Systemic Therapy For Stage Iv Or Recurrent Metastatic Hr
Women with stage IV or recurrent disease characterized by HR-positive, HER2-negative tumors with no visceral crisis are treated with endocrine therapy alone or endocrine therapy in combination with targeted agents.
Women whose disease progresses after a year from the end of adjuvant endocrine-based therapy and those who present with de novo stage IV/metastatic breast cancer are eligible for first-line endocrine therapies.
Many premenopausal and postmenopausal women with HR-positive breast cancer benefit from sequential use of endocrine therapies at disease progression. Therefore, women with breast cancers who respond to an endocrine-based therapy with either shrinkage of the tumor or long-term disease stabilization should receive additional endocrine therapy at disease progression. Those who progress on or within 12 months of completing adjuvant endocrine therapy or patients who progress on first-line endocrine therapy for metastatic disease are eligible for second-line endocrine therapy either as monotherapy or in combination with a targeted agent. The optimal sequence for endocrine therapy is not well defined. The choice would depend on previous therapy, tolerance of treatment, and patient preference.
Preferred First-Line Therapy for HR-Positive, HER2-Negative Breast Cancer
Aromatase Inhibitor in Combination With Cyclin-Dependent Kinase 4/6 Inhibitor
Single Agent Fulvestrant
Fulvestrant + CDK 4/6 Inhibitor
Fulvestrant + Nonsteroidal AI
Monotherapy With Endocrine Agents
Management Of Dcis After Primary Treatment
Tamoxifen
DCIS falls between atypical ductal hyperplasia and invasive ductal carcinoma within the spectrum of breast proliferative abnormalities. The Breast Cancer Prevention Trial performed by NSABP showed a 75% reduction in the occurrence of invasive breast cancer in patients with ADH treated with tamoxifen.54,55 These data also showed that tamoxifen led to a substantial reduction in the risk of developing invasive breast disease.56 The Early Breast Cancer Trialists Collaborative Group overview analysis showed that, with 5 years of tamoxifen therapy, patients with ER-positive or receptor-unknown invasive tumors had a 39% reduction in the annual odds of recurrence of invasive breast cancer.57
A phase III trial randomized patients with excised DCIS to receive WBRT or no WBRT and tamoxifen versus no tamoxifen.20 The randomization was independent for each of the 2 treatments . With 12.7 years of median follow-up, the use of tamoxifen decreased all new breast events . The use of tamoxifen decreased ipsilateral and contralateral breast events in the subjects not given WBRT , but not in those receiving WBRT .
Anastrozole
Results of the IBIS-II and the NSABP-B-35 studies indicate that anastrozole provides at least a comparable benefit as adjuvant treatment for postmenopausal patients with hormone-receptor-positive DCIS treated with BCS and RT, with a different toxicity profile.
NCCN Recommendations for Management of DCIS After Primary Treatment
Individuals Who Provided Content Development And/or Authorship Assistance:
William J. Gradishar, MD, Panel Chair, has disclosed serving as a scientific advisor for AstraZeneca Pharmaceuticals LP, MacroGenics, Inc., Roche Laboratories, Inc./Genentech, Inc., Pfizer Inc., and Seattle Genetics, Inc.
Jame Abraham, MD, Panel Member, has disclosed no relevant financial relationships.
Kimberly H. Allison, MD, Panel Member, has disclosed serving as a scientific advisor for Mammotome.
Chau Dang, MD, Panel Member, has disclosed receiving grant/research support from PUMA and Roche/Genentech.
Anthony D. Elias, MD, Panel Member, has disclosed serving as a scientific advisor for Seiyax.
Sharon H. Giordano, MD, MPH, Panel Member, has disclosed no relevant financial relationships.
Matthew P. Goetz, MD, Panel Member, has disclosed serving as a scientific advisor for Biotheranostics, Novartis Pharmaceuticals Corporation, Context Therapeutics, Eagle Pharmaceuticals, Sermonix, and Pfizer Inc. and receiving grant/research support from Eli Lilly and Company, Sermonix, and Pfizer Inc.
Karen Lisa Smith, MD, MPH, Panel Member, has disclosed receiving equity interest/stock options in Abbott Laboratories and AbbVie, Inc. and grant/research support from Pfizer Inc.
Hatem Soliman, MD, Panel Member, has disclosed receiving consulting fees from Immunomedics, Eisai, Novartis Pharmaceuticals Corporation, AstraZeneca, and Seattle Genetics.
John H. Ward, MD, Panel Member, has disclosed no relevant financial relationships.
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New Nccn Guidelines For Mammography: All Women Over 40
Sharon Worcester, MA
New evidence-based patient-facing breast cancer guidelines from the National Comprehensive Cancer Network call for annual mammograms for all average-risk women over age 40 years.
This simplifies the message, says the NCCN.
