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BackgroundThe Pathways to Wellness trial tested the efficacy of 2 interventions for younger breast cancer survivors: mindful awareness practices (MAPs) and survivorship education (SE). This planned secondary analysis examines intervention effects on stress, positive psychological outcomes, and inflammation (Clincaltrials.gov NCT03025139).MethodsWomen diagnosed with breast cancer at or before age 50 years who had completed treatment and had elevated depressive symptoms were randomly assigned to 6 weeks of MAPs, SE, or wait-list control (WLC). Assessments conducted at pre- and postintervention and at 3- and 6-month follow-up measured general stress perceptions, cancer-related intrusive thoughts and worry, positive affect, meaning and peace in life, altruism and empathy, and markers of inflammation. Analyses compared change in outcomes over time in each intervention group relative to WLC using linear mixed models.ResultsA total 247 women were randomly assigned to MAPs (n = 85), SE (n = 81), or WLC (n = 81). MAPs statistically significantly decreased intrusive thoughts and worry at postintervention and 3-month follow-up relative to WLC (P

* Purpose.--To update the American Society of Clinical Oncology-College of American Pathologists (ASCO-CAP) recommendations for human epidermal growth factor receptor 2 (HER2) testing in breast cancer. An Update Panel is aware that a new generation of antibody-drug conjugates targeting the HER2 protein is active against breast cancers that lack protein overexpression or gene amplification. Methods.--The Update Panel conducted a systematic literature review to identify signals for updating recommendations. Results.--The search identified 173 abstracts. Of 5 potential publications reviewed, none constituted a signal for revising existing recommendations. Recommendations.--The 2018 ASCO-CAP recommendations for HER2 testing are affirmed. Discussion.--HER2 testing guidelines have focused on identifying HER2 protein overexpression or gene amplification in breast cancer to identify patients for therapies that disrupt HER2 signaling. This update acknowledges a new indication for trastuzumab deruxtecan when HER2 is not overexpressed or amplified but is immunohistochemistry (IHC) 1+ or 2+ without amplification by in situ hybridization. Clinical trial data on tumors that tested IHC 0 are limited (excluded from DESTINY-Breast04), and evidence is lacking that these cancers behave differently or do not respond similarly to newer HER2 antibody-drug conjugates. Although current data do not support a new IHC 0 versus 1+ prognostic or predictive threshold for response to trastuzumab deruxtecan, this threshold is now relevant because of the trial entry criteria that supported its new regulatory approval. Therefore, although it is premature to create new result categories of HER2 expression (eg, HER2-Low, HER2-Ultra-Low), best practices to distinguish IHC 0 from 1+ are now clinically relevant. This update affirms prior HER2 reporting recommendations and offers a new HER2 testing reporting comment to highlight the current relevance of IHC 0 versus 1+ results and best practice recommendations to distinguish these often subtle differences. Additional information is available at www.asco.org/breast-cancer-guidelines., The American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) first published a practice guideline on human epidermal growth factor receptor 2 (HER2) testing in breast [...]

PurposeYounger women are at risk for depression and related symptoms following breast cancer. The Pathways to Wellness study, a randomized, multi-institution, three-arm trial, tested the efficacy of two behavioral interventions for younger breast cancer survivors with elevated depressive symptoms: mindful awareness practices (MAPs) and survivorship education (SE) (Clincaltrials.gov identifier: NCT03025139).MethodsWomen diagnosed with breast cancer at or before 50 years of age who had completed treatment and had elevated depressive symptoms were randomly assigned to 6 weeks of MAPs, SE, or wait-list control (WLC). Assessments were conducted preintervention and postintervention and at 3-month and 6-month postintervention follow-ups. Analyses compared each intervention to WLC using linear mixed models. The primary outcome was change in depressive symptoms from preintervention to postintervention on the Center for Epidemiologic Studies-Depression Scale; secondary outcomes included change in fatigue, insomnia, and vasomotor symptoms.ResultsTwo hundred forty-seven women (median age = 46 years) were randomly assigned to MAPs (n = 85), SE (n = 81), or WLC (n = 81). MAPs and SE led to significant decreases in depressive symptoms from preintervention to postintervention relative to WLC (mean change relative to WLC [95% CI]: MAPs, -4.7 [-7.5 to -1.9]; SE, -4.0 [-6.9 to -1.1]), which persisted at 6-month follow-up for MAPs (mean change relative to WLC [95% CI]: MAPs, -3.7 [-6.6 to -0.8]; SE, -2.8 [-5.9 to 0.2]). MAPs, but not SE, also had beneficial effects on fatigue, insomnia, and vasomotor symptoms that persisted at 6-month follow-up (P < .05).ConclusionMindfulness meditation and SE reduced depressive symptoms in younger breast cancer survivors. These interventions can be widely disseminated over virtual platforms and have significant potential benefit for quality of life and overall survivorship in this vulnerable group.

