Treatments for breast cancer in men: late effects and impact on quality of life.

PURPOSE: Male breast cancer accounts for approximately 1% of all breast cancer diagnoses. Unfortunately, a lack of information exists regarding late effects of breast cancer treatment in men. METHODS: An online survey directed towards male breast cancer patients was distributed via social medial and emails from June to July 2022. Participants were asked about their disease characteristics, treatments and side effects from the disease or treatment. Patients and treatment variables were reported via descriptive statistics. Univariate logistic regression was performed to evaluate associations between different treatment variables and outcomes expressed by odds ratio. RESULTS: A total of 127 responses were analyzed. Median age of the participants was 64 years (range 56-71 years). A total of 91 participants (71.7%) revealed they experienced late effects secondary to their cancer or cancer treatment. The most concerning physical and psychological symptoms reported were fatigue and fear of recurrence respectively. Axillary lymph node dissection was associated with swollen arm and with difficulty in arm or shoulder movement. Systemic chemotherapy was related to bothersome hair loss and changes on interest in sex; and endocrine therapy was associated with feeling less masculine. CONCLUSION: Our study showed that men suffer several late effects from treatments for breast cancer. Lymphedema, difficulty with arm and shoulder movement, sexual dysfunction and hair loss should be discussed with males as it can be distressing for some patients and decrease their quality of life.

Advances in the Management of Central Nervous System Metastases from Breast Cancer.

Central nervous system (CNS) metastases are common in breast cancer (BC) patients and are particularly relevant as new treatments for BC are prolonging survival. Here, we review advances in the treatment of CNS metastases from BC, including radiotherapy, systemic therapies, and the evolving role of immunotherapy. The use of radiotherapy and chemotherapy is the cornerstone of treatment for CNS metastases. However, new targeted therapies have recently been developed, including anti-HER2 agents and antibody-drug conjugates that have presented promising results for the treatment of these patients.

Efficacy of neoadjuvant chemotherapy in male breast cancer compared with female breast cancer.

BACKGROUND: Neoadjuvant chemotherapy (NAC) is standard for many females with breast cancer (FBC). The efficacy of NAC in male breast cancer (MaBC) is unclear. The aim of this study was to compare proportions of pathologic complete response (pCR) between MaBC and FBC by tumor subtype (TS). METHODS: MaBC and FBC treated with NAC between 2010 and 2016, with known TS, were evaluated from the National Cancer Database. Proportions of pCR (ypT0/Tis ypN0) were compared between sexes within TS by Fisher test. Multivariable logistic regression assessed the independent association of sex with pCR. Overall survival (OS) was estimated by Kaplan-Meier. RESULTS: A total of 385 MaBC and 68,065 FBC were included. Median time from initiation of NAC to surgery was 143 days in MaBC and 148 days in FBC. Proportions of pCR in MaBC and FBC by TS were: hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-): 4.9% vs 9.7%, p = .01; HR+/HER2+: 16.1% vs 33.6%, p < .001; HR-/HER2+: 44.0% vs 53.2%, p = .42; and HR-/HER2-: 21.4% vs 32.1%, p = .18, respectively. FBC had twice the odds of pCR than MaBC (adjusted odds ratio, 2.0; 95% CI, 1.5-2.8; p < .001). Five-year OS for MaBC with pCR vs not was 90% vs 64.7%; p = .02. Five-year OS for FBC with pCR vs not was 91.9% vs 75.3%; p < .01. CONCLUSIONS: Proportions and odds of pCR to NAC were numerically lower in MaBC compared with FBC for each TS and statistically significant for HR+/HER2- and HR+/HER2+. The independent association of sex with pCR was confirmed in multivariable analysis. pCR is prognostic in both MaBC and FBC.

Male Breast Cancer: An Updated Review of Epidemiology, Clinicopathology, and Treatment.

Male breast cancer (MaBC) is a rare clinical entity, which makes up approximately 1% of all breast cancers. However, the incidence of MaBC has been steadily increasing over the past few decades. The risk factors for MaBC include age, black race, family history of breast cancer, genetic mutations, liver cirrhosis, and testicular abnormalities. The majority of patients with MaBC present with painless lumps, and about half of the patients have at least one lymph node involved at the time of diagnosis. The treatment of MaBC models that of female breast cancer (FeBC), but this is mainly due to lack of prospective studies for MaBC patients. The treatment modality includes surgery, adjuvant radiation, endocrine therapy, and chemotherapy. However, there are some distinct features of MaBC, both clinically and molecularly, that may warrant a different clinical approach. Ongoing multinational effort is required, to conduct clinical trials for MaBC, or the inclusion of MaBC patients in FeBC trials, to help clinicians improve care for MaBC patients.

