Release Date: March 22, 2018Expiration Date: March 22, 2019

This activity is provided free of charge.

STATEMENT OF NEED

This CE article is designed to serve as an update on cancer detection and prevention and to facilitate clinical awareness of current and new research regarding state-of-the-art care for those with or at risk for cancer.

TARGET AUDIENCE

Advanced practice nurses, registered nurses, and other healthcare professionals who care for cancer patients may participate in this CE activity.

EDUCATIONAL OBJECTIVES

Upon completion, participants should be able to:

• Describe new preventive options and treatments for patients with cancer
• Identify options for individualizing the treatment for patients with cancer
• Assess new evidence to facilitate survivorship and supportive care for patients with cancer

ACCREDITATION/CREDIT DESIGNATION STATEMENT

Physicians’ Education Resource®, LLC is approved by the California Board of Registered Nursing, Provider #16669 for 1 Contact Hour.

DISCLOSURES/RESOLUTION OF COI

It is the policy of Physicians’ Education Resource®, LLC (PER®) to ensure the fair balance, independence, objectivity, and scientific objectivity in all of our CE activities. Everyone who is in a position to control the content of an educational activity is required to disclose all relevant financial relationships with any commercial interest as part of the activity planning process. PER® has implemented mechanisms to identify and resolve all conflicts of interest prior to release of this activity.The planners and authors of this CE activity have disclosed no relevant financial relationships with any commercial interests pertaining to this activity.

METHOD OF PARTICIPATION

• Read the articles in this section in its entirety.
• Go to www.gotoper.com/go/ONN18March
• Complete and submit the CE posttest and activity evaluation.
• Print your CE Certificate.

OFF-LABEL DISCLOSURE/DISCLAIMER

This CE activity may or may not discuss investigational, unapproved, or off-label use of drugs. Participants are advised to consult prescribing information for any products discussed. The information provided in this CE activity is for continuing medical nursing purposes only and is not meant to substitute for the independent medical judgment of a nurse or other healthcare provider relative to diagnostic, treatment, or management options for a specific patient’s medical condition. The opinions expressed in the content are solely those of the individual authors and do not reflect those of PER®.

Gynecological Cancers

Cotesting Unlikely to Detect More Cervical Cancers Than HPV Testing Alone

Jason Harris

Use of both a Pap smear and a human papillomavirus HPV) test did not identify more cervical cancers than HPV testing alone, according to results from a study of more than 1.2 million women screened since 2003.

The Pap test detected only a small percentage of precancers (3.5%) and cancers (5.9%) missed on the HPV test. Investigators observed that these cancers were more likely to be regional or distant stage.

Given the relative rarity of cervical cancer—the Centers for Disease Control and Prevention says roughly 12,000 women receive a diagnosis annually—investigators concluded that adding the Pap test to HPV screening translated to earlier detection of at most 5 cases per million women per year. Cotesting is “unlikely to detect cancer cases that wouldn’t be found using HPV testing alone,” the investigators said.

“The choice between the two strategies and the screening interval chosen, whether 3 years or 5 years or more, depends on societal judgments (eg, cancer prevention benefits vs resource allocation) and not scientific facts,” first author Mark Schiffman, MD, MPH, division of cancer epidemiology and genetics, National Cancer Institute, et al wrote.

“Nevertheless, even using cotesting at 3-year intervals (the most aggressive strategy in common use), cervical cancer continues to occur rarely (albeit typically at a curable stage). Excessive screening in an attempt to prevent every case could have minimal cancer prevention benefits while increasing the harms of screening.”

HPV testing is more sensitive than the Pap test for detecting precancer. The HPV test captures the known cancer-causing viruses, but some gynecologists conduct cotesting because of reports of rare HPV-negative, Pap test—positive cancers, even though using both tests is more expensive.

Investigators quantified the detection of cervical precancer and cancer by cotesting compared with HPV testing alone at Kaiser Permanente, where 1,208,710 women have undergone cervical cotesting every 3 years since 2003. Investigators reviewed screening histories preceding cervical cancers in 623 women and precancers in 5369 women to assess the relative contributions of the Pap test and HPV test components in identifying patients.