BackgroundMajor cancer organizations recommend depression screening in patients and survivors. The 9-item Patient Health Questionnaire (PHQ-9) is often suggested, with limited information about its use.MethodsEnrollment data collected from younger breast cancer survivors participating in a behavioral intervention trial were used to examine the relationship between PHQ-9 scores (range = 0-27), patient characteristics, and responses to standardized psychosocial assessment tools. Major depressive disorder criterion was met if responses to the first 2 PHQ-9 items (range = 0-6) were 3 or greater. The sample was categorized by total PHQ-9 scores: less than 5 (minimal depressive symptoms), 5-9 (mild to moderate depressive symptoms), and 10 or greater (moderate to severe depression). PHQ-9 category associations with medical, demographic, psychosocial, and behavioral characteristics were examined using analysis of variance for continuous variables and χ2 tests for categorical variables.ResultsA total of 231 women met the study prescreening eligibility criterion of mild depressive symptoms and enrolled in the study. On average, they were 45.2 years old and 2.6 years since diagnosis. At enrollment, 22.1% met the screening criterion for possible major depressive disorder; among those with PHQ-9 scores of 10 or greater, 58.3% met this criterion. Anxiety, fatigue, insomnia, and intrusive thoughts about cancer were frequent and were associated with depressive symptom severity (all P < .001). In contrast, neither demographic nor cancer treatment characteristics were associated with depressive symptoms.ConclusionsDepressive symptoms in this selected sample of younger breast cancer survivors were independent of demographic characteristics or cancer treatment history, suggesting that depression screening is necessary to detect uncontrolled depressive symptoms.

BackgroundMajor cancer organizations recommend depression screening in patients and survivors. The 9-item Patient Health Questionnaire (PHQ-9) is often suggested, with limited information about its use.MethodsEnrollment data collected from younger breast cancer survivors participating in a behavioral intervention trial were used to examine the relationship between PHQ-9 scores (range = 0-27), patient characteristics, and responses to standardized psychosocial assessment tools. Major depressive disorder criterion was met if responses to the first 2 PHQ-9 items (range = 0-6) were 3 or greater. The sample was categorized by total PHQ-9 scores: less than 5 (minimal depressive symptoms), 5-9 (mild to moderate depressive symptoms), and 10 or greater (moderate to severe depression). PHQ-9 category associations with medical, demographic, psychosocial, and behavioral characteristics were examined using analysis of variance for continuous variables and χ2 tests for categorical variables.ResultsA total of 231 women met the study prescreening eligibility criterion of mild depressive symptoms and enrolled in the study. On average, they were 45.2 years old and 2.6 years since diagnosis. At enrollment, 22.1% met the screening criterion for possible major depressive disorder; among those with PHQ-9 scores of 10 or greater, 58.3% met this criterion. Anxiety, fatigue, insomnia, and intrusive thoughts about cancer were frequent and were associated with depressive symptom severity (all P < .001). In contrast, neither demographic nor cancer treatment characteristics were associated with depressive symptoms.ConclusionsDepressive symptoms in this selected sample of younger breast cancer survivors were independent of demographic characteristics or cancer treatment history, suggesting that depression screening is necessary to detect uncontrolled depressive symptoms.

