data were collected from April 2014 to March 2016. The study analyses were performed from January 2018 to March 2019. INTERVENTIONS: Neoadjuvant chemotherapy with paclitaxel followed by doxorubicin and cyclophosphamide, or this same regimen with carboplatin or carboplatin plus veliparib. MAIN OUTCOMES AND MEASURES: Association of gene expression-based molecular subtype (PAM50 and TNBC subtypes) with pCR. RESULTS: Of the 634 women (median age, 51 [range, 22-78] years) enrolled in BrighTNess, 482 (76%) patients had evaluable RNA sequencing data, with similar baseline characteristics relative to the overall intention-to-treat population. Pathologic complete response was significantly more frequent in PAM50 basal-like vs nonbasal-like cancers overall (202 of 386 [52.3%] vs 34 of 96 [35.4%]; P = .003). Carboplatin benefit was not significantly different in basal-like vs nonbasal-like subgroups (P = .80 for interaction). In multivariable analysis, proliferation (hazard ratio, 0.36; 95% CI, 0.21-0.61; P < .001) and immune (hazard ratio, 0.62; 95% CI, 0.49-0.79; P < .001) signatures were independently associated with pCR. Tumors above the median for proliferation and immune signatures had the highest pCR rate (84 of 125; 67%), while those below the median for both signatures had the lowest pCR rate (42 of 125; 34%). Exploratory gene expression immune analyses suggested that tumors with higher inferred CD8+ T-cell infiltration may receive greater benefit with addition of carboplatin. CONCLUSIONS AND RELEVANCE: In this secondary analysis of a randomized clinical trial, triple-negative breast cancer subtyping revealed high pCR rates in basal-like and immunomodulatory subsets. Analysis of biological processes related to basal-like and immunomodulatory phenotypes identified tumor cell proliferation and immune scores as independent factors associated with achieving pCR; the benefit of carboplatin on pCR was seen across all molecular subtypes. Further validation of immunophenotype with existing biomarkers may help to escalate or de-escalate therapy for patients with TNBC. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02032277.

O’Shaughnessy, J., Brezden-Masley, C., Cazzaniga, M., Dalvi, T., Walker, G., Bennett, J. and Ohsumi, S. (2020). “Prevalence of germline BRCA mutations in HER2-negative metastatic breast cancer: global results from the real-world, observational BREAKOUT study.” Breast Cancer Res 22(1): 114.

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BACKGROUND: The global observational BREAKOUT study investigated germline BRCA mutation (gBRCAm) prevalence in a population of patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC). METHODS: Eligible patients had initiated first-line cytotoxic chemotherapy for HER2-negative MBC within 90 days prior to enrollment. Hormone receptor (HR)-positive patients had experienced disease progression on or after prior endocrine therapy, or endocrine therapy was considered unsuitable. gBRCAm status was determined using baseline blood samples or prior germline test results. For patients with a negative gBRCAm test, archival tissue was tested for somatic BRCAm and homologous recombination repair mutations (HRRm). Details of first-line cytotoxic chemotherapy were also collected. RESULTS: Between March 2017 and April 2018, 384 patients from 14 countries were screened and consented to study enrollment; 341 patients were included in the full analysis set (median [range] age at enrollment: 56 [25-89] years; 256 (75.3%) postmenopausal). Overall, 33 patients (9.7%) had a gBRCAm (16 [4.7%] in gBRCA1 only, 12 [3.5%] in gBRCA2 only, and 5 [1.5%] in both gBRCA1 and gBRCA2). gBRCAm prevalence was similar in HR-positive and HR-negative patients. gBRCAm prevalence was 9.0% in European patients and 10.6% in Asian patients and was higher in patients aged ≤ 50 years at initial breast cancer (BC) diagnosis (12.9%) than patients aged > 50 years (5.4%). In patients with any risk factor for having a gBRCAm (family history of BC and/or ovarian cancer, aged ≤ 50 years at initial BC diagnosis, or triple-negative BC), prevalence was 10.4%, versus 5.8% in patients without these risk factors. HRRm prevalence was 14.1% (n = 9/64) in patients with germline BRCA wildtype. CONCLUSIONS: Patient demographic and disease characteristics supported the association of a gBRCAm with younger age at initial BC diagnosis and family history of BC and/or ovarian cancer. gBRCAm prevalence in this cohort, not selected on the basis of risk factors for gBRCAm, was slightly higher than previous results suggested. gBRCAm prevalence among patients without a traditional risk factor for harboring a gBRCAm (5.8%) supports current guideline recommendations of routine gBRCAm testing in HER2-negative MBC, as these patients may benefit from poly(ADP-ribose) polymerase (PARP) inhibitor therapy.

Huang, M., O’Shaughnessy, J., Zhao, J., Haiderali, A., Cortés, J., Ramsey, S.D., Briggs, A., Hu, P., Karantza, V., Aktan, G., Qi, C.Z., Gu, C., Xie, J., Yuan, M., Cook, J., Untch, M., Schmid, P. and Fasching, P.A. (2020). “Association of Pathological Complete Response with Long-Term Survival Outcomes in Triple-Negative Breast Cancer: A Meta-analysis.” Cancer Res Sep 14;canres.1792.2020. {Epub ahead of print.].

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Pathological complete response (pCR) following neoadjuvant therapy has been associated with improved event-free survival (EFS) and overall survival (OS) in early-stage breast cancer (BC). The magnitude of this association varies by BC subtype, yet further research focusing on subtype-specific populations is limited. Here we provide an updated and comprehensive evaluation of the association between pCR and survival outcomes in triple-negative BC (TNBC). A literature review identified neoadjuvant studies, including clinical trials, real-world cohort studies and studies that pooled multiple trials or cohorts, which reported EFS/OS results by pCR in early-stage TNBC patients. Meta-analyses were performed to evaluate the association between pCR and EFS/OS and to predict long-term survival outcomes based on pCR status. Sensitivity analyses were conducted to assess the impact of cross-study variations. Twenty-five studies with over 4000 TNBC patients were identified. A synthesis of evidence from these studies suggested substantial improvement in EFS and OS for pCR vs. non-pCR (EFS HR [95% confidence interval]: 0.24 [0.20; 0.29]; OS: 0.19 [0.15; 0.24]); consistent results were reported in sensitivity analyses. Collectively, our findings suggest that adjuvant therapy is associated with improved EFS/OS in TNBC patients who received neoadjuvant therapy, regardless of pCR status.