Overall, prediagnostic HPV testing was more clinically sensitive than cytology (76.7% vesus 59.1%; P<.001 for paired comparison). About 82% of all prediagnostic cotests were positive by HPV and/or cytology. Stratified by histopathology, the differences in positivity between HPV and cytology were smaller for squamous cell carcinoma (75.0% vesus 69.6%; P = .03) than for adenocarcinoma (79.0% vesus 45.4%; P<.001).

Among those with cancer, women diagnosed with microinvasive cancer tended to be younger than women with other cancers (40 vesus 57 years). The median age for women diagnosed with squamous cell carcinomas or adenocarcinomas was 47 years. Women diagnosed with precancer had a median age of 38 years. Investigators noted that this analysis excluded women younger than age 30, elevating the average age of patients with precancer.

HPV testing identified more women who subsequently received a diagnosis of cancer and precancer than the Pap test. Overall, prediagnostic HPV testing was more likely to be positive than cytology (83.8% vesus 61.9%; P<.001). Almost 9 in 10 prediagnostic cotests (87.3%) were positive by HPV and/or cytology. HPV testing was more likely to be positive than cytology prior to both cervical intraepithelial neoplasia grade 3 (83.9% vesus 62.8%; P<.001) and adenocarcinoma in situ (82.2% vesus 53.2%; P<.001).

Cotests done within 12 months of diagnosis were more likely to be HPV and/or cytology positive than cotests done ≥12 months before the diagnosis. HPV was statistically significantly more likely to be positive than cytology less than 12 months prior to a precancer diagnosis (96.2% vesus 89.8%; P<.001) but not immediately prior to a cancer diagnosis (89.2% vesus 86.3%; P = .1).

At ≥12 months, HPV was statistically significantly more likely to be positive than cytology for both a precancer diagnosis (70.6% vesus 32.4%; P<.001) and a cancer diagnosis (62.8% vesus 28.7%; P<.001).

REFERENCE

Schiffman M, Kinney WK, Cheung LC, et al. Relative performance of HPV and cytology components of cotesting in cervical screening [published online November 14, 2017]. J Natl Cancer Inst. doi: 10.1093/jnci/djx225.

Myeloma

Timely Hospice Use Increases Among Patients With Myeloma

Kristie L. Kahl

Hospice use has significantly increased over time among patients with myeloma, which in turn hopefully highlights the need for timely enrollment, according to a retrospective analysis published in the journal Blood.

Timely hospice enrollment helps quality end-of-life care. However, previous research has shown an increase in “late” enrollment, which is defined as 3 or more days before death, among patients with blood cancers. “Late hospice enrollment limits the ability of patients and their families to receive the full palliative and supportive benefits of hospice services,” said Oreofe O. Odejide, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts.

Therefore, the investigators characterized hospice use among 12,803 patients, in particular on prevalence and predictors of late enrollment. Patients were 65 years of age or older, had a primary diagnosis of myeloma between 2000 and 2013, and lived for at least 30 days after their diagnosis.

The investigators chose myeloma because of the distinct features associated with the disease compared with other blood cancers, Odejide said.

“For example, myeloma is incurable at diagnosis, there is a very high prevalence of pain among patients with myeloma because of bony involvement by their disease, and there is a high likelihood of renal involvement with possible need for dialysis,” he said. “We felt that these characteristics could potentially impact hospice use and, thus, sought to characterize patterns of hospice use and barriers to timely enrollment in this unique population.”

Overall, 47.9% of patients enrolled in hospice, with the majority using outpatient/home hospice services (80.5%), for approximately 12 days. Among those enrolled, 17.8% of patients spent 3 days or more in hospice. The investigators found a significant trend toward increased hospice use from 18.6% in 2000 to 56.4% in 2013; however, they saw no significant increase in late enrollment (from 12% to 16.7%, respectively). “This suggests that there have been meaningful changes in hospice use for patients with myeloma,” said Odejide. “Distinct features of myeloma such as incurability and high prevalence of pain may make the need for hospice services clearer and encourage timely use.”

In particular, transfusion-dependent patients (37.9%) and patients on dialysis (32.9%) were more likely to experience late enrollment. Odejide acknowledged that this finding suggests that transfusion dependence is a key barrier to timely enrollment. “The current reimbursement pattern for hospices precludes many hospices from being able to provide transfusions even though they are palliative,” he said. “Policy changes and reimbursement reform that will enable provision of palliative transfusions while enrolled in hospice are thus likely to promote even more timely enrollment for patients with myeloma.”