PURPOSE:The Adjuvant Paclitaxel and Trastuzumab trial was designed to address treatment of patients with small human epidermal growth factor receptor 2 (HER2)-positive breast cancer. The primary analysis of the Adjuvant Paclitaxel and Trastuzumab trial demonstrated a 3-year disease-free survival (DFS) of 98.7%. In this planned secondary analysis, we report longer-term outcomes and exploratory results to characterize the biology of small HER2-positive tumors and genetic factors that may predispose to paclitaxel-induced peripheral neuropathy (TIPN). PATIENTS AND METHODS:In this phase II study, patients with HER2-positive breast cancer with tumors 3 cm or smaller and negative nodes received paclitaxel (80 mg/m2) with trastuzumab for 12 weeks, followed by trastuzumab for 9 months. The primary end point was DFS. Recurrence-free interval (RFI), breast cancer-specific survival, and overall survival (OS) were also analyzed. In an exploratory analysis, intrinsic subtyping by PAM50 (Prosigna) and calculation of the risk of recurrence score were performed on the nCounter analysis system on archival tissue. Genotyping was performed to investigate TIPN. RESULTS:A total of 410 patients were enrolled from October 2007 to September 2010. After a median follow-up of 6.5 years, there were 23 DFS events. The 7-year DFS was 93% (95% CI, 90.4 to 96.2) with four (1.0%) distant recurrences, 7-year OS was 95% (95% CI, 92.4 to 97.7), and 7-year RFI was 97.5% (95% CI, 95.9 to 99.1). PAM50 analyses (n = 278) showed that most tumors were HER2-enriched (66%), followed by luminal B (14%), luminal A (13%), and basal-like (8%). Genotyping (n = 230) identified one single-nucleotide polymorphism, rs3012437, associated with an increased risk of TIPN in patients with grade 2 or greater TIPN (10.4%). CONCLUSION:With longer follow-up, adjuvant paclitaxel and trastuzumab is associated with excellent long-term outcomes. Distribution of PAM50 intrinsic subtypes in small HER2-positive tumors is similar to that previously reported for larger tumors.

PurposeWomen with HER2-positive breast cancer treated prior to effective anti-HER2 therapy have higher rates of local-regional recurrence (LRR) than those with HER2-negative disease. Effective systemic therapy, however, has been shown to decrease LRR. This study examines LRR in women with HER2-positive breast cancer treated on a single-arm prospective multicenter trial of adjuvant trastuzumab (H) and paclitaxel (T).MethodsPatients with HER2-positive tumors ≤ 3.0 cm with negative axillary nodes or micrometastatic disease were eligible. Systemic therapy included weekly T and H for 12 weeks followed by continuation of H to complete 1 year. Radiation therapy (RT) was required following breast-conserving surgery (BCS), but dose and fields were not specified. Disease-free survival (DFS) and LRR-free survival were calculated using the Kaplan-Meier method.ResultsOf the 410 patients enrolled from September 2007 to September 2010, 406 initiated protocol therapy and formed the basis of this analysis. A total of 272 (67%) had hormone receptor-positive tumors. Of 162 patients undergoing mastectomy, local therapy records were unavailable for two. None of the 160 for whom records were available received RT. Among 244 BCS patients, detailed RT records were available for 217 (89%). With a median follow-up of 6.5 years, 7-year DFS was 93.3% (95% CI 90.4-96.2), and LRR-free survival was 98.6% (95% CI 97.4-99.8).ConclusionLRR in this select group of early-stage patients with HER2-positive disease receiving effective anti-HER2 therapy is extremely low. If confirmed in additional studies, future investigational efforts should focus on de-escalating local therapy.

PURPOSE:Addition of alpelisib to fulvestrant significantly extended progression-free survival in PIK3CA-mutant, hormone receptor-positive (HR+) advanced/metastatic breast cancer in the phase III SOLAR-1 study. The combination of alpelisib and letrozole also had promising activity in phase I studies of HR+ advanced/metastatic breast cancer. NEO-ORB aimed to determine whether addition of alpelisib to letrozole could increase response rates in the neoadjuvant setting.Patients and Methods: Postmenopausal women with HR+, human epidermal growth factor receptor 2-negative, T1c-T3 breast cancer were assigned to the PIK3CA-wild-type or PIK3CA-mutant cohort according to their tumor PIK3CA status, and randomized (1:1) to 2.5 mg/day letrozole with 300 mg/day alpelisib or placebo for 24 weeks. Primary endpoints were objective response rate (ORR) and pathologic complete response (pCR) rate for both PIK3CA cohorts. RESULTS:In total, 257 patients were assigned to letrozole plus alpelisib (131 patients) or placebo (126 patients). Grade ≥3 adverse events (≥5% of patients) in the alpelisib arm were hyperglycemia (27%), rash (12%), and maculo-papular rash (8%). The primary objective was not met; ORR in the alpelisib versus placebo arm was 43% versus 45% and 63% versus 61% in the PIK3CA-mutant and wild-type cohorts, respectively. pCR rates were low in all groups. Decreases in Ki-67 were similar across treatment arms and cohorts. In PIK3CA-mutant tumors, alpelisib plus letrozole treatment induced a greater decrease in phosphorylated AKT versus placebo plus letrozole. CONCLUSIONS:In contrast to initial results in advanced/metastatic disease, addition of alpelisib to 24-week neoadjuvant letrozole treatment did not improve response in patients with HR+ early breast cancer.