“There are many, often conflicting, recommendations surrounding breast cancer screening, which causes a lot of confusion and apprehension,” commented Therese Bevers, MD, professor of clinical cancer prevention at the University of Texas MD Anderson Cancer Center and chair of the guidelines panel
“These are the latest, evidence-based guidelines from experts in the field of breast cancer screening and diagnosis from more than two dozen leading cancer centers in the United States,” she said in a statement.
The NCCN guidelines, Breast Cancer Screening and Diagnosis, were published “to help people understand their personal risk for breast cancer, when they should begin screening, and how often to screen in order to detect cancer earlier, for more treatment options and better outcomes,” the organization explained in its press release.
They are available for free at NCCN.org/patientguidelines and via the NCCN Patient Guides for Cancer App.
An earlier start may be recommended for those with additional risk factors, Bevers noted. Screening is also important for those who are pregnant or breastfeeding.
Nccn Guidelines: Updates From Recent Fda Approvals For Sacituzumab Govitecan
Sacituzumab govitecan-hziy is a first-in-class antibody and topoisomerase inhibitor conjugate that attaches to the Trop-2 receptor located on cancer tumor cells. Trop-2 is a protein that is overexpressed in multiple types of epithelial tumors, including metastatic triple-negative breast cancer , in which high expression is associated with decreased patient survival and higher rates of disease relapse.1 SG is indicated for adult patients with mTNBC who received 2 prior therapies, with 1 prior treatments for metastatic disease.1 The National Comprehensive Cancer Network Breast Cancer Guidelines now contain updates that include the recent FDA approvals of SG for this invasive breast cancer.2
SG was approved by the FDA for patients with previously treated mTNBC through a fast-track designation in April 2020. In April 2021, SG gained full FDA approval for mTNBC with an extended approved indication for second-line metastatic disease and became the first FDA-approved treatment for mTNBC shown to improve progression-free survival and overall survival.3
The NCCN guidelines recommend SG as a preferred regimen for treatment of adult patients with mTNBC, have received 2 prior therapies, 1 for metastatic disease. The NCCN also recommends SG as a second-line later therapy in patients with unresectable locally advanced or mTNBC.2 SG is the first monotherapy treatment to advance overall survival in mTNBC, a disease with limited treatment options.1
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Nccn Clinical Practice Guidelines In Oncology: 2022 Updates
In 1996, the National Comprehensive Cancer Network® published its first set of Clinical Practice Guidelines in Oncology® covering eight tumor types. Guidelines are now published for more than 60 tumor types, subtypes, and topics. During the NCCNs 27th Annual Conference, which was again held virtually, updates to the NCCN Guidelines were presented for several tumor types. We briefly described here the latest key recommendations.
Inaugural Guidelines for Ampullary Adenocarcinoma
Ampullary adenocarcinoma may have a slightly better prognosis than pancreas cancer, but it remains a highly lethal disease.
Stephen W. Behrman, MD
Stephen W. Behrman, MD
Ampullary adenocarcinoma is a rare cancer that accounts for 0.2% of all gastrointestinal malignancies. There are two main histologic subtypes: intestinal, which resembles adenocarcinoma of the colon, and pancreaticobiliary, which resembles pancreatic cancer. Treatment of this cancer is based on the subtype.
The first version of the NCCN Guidelines for Ampullary Adenocarcinoma was released on March 9, 2022. Stephen W. Behrman, MD, Professor of Surgery at the University of Tennessee Health Science Center, Memphis, described ampullary adenocarcinoma at the conference and gave attendees an overview of these new recommendations. Here are some highlights from the first version of these guidelines:
Colorectal Cancer Screening
Reid M. Ness, MD, MPH
Reid M. Ness, MD, MPH
Locoregional Management of Early-Stage Breast Cancer
Pathologic T13 Hr+/her2 Tumors
Patients with HR+/HER2â tumors receive adjuvant endocrine therapy to reduce the risk of recurrence. Those deemed at high risk for distant recurrence despite adjuvant endocrine therapy may also receive adjuvant chemotherapy. The decision whether to administer adjuvant chemotherapy in patients with HR+/HER2â tumors is based on many factors, including lymph node status, tumor size, patient age, comorbid conditions, and risk assessment based on results of a validated gene expression assay.
Among patients with pathologic T1â3 HR+/HER2â tumors, on one end of the spectrum are those with small and node-negative tumors. These patients with small tumors up to 0.5 cm in greatest diameter that do not involve the LNs have low clinical risk of recurrence and a favorable prognosis. The incremental benefit of adding adjuvant chemotherapy to endocrine therapy in patients with such tumors is minimal.3 On the other end of the spectrum are patients with high-risk features, such as â¥4 positive LNs. In this group, the addition of systemic chemotherapy to adjuvant endocrine therapy may play a role in reducing recurrence risk.