Odejide commended the fact that meaningful progress in hospice use among patients with myeloma has been made. However, more work can be done. “Even though the majority enrolled by 2013, there is still room for additional improvement,” he said. “Accordingly, it is important for healthcare teams to engage in timely goals-of-care discussions with patients and families in order to understand and honor preferences regarding hospice care.”

REFERENCE

Odejide O, Li L, Cronin A, et al. Hospice use among patients with myeloma. Blood, 2017;130(suppl 1):346..

Nurse Perspective

Kate Carlson Wrammert, MSN, ANP-BC, WHNP-BC, AOCNP

Kate Carlson Wrammert, MSN, ANP-BC, WHNP-BC, AOCNPNurse Practitioner, McKelvey Lung Transplant Program, Emory University Hospital, Atlanta, GA

Patients with multiple myeloma, an advanced neoplasm of the plasma cells with a limited survival, generally carry a high symptom burden including anemia, bone pain, and renal failure. For patients who become transfusion dependent or require hemodialysis, reimbursement limitations may postpone enrollment in hospice services.

As defined by Medicare, hospice care is appropriate for any individual with a life expectancy of less than 6 months, yet many people misunderstand hospice care to be applicable only when a patient is in the last days to weeks of life. Often, patients who enroll late spend their final days hospitalized—possibly in an intensive care unit&mdash;rather than at home, leading to poorly controlled symptoms and prolonged grief for the family. By using hospice care earlier in the disease process, the patient and family can experience an improved quality of life and reduced symptom burden, as demonstrated by extensive research.

According to the American Society of Clinical Oncology, concurrent use of oncologic care with palliative care with eventual transition to hospice care demonstrates reduced symptom burden, better outcomes for caregivers, and equal or better survival in some patients. Perhaps, if this were available in the community, transfusion-dependent and/or dialysis-dependent patients could benefit from enrolling in aggressive care with palliative care before developing a high symptom burden. Given the known prognosis of myeloma, early referral to an outpatient palliative care program could facilitate conversations and further educate the patient and family regarding the appropriate timing of hospice care. Patients would be enabled to make informed decisions regarding earlier enrollment, thus reducing the percentage of late referrals in this population.

Hematological Malignancies

Understanding Predictors Can Decrease Unplanned Hospital Readmissions

Kristie L. Kahl

Patients with blood cancers are at an increased risk of multiple hospital readmissions. However, multidisciplinary teams and patients can work together to identify predictors and avoid these occurrences.

Newly diagnosed, hospitalized patients with hematologic malignancies tend to have high symptom burdens from the diagnosis itself. This population also needs prolonged courses of chemotherapy and consequent transfusion support. Therefore, they are predisposed to unplanned readmissions to the hospital.

Investigators from the Taussig Cancer Institute at the Cleveland Clinic evaluated 30-day unplanned readmissions, defined as hospitalization within 30 days of original admission for any reason other than planned chemotherapy, that occurred at their institution from January 2011 to February 2016.

“We specifically looked at how we can predict a readmission after the first readmission,” said Girish Kunapareddy, MD, of the Leukemia Program.

Hematologic malignancies included acute leukemias, myelodysplastic syndromes and aggressive lymphomas. To evaluate associated predictors, the investigators collected information regarding demographics, clinical characteristics, disease status, body mass index at discharge, absolute neutrophil count at discharge/readmission, reason for readmission, length of stay at original admission/ readmission, and discharge characteristics.

The investigators observed 259 thirty-day unplanned readmissions in 157 patients, including 107 patients who had a single occurrence, and 50 with more than 2.

The majority of patients were men (59%), with a median age of 66 years, and had acute myeloid leukemia (44%), including half with relapsed or refractory disease. Median income was approximately $51,000, and 86% of patients had more than a high school education, according to census tract—based data. In addition, 49% of patients were covered by Medicare, 21% by Medicaid, and 36% by private insurance.

Following unplanned readmission discharges, patients were sent home (50%), sent home with home health (32%), sent to a nursing facility (15%), or received hospice care (3%). Among these readmission discharges, 10% of patients were sent home on intravenous antibiotics, 44% on opioids, and 48% on psychotropic drugs.

Neutropenic fever appeared to be the primary diagnosis (61%) at readmission, with 59% demonstrating symptoms at presentation of readmission.