PURPOSE: Depression is associated with poor outcomes in breast cancer survivors (BCSs), with higher prevalence among younger women. The Pathways to Wellness (PTW; ClinicalTrials.gov identifier: NCT03025139) randomized controlled trial (RCT) demonstrated beneficial effects of two behavioral interventions (survivorship education [SE] and mindful awareness practices [MAPs]) on depressive symptoms in younger BCS. We conducted an exploratory secondary analysis to identify moderators of intervention effects. METHODS: Women diagnosed with stage 0 to III breast cancer at or before age 50 years who completed cancer treatment were randomly assigned to 6 weeks of SE (n = 81), MAPs (n = 85), or waitlist control (WLC; n = 81). Moderators assessed at baseline included psychological distress (depression and anxiety), intervention preference, preparedness for survivorship, and time since initial diagnosis. Linear regression models tested the modifying effects of each variable on postintervention depression in SE versus WLC and MAPs versus WLC. RESULTS: Baseline levels of depression (β = –.03, P <.01) and anxiety (β = –.64, P =.02) moderated effects of SE on depressive symptoms, as did preparedness for survivorship (β = 3.17, P =.02). Participants randomly assigned to SE who had the highest levels of depression or anxiety and who felt least prepared for survivorship showed the largest reductions in depressive symptoms from preintervention to postintervention. Similar effects were not observed for MAPs. Intervention preference and time since diagnosis did not moderate intervention effects for either SE or MAPs. CONCLUSION: Our 6-week, group-based SE program may be most beneficial for women with higher levels of psychological distress and those who feel least prepared for cancer survivorship. By contrast, a 6-week mindfulness awareness practice intervention appears to benefit younger BCS regardless of pretreatment characteristics. Several qualities influence treatment efficacy of a survivorship ed. course in younger breast cancer survivors. [ABSTRACT FROM AUTHOR]

Tumor genomic profiling for personalized oncology therapy is being widely applied in clinical practice even as it is being evaluated more formally in clinical trials. Given the complexities of genomic data and its application to clinical use, molecular tumor boards with diverse expertise can provide guidance to oncologists and patients seeking to implement personalized genetically targeted therapy in practice. A multidisciplinary molecular tumor board reviewed tumor molecular profiling reports from consecutive referrals at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins over a 3-year period. The tumor board weighed evidence for actionability of genomic alterations identified by molecular profiling and provided recommendations including US Food and Drug Administration-approved drug therapy, clinical trials of matched targeted therapy, off-label use of such therapy, and additional tumor or germline genetic testing. One hundred fifty-five patients were reviewed. Actionable genomic alterations were identified in 132 patients (85%). Off-label therapies were recommended in 37 patients (24%). Eleven patients were treated off-label, and 13 patients were enrolled onto clinical trials of matched targeted therapies. Median progression-free survival of patients treated with matched therapies was 5 months (95% CI, 2.9 months to not reached), and the progression-free survival probability at 6 months was 43%(95% CI, 26% to 71%). Lack of locally available clinical trials was the major limitation on clinical actionability of tumor profiling reports. The molecular tumor board recommended off-label targeted therapies for a quarter of all patients reviewed. Outcomes were heterogeneous, although 43% of patients receiving genomically matched therapy derived clinical benefit lasting at least 6 months. Until more data become available from precision oncology trials, molecular tumor boards can help guide appropriate use of tumor molecular testing to direct therapy.

