Exceptional responses to PARP inhibitors in patients with metastatic breast cancer in oncologic crisis.

PURPOSE: Cancers deficient in homologous recombination DNA repair, such as those with BRCA1 or BRCA2 (BRCA1/2) mutations rely on a pathway mediated by the enzyme poly(adenosine diphosphate-ribose) polymerase (PARP). PARP inhibitors (PARPi's) have demonstrated efficacy in treating patients with germline (g)BRCA1/2, somatic (s)BRCA1/2, and gPALB2 mutations in clinical trials. However, patients with a poor performance status (PS) and those with severe organ impairment are often excluded from clinical trials and cancer-directed treatment. METHODS: We report the cases of two patients with metastatic breast cancer who had poor PS, significant visceral disease, and gPALB2 and sBRCA mutations, who derived significant clinical benefit from treatment with PARP inhibition. RESULTS: Patient A had germline testing demonstrating a heterozygous PALB2 pathogenic mutation (c.3323delA) and a BRCA2 variant of unknown significance (c.9353T>C), and tumor sequencing revealed PALB2 (c.228_229del and c.3323del) and ESR1 (c.1610A>C) mutations. Patient B was negative for pathologic BRCA mutations upon germline testing, but tumor sequencing demonstrated somatic BRCA2 copy number loss and a PIK3CA mutation (c.1633G>A). Treatment with PARPi's in these two patients with an initial PS of 3-4 and significant visceral disease resulted in prolonged clinical benefit. CONCLUSION: Patients with a poor PS, such as those described here, may still have meaningful clinical responses to cancer treatments targeting oncogenic drivers. More studies evaluating PARPi's beyond gBRCA1/2 mutations and in sub-optimal PS would help identify patients who may benefit from these therapies.

Initiation of exemestane in two warfarin-treated patients leading to elevation and variability of INR.

Aromatase inhibitors are sometimes chosen for adjuvant therapy in post-menopausal breast cancer patients with a history of venous thromboembolism over an antiestrogen due to the lower risk of venous thromboembolism associated with aromatase inhibitors compared to antiestrogens. We report two cases where patients on warfarin therapy had an increase in their international normalized ratio with the initiation of exemestane therapy. Initially, the patients also showed international normalized ratio variability possibly due to variable absorption of exemestane. We suggest patients being treated with warfarin and exemestane concomitantly need close monitoring and education in order to decrease the risk of adverse events that could be associated with this possible interaction. To our knowledge, there are no similar reported cases in the literature.

Palbociclib: A Novel Cyclin-Dependent Kinase Inhibitor for Hormone Receptor-Positive Advanced Breast Cancer.

OBJECTIVE: To review palbociclib, a novel small-molecule inhibitor of cyclin-dependent kinases 4 and 6, and its current place in therapy for the treatment of hormone receptor (HMR)-positive, human epidermal growth factor receptor 2 (Her2)-negative advanced breast cancer. STUDY SELECTION AND DATA ABSTRACTION: Four phase I trials, 2 phase II trials, and 1 phase III trial were identified from May 2004 to May 2015 using PubMed, American Society of Clinical Oncology (ASCO) abstracts, and European Society of Medical Oncology (ESMO) abstracts. DATA SYNTHESIS: In the first-line setting, the phase II PALbociclib: Ongoing trials in the Management of breast cAncer (PALOMA)-1 trial randomized patients to receive letrozole alone or letrozole plus palbociclib 125 mg daily for 3 weeks, followed by 1 week off, as initial therapy for advanced breast cancer. The investigator-assessed median progression-free survival (PFS) was 20. 2 months for the combination versus 10.2 months for letrozole alone (hazard ratio [HR] = 0.488; 95% CI = 0.319-0.748; 1-sided P = 0.0004). The ensuing Food and Drug Administration approval of palbociclib was given a "breakthrough therapy" designation, where preliminary evidence suggests substantial improvement over existing therapies for a serious or life-threatening disease. A confirmatory phase III trial, PALOMA-2, is under way. In patients who were previously treated with endocrine therapy for advanced breast cancer, the phase III PALOMA-3 trial randomized patients to fulvestrant plus palbociclib versus fulvestrant plus placebo. The investigator-assessed median PFS at the time of a preplanned analysis was 9.2 months with palbociclib-fulvestrant compared with 3.8 months with placebo-fulvestrant (HR = 0.42; 95% CI = 0.32-0.56; P < 0.001). CONCLUSIONS: Palbociclib, the first-in-class CDK4/6 inhibitor, significantly extended PFS in combination with endocrine therapy in the first and subsequent lines of treatment for HMR-positive, Her2-negative advanced breast cancer.