Central Nervous System Metastases from Triple-Negative Breast Cancer: Current Treatments and Future Prospective.

It is estimated that approximately one-third of patients with triple-negative breast cancer (TNBC) will develop brain metastases. The prognosis for patients with breast cancer brain metastasis has improved in the recent past, especially for hormone receptor and human epidermal growth factor receptor 2 (HER) positive subtypes. However, the overall survival rate for patients with triple-negative subtype remains poor. The development of newer treatment options, including antibody-drug conjugates such as Sacituzumab govitecan, is particularly encouraging. This article reviews the clinical outcomes, challenges, and current approach to the treatment of brain metastasis in TNBC. We have also briefly discussed newer treatment options and ongoing clinical trials. The development of brain metastasis significantly decreases the quality of life of patients with TNBC, and newer treatment strategies and therapeutics are the need of the hour for this disease subgroup.

Perceptions of patients and medical oncologists toward biospecimen donation in the setting of abnormal breast imaging findings.

PURPOSE: We sought to understand the attitudes of individuals with abnormal breast imaging findings prompting a diagnostic breast biopsy toward donation of blood, excised tissue, or percutaneous biospecimens for research, and to understand medical oncologists' attitudes toward research biospecimen collection in this population. METHODS: We included individuals who presented to a single academic medical center for a clinically indicated, image-guided, percutaneous breast biopsy. We administered a survey prior to knowledge of biopsy results to assess willingness to consider, entirely for research purposes, donating blood or excess excised breast tissue, or having additional biospecimens (AB) obtained during a clinically indicated percutaneous biopsy. We also surveyed breast medical oncologists from National Cancer Institute-designated cancer centers to assess attitudes toward approaching patients for biospecimen research. RESULTS: Overall, 53/63 patients responded to the survey; 70% would consider donating blood, 85% would consider donating excess excised breast tissue, and 32% would consider having AB obtained during a clinically indicated biopsy. Main motivating factors for considering AB included contributing to scientific knowledge and return of study or biopsy results, whereas anxiety and the potential discomfort were the main dissuading factors. Among 191 medical oncologists, most were very comfortable (59.2%), or somewhat comfortable (32.5%) asking patients to have AB obtained during a clinically indicated breast biopsy. Medical oncologists reported hesitancy to refer a patient for AB due to potential pain/discomfort, and other procedure risks. CONCLUSIONS: Only one-third of individuals with breast imaging findings would consider consenting to AB during a diagnostic biopsy, whereas most were open to donating blood or excess excised breast tissue. Most medical oncologists would be comfortable asking patients to have AB obtained during the biopsy. Understanding patients' and oncologists' baseline attitudes may inform the design and approach to breast biospecimen-based research.

Prospective Study Testing a Simplified Paclitaxel Premedication Regimen in Patients with Early Breast Cancer.