At discharge from unplanned readmissions, median absolute neutrophil count was 870 mL and increased to 940 mL at the time of readmission. Patients stayed for a median of 5 days and were readmitted approximately 11 days later.

Unplanned readmissions originated from visits to outpatient clinics, emergency departments or patients’ homes (46%), and non-healthcare facilities (27%) or outside hospital transfers (22%).

The investigators found 30-day readmissions were associated with absolute neutrophil counts of more than 2000 mL at last discharge; constitutional symptoms, such as fevers, chills, sweats, and severe fatigue, at admission presentation; gastrointestinal symptoms; whether patients were transferred from an outside facility; febrile neutropenia; relapsed or refractory disease; and higher education.

Of note, Kunapareddy and colleagues were most surprised by higher education having an association with increased 30-day unplanned readmissions. “Maybe having higher education means these patients are more likely to follow instructions or know what symptoms to look for to come in to the hospital,” he said. “Or it may be other reasons for socioeconomic status, like having good transportation, having good access to care, being able to miss work, or having family who can take off to bring you to the hospital, or if you are more financially stable.”

To address high hospital readmissions rates, Kunapareddy recommends that physicians create individualized care plans and follow up more closely with patients. “It is better to create indiidualized plans for each patient. The only way you can do that is if you have a multidisciplinary team—social work, case management, care coor-dinators, physician assistants, palliative medicine oncology&mdash;that sits around a round table and discusses this particular patient’s issues and figures out things we can do to help.”

Patients should also be their own advocates, utilize additional resources at institutions, and, most important, not wait to see their physicians at the onset of symptoms, Kunapareddy added. “Reporting these findings earlier to the doctor, even if patients think it seems minor, helps with better symptom control early on.”

Nurse Perspective

Phyllis McKiernan, MSN, APN, OCN

Phyllis McKiernan, MSN, APN, OCNBlood & Marrow Transplant Program, John Theurer Cancer Center, Hackensack, NJ

Unplanned hospital readmissions for patients with hematologic malignancies create stress for those patients and their families as well as for the healthcare system. Patients lose time with family members and friends and at work or school. The financial burden includes not only lost wages but also insurance co-payments for hospitalizations. The emergency room, hospital or physician clinic, and medical transportation are all used. The on-call medical team needs to evaluate and admit the patient, and the hospital staff on the unit will need to tap resources for the admission.

In addition, hospital beds used for unplanned admissions are subsequently not available for planned admissions. Understanding predictors for unplanned readmissions is the first step in developing strategies to mitigate risk for these occurrences. The most common diagnosis leading to unplanned readmission was, not surprisingly, neutropenic fever. Risk reduction methods include patient education regarding precautions, antimicrobial prophylaxis, and the use of growth factor support. Patients receiving regimens most commonly associated with neutropenic fever could be followed more closely as outpatients in an attempt to recognize signs of impending fever or infection. Early identification of symptoms may allow a patient with uncomplicated neutropenic fever to be treated as an outpatient and avoid readmission.

Interestingly, patients with higher education had an increased incidence of unplanned readmissions. Providing all patients with education regarding signs and symptoms to report to the physician and team may help bridge the education gap. Keeping open communication with patients and using technology, such as e-mail and online chart access, will allow patients to have real-time contact with the healthcare team and may lead to early symptom control. Addressing social issues proactively could prevent delays in access to care. As mentioned above, a multidisciplinary team approach may decrease the incidence of unplanned hospital readmissions, thus alleviating strain on the patients and the healthcare system.

Pancreatic Cancer

Nab-Paclitaxel/Gemcitabine Effective for Locally Advanced Pancreatic Cancer

Silas Inman

Induction treatment with nab-paclitaxel (Abraxane) plus gemcitabine demonstrated a time to treatment failure (TTF) of 8.8 months (90% CI, 6.67-9.82) for patients with newly diagnosed locally advanced pancreatic cancer, according to updated findings from the phase II LAPACT trial presented at the 2018 Gastrointestinal Cancers Symposium.

In the single-arm, international trial, the nab-paclitaxel regimen elicited an objective response rate of 32%. The overall disease control rate (DCR) was 77.6%. The median progression-free survival was 10.8 months (90% CI, 9.26-11.63) with the combination, and the 12-month overall survival (OS) rate was 72% (90% CI, 64.5%-78.9%).