* Purpose.--To update key recommendations of the American Society of Clinical Oncology/College of American Pathologists estrogen receptor (ER) and progesterone receptor (PgR) testing in breast cancer guideline. Methods.--A multidisciplinary international Expert Panel was convened to update the clinical practice guideline recommendations informed by a systematic review of the medical literature. Recommendations.--The Expert Panel continues to recommend ER testing of invasive breast cancers by validated immunohistochemistry as the standard for predicting which patients may benefit from endocrine therapy, and no other assays are recommended for this purpose. Breast cancer samples with 1% to 100% of tumor nuclei positive should be interpreted as ER positive. However, the Expert Panel acknowledges that there are limited data on endocrine therapy benefit for cancers with 1% to 10% of cells staining ER positive. Samples with these results should be reported using a new reporting category, ER Low Positive, with a recommended comment. A sample is considered ER negative if < 1% or 0% of tumor cell nuclei are immunoreactive. Additional strategies recommended to promote optimal performance, interpretation, and reporting of cases with an initial low to no ER staining result include establishing a laboratory-specific standard operating procedure describing additional steps used by the laboratory to confirm/adjudicate results. The status of controls should be reported for cases with 0% to 10% staining. Similar principles apply to PgR testing, which is used primarily for prognostic purposes in the setting of an ER-positive cancer. Testing of ductal carcinoma in situ (DCIS) for ER is recommended to determine potential benefit of endocrine therapies to reduce risk of future breast cancer, while testing DCIS for PgR is considered optional. Additional information can be found at www.asco.org/breast-cancer-guidelines. (Arch Pathol Lab Med. 2020;144:545-563; doi: 10.5858/arpa.2019-0904-SA), INTRODUCTION First released in 2010, the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) estrogen receptor (ER) and progesterone receptor (PgR) testing guideline is aimed at improving the [...]

PurposeTigatuzumab (TIG), an agonistic anti-DR5 antibody, triggers apoptosis in DR5(+) human tumor cells without crosslinking. TIG has strong in vitro/in vivo activity against basal-like breast cancer cells enhanced by chemotherapy agents. This study evaluates activity of TIG and chemotherapy in patients with metastatic triple-negative breast cancer (TNBC).Experimental designRandomized 2:1 phase II trial of albumin-bound paclitaxel (nab-PAC) ± TIG in patients with TNBC stratified by prior chemotherapy. Patients received nab-PAC weekly × 3 ± TIG every other week, every 28 days. Primary objective was within-arm objective response rate (ORR). Secondary objectives were safety, progression-free survival (PFS), clinical benefit, and TIG immunogenicity. Metastatic research biopsies were required.ResultsAmong 64 patients (60 treated; TIG/nab-PAC n = 39 and nab-PAC n = 21), there were 3 complete remissions (CR), 8 partial remissions (PR; 1 almost CR), 11 stable diseases (SD), and 17 progressive diseases (PD) in the TIG/nab-PAC arm (ORR, 28%), and no CRs, 8 PRs, 4 SDs, and 9 PDs in the nab-PAC arm (ORR, 38%). There was a numerical increase in CRs and several patients had prolonged PFS (1,025+, 781, 672, 460, 334) in the TIG/nab-PAC arm. Grade 3 toxicities were 28% and 29%, respectively, with no grade 4-5. Exploratory analysis suggests an association of ROCK1 gene pathway activation with efficacy in the TIG/nab-PAC arm.ConclusionsORR and PFS were similar in both. Preclinical activity of TIG in basal-like breast cancer and prolonged PFS in few patients in the combination arm support further investigation of anti-DR5 agents. ROCK pathway activation merits further evaluation.

Chemotherapy-related amenorrhea (CRA) is associated with infertility and menopausal symptoms. Learning how frequently paclitaxel and trastuzumab cause amenorrhea is important. Most other adjuvant breast cancer therapies induce CRA in approximately 50 % of all premenopausal recipients [1]. 410 patients enrolled on the APT Trial, a single-arm phase 2 adjuvant study of 12 weeks of paclitaxel and trastuzumab followed by nine months of trastuzumab monotherapy. Eligible patients had ≤3 cm node-negative HER2 + breast cancers. Premenopausal enrollees were asked to complete menstrual surveys every 3-12 months for 72 months. Women who responded to at least one survey at least 15 months after chemotherapy initiation (and who did not undergo hysterectomy and/or bilateral oophorectomy or receive ovarian suppressing medications prior to 15 months) were included in this analysis. A participant was defined as having amenorrhea in follow-up if her self-reported last menstrual period at last follow-up was greater than 12 months prior to the survey. Among the 64 women in the evaluable population (median age at study entry 44 years, range 27-52 years), the median time between chemotherapy initiation and last menstrual survey was 51 months (range 16-79). 18 of 64 women (28 %, 95 % CI 18-41 %) were amenorrheic at that time point. Amenorrhea rates among premenopausal women treated with adjuvant paclitaxel and trastuzumab for early stage breast cancer appear lower than those seen historically with standard alkylator-based breast cancer regimens. Future studies are needed to understand the impact of this regimen on related issues of fertility and menopausal symptoms.