Incidence and Severity of Myelosuppression With Palbociclib After Palliative Bone Radiation in Advanced Breast Cancer: A Single Center Experience and Review of Literature.

BACKGROUND: Palbociclib is a cyclin-dependent kinase (CDK) 4/6 inhibitor with a primary toxicity of myelosuppression, especially neutropenia, due to cytostatic CDK6 inhibition on bone marrow. Preclinical studies suggest palbociclib may enhance radiation toxicity, but this was only evaluated in limited case series of palliative radiotherapy and not specific to radiation targeting bony metastases. PATIENTS AND METHODS: This was a single institution retrospective cohort study. We included female patients who initiated palbociclib for advanced breast cancer between 2015 and 2019. The primary exposure was receipt of palliative radiation to bony metastases within 1 year prior to starting palbociclib. The primary outcome was the incidence and severity of myelosuppression during cycle one. Secondary outcomes include treatment interruptions and cycle 2 dose reductions, with subgroup analysis of radiation timing, type, dose, and location. RESULTS: Of the 247 patients, 47 received radiation to bone metastases. Only absolute lymphocyte count (ALC) after cycle one of palbociclib was significantly lower in the group receiving radiation (median ALC 0.84 vs. 1.10 K/mm3, P < .001), with similar rates of neutropenia, anemia, and thrombocytopenia. Patients who received ≥10 fractions radiation were more likely to have cycle one interrupted than those receiving shorter radiation courses (42.9% vs. 11.1%, P = .03). No radiation characteristics were associated with other hematologic toxicities or dose reduction. CONCLUSION: Palliative bone radiation within 1 year prior to palbociclib initiation was associated with greater lymphopenia during the first cycle than patients unexposed to radiation, but not neutropenia, anemia, or thrombocytopenia that would modify treatment.

Olaparib Use in Patients With Metastatic Breast Cancer Harboring Somatic BRCA1/2 Mutations or Mutations in Non-BRCA1/2, DNA Damage Repair Genes.

BACKGROUND: Poly-ADP ribose polymerase (PARP) inhibitors (PARPi) are active in patients with germline BRCA1/2 (gBRCA1/2)-mutated breast cancer, accounting for 5% to 10% of all breast cancers. Another 5% to 10% harbor somatic BRCA1/2 (sBRCA1/2) mutations or mutations in non-BRCA1/2, homologous recombination repair (HRR) genes but until recently, there were no data for the use of PARPi in these patients. This study examines the use of olaparib in patients with metastatic breast cancer harboring sBRCA1/2 or germline or somatic non-BRCA1/2, HRR mutations and demonstrates potential activity of PARPi in this setting. METHODS: In this retrospective, single institution study, patients who were treated with off-label, off-protocol olaparib for metastatic breast cancer harboring sBRCA1/2 or germline or somatic non-BRCA1/2, HRR mutations were identified. The primary aim was to describe these patients' demographics, tumor characteristics, mutations, safety and tolerability, response rates, progression free survival, PARPi-associated survival and subsequent treatment. RESULTS: Seven patients were treated off-label, off-trial with olaparib for sBRCA1/2-mutated cancers (n = 4) or non-BRCA1/2, HRR-mutated cancers (n = 3). All patients with sBRCA1/2-mutated cancers responded to PARP inhibition; patients with non-BRCA1/2, HRR-mutated cancers did not respond. The median progression free survival in patients with a sBRCA1/2 mutation was 6.5 months (range 5-9 months) vs. 3 months (range 2-4 months) in patients with non-BRCA1/2, HRR mutations. CONCLUSION: This single institution experience adds to recent larger reports confirming evidence for PARPi therapy in patients with metastatic breast cancer harboring sBRCA1/2 mutations. No activity was observed in patients with either germline or somatic non-BRCA1/2, HRR-mutated cancers.