“Disease control is key in our patients with locally advanced disease, as it may lead to opportunities for additional treatment interventions, including radiotherapy, or even, in some favorable cases, surgical resection,” lead study author Pascal Hammel, MD, PhD, Gastroenterologist/Oncologist, Hôpital Beau-jon, Clichy, France, said in a statement. “The results from this study are encouraging, as it shows that induction therapy has the potential to help us achieve disease control in these locally advanced patients.”

The study enrolled 106 patients at a median age of 65 years with locally advanced pancreatic cancer. Induction therapy was administered with nab-paclitaxel at 125 mg/m2 plus gemcitabine at 1000 mg/m2 on days 1, 8, and 15 of a 28-day cycle for 6 total cycles. All patients had not received prior therapy for pancreatic cancer and were classified as unresectable. Following the induction phase, patients were offered continuation of nab-paclitaxel/gemcitabine or a switch to another treatment.

The primary endpoint of the study was TTF, with a goal of achieving a median of 6.6 months. All responses in the study were partial responses. The stable disease rate for ≥16 weeks was 44.9%, and 32.7% of patients had stable disease for ≥24 weeks. The DCR for ≥16 weeks was 77.6%, and the DCR for ≥24 weeks was 65.4%.

All 6 cycles of induction therapy were completed by 57.5% of patients in the trial. Overall, 15% of patients went on to subsequent surgical resection following treatment with the regimen. Those who completed induction but did not receive surgery went on to chemoradiation (16%) or continued nab-paclitaxel and gemcitabine (11%).

Of those who did not complete induction therapy, the most common causes for treatment discontinuation were adverse events (AEs; n = 20), progressive disease (n = 8), protocol noncompliance (n = 5), physician decision (n = 6), death (n = 2), and other reasons (n = 4).

The most frequently observed grade ≥3 treatment-emergent AEs were neutropenia (42%), anemia (11%), fatigue (10%), thrombocytopenia (7.5%), peripheral sensory neuropathy (3.8%), diarrhea (3.8%), and febrile neutropenia (3.8%).

“Pancreatic cancer remains an extremely challenging disease to treat because it is often diagnosed at the metastatic stage, and even those diagnosed with locally advanced disease typically have a poor prognosis,” noted Hammel.

The combination of nab-paclitaxel and gemcitabine was approved for patients with metastatic pancreatic cancer in 2013, based on findings from the phase III MPACT trial. In this trial, the median OS was 8.5 months with nab-paclitaxel plus gemcitabine compared with 6.7 months for patients treated with gemcitabine alone (HR, 0.72; 95% CI, 0.62-0.84; P<.0001).

“Since its approval to treat metastatic pancreatic cancer in 2013, the Abraxane-plus-gemcitabine regimen has become a standard of care in first-line metastatic pancreatic cancer,” Nadim Ahmed, president, Hematology and Oncology, at Celgene, the company developing the regimen, said in a statement. “The findings from LAPACT offer insight into the potential of Abraxane-based treatment for locally advanced pancreatic cancer patients, and it’s encouraging to see a nearly 9-month time to treatment failure in these patients treated with an Abraxane regimen.” Several trials continue to assess nab-pacli-taxel for patients with pancreatic cancer. In this setting, the agent is being explored in combination with more than 50 other agents across 130 clinical trials, according to Celgene. Most notably, the phase III APACT trial exploring adjuvant nab-paclitaxel/gemcitabine compared with gemcitabine alone recently completed enrollment of 866 participants. Initial findings from this open-label trial are anticipated in early 2019 (NCT01964430).

REFERENCE

Hammel P, Lacy J, Portales F, et al. Phase II LAPACT trial of nab-paclitaxel (nab-P) plus gemcitabine (G) for patients with locally advanced pancreatic cancer (LAPC). J Clin Oncol. 2018;36(suppl 4S; abstr 204).

Breast Cancer

Study Finds No Cardiac Toxicity Increase With Trastuzumab in Patients With HER2+ Breast Cancer

Jason Harris

Trastuzumab (Herceptin) did not reduce cardiac function in women with node-positive, HER2-positive, early-stage breast cancer, according to long-term follow-up (LTF) results from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 trial published in the Journal of Clinical Oncology.