BACKGROUND: In early trials, hypersensitivity reactions (HSRs) to paclitaxel were common, thus prompting the administration of antihistamines and corticosteroids before every paclitaxel dose. We tested the safety of omitting corticosteroids after cycle 2 during the paclitaxel portion of the dose-dense (DD) doxorubicin-cyclophosphamide (AC)-paclitaxel regimen. PATIENTS, MATERIALS, AND METHODS: In this prospective, single-arm study, patients who completed four cycles of DD-AC for stage I-III breast cancer received paclitaxel 175 mg/m2 every 2 weeks for four cycles. Patients received a standard premedication protocol containing dexamethasone, diphenhydramine, and a histamine H2 blocker prior to the first two paclitaxel cycles. Dexamethasone was omitted in cycles three and four if there were no HSRs in previous cycles. We estimated the rate of grade 3-4 HSRs. RESULTS: Among 127 patients enrolled, 125 received more than one dose of protocol therapy and are included in the analysis. Fourteen (11.2%; 90% confidence interval, 6.9%-20.0%) patients had any-grade HSRs, for a total of 22 (4.5%; 3.1%-6.4%) HSRs over 486 paclitaxel cycles. Any-grade HSRs occurred in 1.6% (0.3%-5.0%), 6.5% (3.3%-11.3%), 7.4% (3.9%-12.5%), and 2.6% (0.7%-6.6%) of patients after paclitaxel cycles 1, 2, 3, and 4, respectively. Dexamethasone use was decreased by 92.8% in cycles 3 and 4. Only one patient experienced grade 3 HSR in cycles 3 or 4, for a rate of grade 3/4 HSR 0.4% (0.02%-2.0%) (1/237 paclitaxel infusions). That patient had grade 2 HSR during cycle 2, and the subsequent grade 3 event occurred despite usual dexamethasone premedication. A sensitivity analysis restricted to patients not known to have received dexamethasone in cycles 3 and 4 found that any-grade HSRs occurred in 2.7% (3/111; 0.7%-6.8%) and 0.9% (1/109; 0.05%-4.3%) of patients in cycle 3 and 4, respectively. CONCLUSION: Corticosteroid premedication can be safely omitted in cycles 3 and 4 of dose-dense paclitaxel if HSRs are not observed during cycles 1 and 2. IMPLICATIONS FOR PRACTICE: Because of the potential for hypersensitivity reactions (HSRs) to paclitaxel, corticosteroids are routinely prescribed prior to each dose, on an indefinite basis. This prospective study, including 125 patients treated with 486 paclitaxel cycles, demonstrates that corticosteroids can be safely omitted in future cycles if HSRs did not occur during cycles 1 and 2 of paclitaxel and that this strategy reduces the use of corticosteroids in cycles 3 and 4 by 92.8% relative to current standard of care.

Management and outcomes of men diagnosed with primary breast cancer.

BACKGROUND: Fewer than 1% of all breast cancers occur in men. As a result, a distinct lack of data exists regarding the management and outcomes in this cohort. METHODS: Any male patient with pathologically confirmed breast cancer diagnosed between August 2000 and October 2017 at either Massachusetts General Hospital or Brigham and Women's Hospital/Dana-Farber Cancer Institute and their affiliate satellite locations were included. Primary chart review was used to assess clinical and pathologic characteristics. Patient and treatment variables were reported via descriptive statistics. Local-regional failure (LRF), overall survival (OS), breast cancer-specific survival (BCSS), and disease-free survival (DFS) were estimated using the Kaplan-Meier method. RESULTS: 100 patients were included in this study. Median follow-up was 112 months (range 1-220 months). Approximately 1/3 of patients experienced at least a 3-month delay to presentation. 83 patients ultimately underwent mastectomy as definitive surgical treatment. 46 patients received adjuvant radiation therapy, and 37 patients received chemotherapy. Of 82 hormone receptor-positive patients with invasive cancer, 94% (n = 77) received endocrine therapy. Of the fifty-eight patients who underwent genetic testing, 15 (26%) tested positive. The 5-year OS, BCSS, DFS, and LRF rates were 91.5%, 96.2%, 86%, and 4.8%, respectively. Delay to presentation was not associated with worse survival. CONCLUSIONS: Male breast cancer remains a rare diagnosis. Despite this, the majority of patients in this study received standard of care therapy and experienced excellent oncologic outcomes. Penetration for genetic testing improved over time.

Tumor subtypes and survival in male breast cancer.

PURPOSE: Male breast cancer is an uncommon disease, and population-based information regarding prognostic factors is limited. Most cases are hormone receptor (HR) positive; however, the association of tumor subtype with overall survival (OS) and breast cancer-specific survival (BCSS) is unclear. METHODS: Using SEER data, we identified men with invasive breast cancer between 2010 and 2017 with known HR and HER2 status. We examined tumor subtypes by patient characteristics and performed multivariate Cox proportional hazards analyses to determine the associations of each variable with OS and BCSS. RESULTS: We included 2389 men with a median follow-up of 43 months (IQR 19-68). Median age was 66 years. Tumor subtype distribution was 84.1% HR+/HER2-, 12.7% HR+/HER2+ , 0.8% HR-/HER2+, and 2.3% triple-negative (TN). In univariate analysis, OS at 5 years was 76.5% for HR+/HER2-, 65.1% for HR+/HER2+ , 84.2% for HR-/HER2+, and 48.1% for TN (p < 0.0001). Of all subtypes, TN had the worst BCSS (p < 0.0001). Stage, tumor subtype and race were significantly associated with OS and BCSS in multivariate analysis. Adjusted Cox hazard ratios for OS by tumor subtype with HR+/HER2- as reference were 1.55 for HR+/HER2+ (p = 0.001), 1.1 for HR-/HER2+ (p = 0.888), and 3.59 for TN (p < 0.001). CONCLUSION: We observed significant differences in survival outcomes by tumor subtype. Poor outcomes among men with HER2+ and TN disease suggest possible under-treatment, aggressive tumor biology, and/or more advanced disease at presentation. Studies to better understand the inferior survival for men with these subtypes are warranted and will likely require international collaboration.