PurposeOutcomes for early-stage breast cancer have improved. First-generation adjuvant chemotherapy trials reported a 0.27% 8-year cumulative incidence of myelodysplastic syndrome/acute myelogenous leukemia. Incomplete ascertainment and follow-up may have underestimated subsequent risk of treatment-associated marrow neoplasm (MN).Patients and methodsWe examined the MN frequency in 20,063 patients with stage I to III breast cancer treated at US academic centers between 1998 and 2007. Time-to-event analyses were censored at first date of new cancer event, last contact date, or death and considered competing risks. Cumulative incidence, hazard ratios (HRs), and comparisons with Surveillance, Epidemiology, and End Results estimates were obtained. Marrow cytogenetics data were reviewed.ResultsFifty patients developed MN (myeloid, n = 42; lymphoid, n = 8) after breast cancer (median follow-up, 5.1 years). Patients who developed MN had similar breast cancer stage distribution, race, and chemotherapy exposure but were older compared with patients who did not develop MN (median age, 59.1 v 53.9 years, respectively; P = .03). Two thirds of patients had complex MN cytogenetics. Risk of MN was significantly increased after surgery plus chemotherapy (HR, 6.8; 95% CI, 1.3 to 36.1) or after all modalities (surgery, chemotherapy, and radiation; HR, 7.6; 95% CI, 1.6 to 35.8), compared with no treatment with chemotherapy. MN rates per 1,000 person-years were 0.16 (surgery), 0.43 (plus radiation), 0.46 (plus chemotherapy), and 0.54 (all three modalities). Cumulative incidence of MN doubled between years 5 and 10 (0.24% to 0.48%); 9% of patients were alive at 10 years.ConclusionIn this large early-stage breast cancer cohort, MN risk after radiation and/or adjuvant chemotherapy was low but higher than previously described. Risk continued to increase beyond 5 years. Individual risk of MN must be balanced against the absolute survival benefit of adjuvant chemotherapy.

BackgroundNo single standard treatment exists for patients with small, node-negative, human epidermal growth factor receptor type 2 (HER2)-positive breast cancers, because most of these patients have been ineligible for the pivotal trials of adjuvant trastuzumab.MethodsWe performed an uncontrolled, single-group, multicenter, investigator-initiated study of adjuvant paclitaxel and trastuzumab in 406 patients with tumors measuring up to 3 cm in greatest dimension. Patients received weekly treatment with paclitaxel and trastuzumab for 12 weeks, followed by 9 months of trastuzumab monotherapy. The primary end point was survival free from invasive disease.ResultsThe median follow-up period was 4.0 years. The 3-year rate of survival free from invasive disease was 98.7% (95% confidence interval [CI], 97.6 to 99.8). Among the 12 relapses seen, 2 were due to distant metastatic breast cancer. Excluding contralateral HER2-negative breast cancers and nonbreast cancers, 7 disease-specific events were noted. A total of 13 patients (3.2%; 95% CI, 1.7 to 5.4) reported at least one episode of grade 3 neuropathy, and 2 had symptomatic congestive heart failure (0.5%; 95% CI, 0.1 to 1.8), both of whom had normalization of the left ventricular ejection fraction after discontinuation of trastuzumab. A total of 13 patients had significant asymptomatic declines in ejection fraction (3.2%; 95% CI, 1.7 to 5.4), as defined by the study, but 11 of these patients were able to resume trastuzumab therapy after a brief interruption.ConclusionsAmong women with predominantly stage I HER2-positive breast cancer, treatment with adjuvant paclitaxel plus trastuzumab was associated with a risk of early recurrence of about 2%; 6% of patients withdrew from the study because of protocol-specified adverse events. (Funded by Genentech; ClinicalTrials.gov number, NCT00542451.).