Management of Breast Cancer During the COVID-19 Pandemic: A Stage- and Subtype-Specific Approach.

The COVID-19 pandemic has rapidly changed delivery of cancer care. Many nonurgent surgeries are delayed to preserve hospital resources, and patient visits to health care settings are limited to reduce exposure to SARS-CoV-2. Providers must carefully weigh risks and benefits of delivering immunosuppressive therapy during the pandemic. For breast cancer, a key difference is increased use of neoadjuvant systemic therapy due to deferral of many breast surgeries during the pandemic. In some cases, this necessitates increased use of genomic tumor profiling on core biopsy specimens to guide neoadjuvant therapy decisions. Breast cancer treatment during the pandemic requires multidisciplinary input and varies according to stage, tumor biology, comorbidities, age, patient preferences, and available hospital resources. We present here the Johns Hopkins Women's Malignancies Program approach to breast cancer management during the COVID-19 pandemic. We include algorithms based on tumor biology and extent of disease that guide management decisions during the pandemic. These algorithms emphasize medical oncology treatment decisions and demonstrate how we have operationalized the general treatment recommendations during the pandemic proposed by national groups, such as the COVID-19 Pandemic Breast Cancer Consortium. Our recommendations can be adapted by other institutions and medical oncology practices in accordance with local conditions and resources. Guidelines such as these will be important as we continue to balance treatment of breast cancer against risk of SARS-CoV-2 exposure and infection until approval of a vaccine.

Stabilization of bone marrow infiltration by metastatic breast cancer with continuous doxorubicin.

Complete bone marrow infiltration with profound pancytopenia is very uncommon in breast cancer. Bone marrow metastasis can frequently occur following development of metastatic breast cancer. However, bone marrow failure as the herald of this disease is not typically seen. Very limited data exists as to the safest and most efficacious manner to treat patients with profound pancytopenia due to metastatic solid tumor involvement. In this case, the patient's thrombocytopenia was particularly worrisome, requiring daily platelet transfusions. There was also concern that cytotoxic chemotherapy would exacerbate the patient's thrombocytopenia and increase bleeding risk. The patient's dramatic response to chemotherapy with full platelet recovery is also highly unusual. For our patient, continuous doxorubicin successfully "unpacked" the bone marrow despite a low baseline platelet level, and without increasing the need for more frequent platelet transfusion or risk of catastrophic bleeding. Given the rarity of this presentation, it is currently unknown if the majority of similar patients experience near full recovery of hematopoietic function after initiation of appropriate systemic treatment for metastatic disease.

Endocrine therapy in breast cancer: the neoadjuvant, adjuvant, and metastatic approach.

OBJECTIVES: To review the rationale for endocrine therapy in the neoadjuvant, adjuvant, and metastatic breast cancer setting and to highlight clinical considerations unique to this treatment. DATA SOURCES: Contemporary literature, clinical guidelines, and national statistics. CONCLUSION: Endocrine therapy represents an important strategy in the management of both early and advanced hormone positive breast cancer. Additional research is required to better define the role of neoadjuvant therapy and the optimal duration of treatment. IMPLICATIONS FOR NURSING PRACTICE: Nurses play a pivotal role in the identification and management of endocrine therapy-associated symptoms. Prompt symptom intervention may improve therapy adherence and ultimately, may improve long-term disease outcomes.