Targeted Therapies for Breast Cancer Brain Metastases.

The management of breast cancer, the most common cancer in the female population, has changed dramatically over years with the introduction of newer therapies. An increased incidence of brain metastases in recent years has created a challenge for oncologists because this population continues to have a poorer prognosis compared to metastatic breast cancer without central nervous system involvement. Historically, the exclusion of breast cancer patients with brain metastases from clinical trials has made treatment options even more limited. Nonetheless, more recently, this unmet need has been recognized by basic and clinical researchers and has led to the development of targeted therapies with better blood-brain barrier penetration and intracranial efficacy. Here we review targeted therapies directed at human epidermal growth factor receptor type 2 (HER2), vascular endothelial growth factor (VEGF), mammalian target of rapamycin (mTOR), epidermal growth factor receptor (EGFR), cyclin-dependent kinase 4 and 6 (CDK4/6) and poly(ADP-ribose) polymerase (PARP) for breast cancer patients with brain metastases. These therapies aim to be more efficacious and less toxic to represent a paradigm shift in the management of breast cancer brain metastases.

The prognostic significance of metastatic pattern in stage IV male breast cancer at initial diagnosis: a population-based study.

PURPOSE: Metastatic pattern (MP) is a prognostic factor in women with breast cancer. However, the prognostic significance of MP in male breast cancer patients remains unknown. METHODS: Using the SEER database, we gathered demographic information and disease characteristics for men diagnosed with de novo metastatic breast cancer from 2010 to 2017. Metastases to bone, brain, liver, and lung were used to define MP (bone-only, visceral, bone and visceral [BV], or other). Statistical analyses were performed to identify associations between overall survival (OS) and MP, as well as other patient and tumor features. We used multivariate logistic regression to evaluate factors associated with sites of metastases. RESULTS: We included 250 patients. MP distribution was bone = 38.8%, visceral = 14.8%, BV = 33.2%, and other = 13.2%. Median OS for each was bone = 33 months, visceral = 23 months, BV = 20 months, and other = 46 months (p = 0.046). Patients with brain metastases had significantly shorter OS compared with no brain metastases (median OS = 9 months vs. 30 months; p < 0.001). Compared with other subtypes, triple negative had the shortest OS (median 9 months, p < 0.001). Logistic regression modeling revealed that compared with HR+/HER2- breast cancers, HR-/HER2+ had higher odds of liver metastases and triple negative had higher odds of brain metastases. Patients younger than 50 years had a significantly greater risk of developing brain metastases. CONCLUSIONS: MP and tumor subtype can predict OS outcomes in men with metastatic breast cancer at diagnosis. Brain metastases confer very poor prognosis.

Perceptions of patients with early stage breast cancer toward research biopsies.

BACKGROUND: The objective of this study was to describe the perspective of patients with early breast cancer toward research biopsies. The authors hypothesized that more patients at academic sites than at community-based sites would be willing to consider these procedures. METHODS: In total, 198 patients with early stage breast cancer were recruited from 3 academic centers (n = 102) and from 1 community oncology practice (n = 96). The primary objective was to compare the proportion of patients willing to consider donating excess tissue biospecimens from surgery, from a clinically indicated breast biopsy, or from a research purposes-only biopsy (RPOB) between practice types. RESULTS: Most patients (93% at academic sites, 94% at the community oncology site) said they would consider donating excess tissue from surgery for research. One-half of patients from academic or community sites would consider donating tissue from a clinically indicated breast biopsy. On univariate analysis, significantly fewer patients from academic sites would consider an RPOB (22% at academic sites, 42% at the community site; P = .003); however, this difference was no longer significant on multivariate analysis (P = .96). Longer transportation times and unfavorable prior experiences were associated with less willingness to consider an RPOB on multivariate analysis. Significantly fewer patients from academic sites (14%) than from the community site (35%) would consider a research biopsy in a clinical trial (P = .04). Contributing to scientific knowledge, return of results, and a personal request by their physician were the strongest factors influencing patients' willingness to undergo research biopsies. CONCLUSIONS: The current results rejected the hypothesis that more patients with early breast cancer at academic sites would be willing to donate tissue biospecimens for research compared with those at community oncology sites. These findings identify modifiable factors to consider in biobanking studies and clinical trials.