Investigators reported that both women who received trastuzumab along with adjuvant chemotherapy and those who received chemotherapy alone maintained good cardiac function. At the LTF, only 4.5% of patients from the control group and3.4% from the trastuzumab group had a >10% decline in left ventricular ejection fraction (LVEF) from baseline to a value <50%.

“Breast cancer patients who received anthracycline and taxane-based chemotherapy, with or without trastuzumab, main-tained excellent cardiac function a median of 8.8 years after treatment was started,” lead author Patricia A. Ganz, MD, director of Cancer Prevention and Control Research, University of California, Los Angeles, Jonsson Comprehensive Cancer Center, said in a press release. “In addition, patient reports of greater cardiac symptoms indicated more cardiac problems in the small group who had difficulties. Overall, for the relatively young women who entered this trial, the risks of cardiac late effects were minimal.”

The NSABP B-31 trial assessed whether adding trastuzumab to standard paclitaxel after doxorubicin and cyclophosphamide (AC) chemotherapy would improve disease-free survival or overall survival (OS) in women with HER2-positive breast cancer. Planned combined efficacy joint analysis with the similar North Central Cancer Treatment Group N9831 trial showed that trastuzumab was associated with a 10-year OS rate of 84% (HR, 0.63).

All patients received 4 cycles of 60/600 mg/m2 AC every 3 weeks followed by 175 mg/m2 of paclitaxel every 3 weeks for 4 cycles or 80 mg/m2 weekly for 12 weeks. Patients randomly assigned to the investigational group also received trastuzumab at 4 mg/kg concurrently with the first dose of paclitaxel followed by 2 mg/kg weekly for a total of 52 weeks.

A total of 128 patients in the control group and 313 in the experimental group agreed to participate in the LTF assessments of cardiac function, patient-reported outcomes (PROs) related to health-related quality of life (HR QoL), and cardiac-related symptoms and morbidity.

Investigators monitored cardiac function using LVEF measured by multigated acquisition (MUGA) scans at 3, 6, 9, and 18 months after random assignment. In the control group, 110 patients completed the MUGA scans and 98 completed HR QoL questionnaires compared with 297 and 268 in the trastuzumab group, respectively.

At 18 months, the mean decline from baseline was 3.2% in the control group and 3.9% in the trastuzumab group.

At the LTF assessments, the mean decline from baseline was 3.9% versus 2.8%, respectively.

Three (2.7%) control group LTF participants had a reported decline of ≥10% to <50% at their 18-month assessment compared with 23 patients (7.7%) in the trastuzumab group. At the LTF assessment, 5 patients (4.5%) in the control group experienced a decline versus 10 (3.4%) in the trastuzumab group. One patient in the control group and 2 in the trastuzumab group with LVEF measurements >50% at 18 months had LTF measurements that declined to <40% at LTF.

Nearly 90% of LTF participants completed PRO surveys. The median time from random assignment to questionnaire completion was 8.7 years (range, 5.5-14.0). Investigators found high scores on the mental component scale (MCS) and physical component scale (PCS) of the 36-Item Short Form Medical Outcomes Study and the Duke Activity Status Index (DASI), “reflecting higher-than-expected physical and mental functioning compared with reference populations of the same age.”

The mean PCS score for all patients was 49.7 (SD, 9.1), and the mean MCS score was 52.9 (SD, 9.4). The mean DASI score was 45.6 (SD, 13.8; range, 7.2-58.2) for the total sample. Investigators said lower DASI scores were linked with age and use of certain medications but did not correlate with the addition of trastuzumab.

“Our study improved the 10-year survival for women with this type of aggressive breast cancer to 84%, and now our long-term follow-up of how these women are doing provides positive and encouraging data specifically about their cardiac function and health,” coauthor Edward Romond, MD, professor, University of Kentucky Markey Cancer Center, said in a press release.

REFERENCE

Ganz PA, Romond EH, Cecchini RS, et al. Long-term follow-up of cardiac function and quality of life for patients in NSABP protocol B-31/NRG Oncology: a randomized trial comparing the safety and efficacy of doxorubicin and cyclophosphamide (AC) followed by paclitaxel with AC followed by paclitaxel and trastuzumab in patients with node-positive breast cancer with tumors overexpressing human epidermal growth factor receptor 2. J Clin Oncol. 2017;35(35):3942-3948. doi: 10.1200/JCO.2017.74.1165.