Phase II trial of carboplatin and bevacizumab in patients with breast cancer brain metastases.

BACKGROUND: We aimed to examine the safety and efficacy of bevacizumab and carboplatin in patients with breast cancer brain metastases. METHODS: We enrolled patients with breast cancer and > 1 measurable new or progressive brain metastasis. Patients received bevacizumab 15 mg/kg intravenously (IV) on cycle 1 day 1 and carboplatin IV AUC = 5 on cycle 1 day 8. Patients with HER2-positive disease also received trastuzumab. In subsequent cycles, all drugs were administered on day 1 of each cycle. Contrast-enhanced brain MRI was performed at baseline, 24-96 h after the first bevacizumab dose (day + 1), and every 2 cycles. The primary endpoint was objective response rate in the central nervous system (CNS ORR) by composite criteria. Associations between germline VEGF single nucleotide polymorphisms (rs699947, rs2019063, rs1570360, rs833061) and progression-free survival (PFS) and overall survival (OS) were explored, as were associations between early (day + 1) MRI changes and outcomes. RESULTS: Thirty-eight patients were enrolled (29 HER2-positive, 9 HER2-negative); all were evaluable for response. The CNS ORR was 63% (95% CI, 46-78). Median PFS was 5.62 months and median OS was 14.10 months. As compared with an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0, patients with ECOG PS 1-2 had significantly worse PFS and OS (all P < 0.01). No significant associations between VEGF genotypes or early MRI changes and clinical outcomes were observed. CONCLUSIONS: The combination of bevacizumab and carboplatin results in a high rate of durable objective response in patients with brain metastases from breast cancer. This regimen warrants further investigation. TRIAL REGISTRATION: NCT01004172 . Registered 28 October 2009.

Avoiding Peg-Filgrastim Prophylaxis During the Paclitaxel Portion of the Dose-Dense Doxorubicin-Cyclophosphamide and Paclitaxel Regimen: A Prospective Study.

PURPOSE: The use of growth factors adds considerable expense and some toxicity to adjuvant breast cancer chemotherapy. We tested the feasibility and safety of omitting routine peg-filgrastim use during the paclitaxel portion of the dose-dense doxorubicin-cyclophosphamide-paclitaxel regimen. PATIENTS AND METHODS: This was a prospective, single-arm study in which patients 18 to 65 years of age who completed 4 cycles of dose-dense doxorubicin-cyclophosphamide for stage I-III breast cancer received paclitaxel 175 mg/m2 every 2 weeks. Peg-filgrastim was administered after paclitaxel only if patients had had febrile neutropenia in a prior cycle or at investigator discretion if patients had infections or treatment delays of > 1 week. Once a patient received peg-filgrastim, it was administered in all future cycles. The primary end point was the rate of paclitaxel completion within 7 weeks from cycle 1 day 1 to cycle 4 day 1. If ≥ 100 out of 125 patients completed 4 cycles of paclitaxel without dose delay, the regimen would be considered feasible. RESULTS: The enrollment goal of 125 patients was met. Median age was 46 years (range, 21-65 years), and 112 patients (90% [95% CI, 83% to 94%]) completed dose-dense paclitaxel within 7 weeks. Omission of peg-filgrastim was not causally related to noncompletion of paclitaxel in any patients. The most common reasons for dose reduction or delays were nonhematologic. One patient experienced febrile neutropenia but was able to complete paclitaxel on time. Eight patients (6.4%) received peg-filgrastim during the trial. Overall, peg-filgrastim was administered in only 4.3% of paclitaxel cycles. CONCLUSION: Omission of routine peg-filgrastim during dose-dense paclitaxel according to a prespecified algorithm seems to be safe and feasible and was associated with a 95.7% reduction in the use of peg-filgrastim relative to the current standard of care.

A phase II study of cabozantinib alone or in combination with trastuzumab in breast cancer patients with brain metastases.

PURPOSE: To analyze the efficacy and tolerability of cabozantinib-a small molecule inhibitor of MET and VEGFR2-alone or with trastuzumab in patients with breast cancer brain metastases (BCBM). METHODS: This single-arm phase II study enrolled patients with new or progressive measurable BCBM into 3 cohorts: Cohort 1 (HER2-positive), Cohort 2 (hormone receptor-positive/HER2-negative), and Cohort 3 (triple-negative). Patients received cabozantinib 60-mg daily on a 21-day cycle. Cohort 1 added trastuzumab every 3 weeks and had a primary objective of central nervous system (CNS) objective response rate (ORR) by RECIST 1.1. Secondary objectives for all cohorts were progression-free survival, overall survival, toxicity, and changes in vascular parameters and circulating biomarkers. Cohorts 2 and 3 also had CNS ORR as a secondary objective. RESULTS: Thirty-six BCBM patients enrolled (cohort 1, n = 21; cohort 2, n = 7; cohort 3, n = 8), with a median age of 50. Patients had a median of 3 prior lines for metastatic disease (range 1-9). Treatments prior to enrollment included craniotomy (n = 4), whole brain radiation (n = 24) and stereotactic radiosurgery (n = 11). CNS ORR was 5% in cohort 1, 14% in cohort 2, and 0% in cohort 3. Most common grade 3/4 adverse events included elevations in lipase (11%), AST (8%), ALT (6%), hyponatremia (8%), and hypertension (6%). Cabozantinib increased plasma concentrations of CA-IX, soluble (s)MET, PlGF, sTIE-2, VEGF, and VEGF-D, and decreased sVEGFR2 and TNF-α and total tumor blood volume. CONCLUSIONS: Cabozantinib had insufficient activity in heavily pretreated BCBM patients. Biomarker analysis showed that cabozantinib had antiangiogenic activity and increased tissue hypoxia. TRIAL REGISTRATION: Clinicaltrial.gov registration: NCT02260531.

Barriers to accrual and enrollment in brain tumor trials.

Many factors contribute to the poor survival of malignant brain tumor patients, some of which are not easily remedied. However, one contributor to the lack of progress that may be modifiable is poor clinical trial accrual. Surveys of brain tumor patients and neuro-oncology providers suggest that clinicians do a poor job of discussing clinical trials with patients and referring patients for clinical trials. Yet, data from the Cancer Action Network of the American Cancer Society suggest that most eligible oncology patients asked to enroll on a clinical trial will agree to do so. To this end, the Society for Neuro-Oncology (SNO) in collaboration with the Response Assessment in Neuro-Oncology (RANO) Working Group, patient advocacy groups, clinical trial cooperative groups, including the Adult Brain Tumor Consortium (ABTC), and other partners are working together with the intent to double clinical trial accrual over the next 5 years. Here we describe the factors contributing to poor clinical trial accrual in neuro-oncology and offer possible solutions.

Correction to: Systemic Therapy of Central Nervous System Metastases of Breast Cancer.

The original version of this article, which published in Current Oncology Reports, Volume 21, Issue 6, June 2019, contained an error in addressing the indication for use of neratinib in early stage breast cancer.

Systemic Therapy of Central Nervous System Metastases of Breast Cancer.

PURPOSE OF THE REVIEW: Historically, systemic treatment options for patients with breast cancer brain metastases have been very limited. This review focuses on important considerations for systemic therapy as well as ongoing clinical trials evaluating novel agents. RECENT FINDINGS: For patients with hormone receptor-positive brain metastases, endocrine therapy or chemotherapy options can be considered. The role of CDK4/6 inhibitors is being explored in ongoing trials. Patients with HER2-positive disease have a number of treatment options, including ado-trastuzumab emtansine (TDM1) or lapatinib-capecitabine, and there is emerging evidence of the efficacy of neratinib- and tucatinib-based chemotherapy combinations in the CNS. Triple-negative tumors may respond to chemotherapy. Although much progress remains to be made, a number of effective systemic treatment options are emerging, particularly for patients with HER2-positive disease. Ongoing clinical trials will help define the role of novel agents.