For patients in whom the decision whether to use chemotherapy is unclear, gene expression assays may be used to assess recurrence risk. The primary role of the gene expression assays is to determine clinical situations that warrant addition of chemotherapy to endocrine therapy to further reduce recurrence risk.
Gene Expression Assays
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Systemic Therapy For Recurrent Or Stage Iv Disease With Germline Brca1/2 Mutations
About 5% of all patients with breast cancer carry the germline breast cancer susceptibility gene mutations and rates of these mutations are higher among those with HER2-negative disease.110,111
Poly Polymerase Inhibitors
The phase III OlympiAD trial randomized patients with metastatic breast cancer harboring the germline BRCA mutations to the poly polymerase inhibitor, olaparib , or physicians choice of nonplatinum chemotherapy .112 An improvement in PFS was seen in those receiving olaparib relative to those receiving chemotherapy .112 The study included all subtypes: those with HR-positive, HER2-negative and -positive, and triple-negative disease. The PFS improvements noted with olaparib were noted in all subtypes and greatest in the triple-negative population. Subsequent follow-up did not show a statistically significant difference in OS between treatment arms, and the study was also not powered to evaluate OS. The median OS with olaparib compared with treatment of physicians choice was 19.3 months versus 17.1 months, respectively .113 QOL was significantly better in the olaparib arm. It is interesting to note that patients who had not received prior chemotherapy in the metastatic setting achieved a 7.9-month longer median OS compared with treatment of physicians choice.113
Platinums
Adjuvant Rt After Bcs
Those who have a positive lymph node have a high risk of recurrence. Therefore, after BCS, WBRT is strongly recommended with or without boost to tumor bed for node-positive disease . This recommendation is supported by the results of a meta-analysis by the EBCTCG showing reduction in 10-year risk of recurrence in those who received WBRT versus those who did not .117 In addition, a significant reduction in 15-year risk of breast cancer death was also observed.117
For patients with a pathologically confirmed, focally positive margin without extensive intraductal component, who do not undergo re-excision after BCS, the use of a higher radiation boost dose to the tumor bed may be considered, since generally a boost to the tumor bed is recommended for patients at higher risk of recurrence.
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Systemic Therapy For Stage Iv Or Recurrent Hr
For patients with HER2-positive, HR-negative recurrent/stage IV breast cancer, the treatment approach is HER2-targeted therapy in combination with systemic chemotherapy. The NCCN panel notes that an FDA-approved biosimilar is an appropriate substitute for trastuzumab. Also, trastuzumab and hyaluronidase-oysk injection for subcutaneous use may be substituted for trastuzumab. This subcutaneous option has different dosage and administration instructions compared with intravenous trastuzumab. Doses and schedules of representative regimens for use in HER2-positive metastatic breast cancer are also included in NCCN Guidelines.
Patients progressing on a HER2-targeted therapy should be offered additional subsequent treatment with a HER2-targeted therapy since it is beneficial to continue suppression of the HER2 pathway. The choice of the HER2-targeted therapy will depend on previously administered therapy, relapse-free interval, and patients preference and access.
The optimal sequence of available HER2-targeted therapies and the optimal duration of HER2-targeted therapy for recurrent/stage IV is currently unknown. The NCCN panel recommends continuing HER2-targted therapy until progression or unacceptable toxicity.
Preferred Regimens for Stage IV/Recurrent HER2-Positive Breast Cancer
Other Regimens for Stage IV/Recurrent HER2-Positive Breast Cancer
Surgery For Recurrent Or Stage Iv Disease
The primary treatment approach recommended by the NCCN panel for women with metastatic breast cancer and an intact primary tumor is systemic therapy, with consideration of surgery after initial systemic treatment of those women requiring palliation of symptoms or with impending complications, such as skin ulceration, bleeding, fungation, and pain.1 Generally, such surgery should be undertaken only if complete local clearance of tumor may be obtained and if other sites of disease are not immediately threatening to life. Alternatively, radiation therapy may be considered as an option to surgery. Often such surgery requires collaboration between the breast surgeon and the reconstructive surgeon to provide optimal cancer control and wound closure.
Retrospective studies suggest a potential survival benefit from complete excision of the in-breast tumor in select patients with metastatic breast cancer.25 Substantial selection biases exist in all of these studies and are likely to confound the study results.6,7
The panel recognizes the need for more data from randomized clinical trials that will address the risks and benefits of local therapy for patients with stage IV disease while eliminating selection biases. Although the available data does not support broadly considering local therapy with surgery and/or RT, this may be reasonable in select patients responding to initial systemic therapy. In such clinical scenarios, patient engagement in the decision is encouraged.
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Regional Nodal Irradiation After Bcs
The reduction in the risk of locoregional and distant recurrence and improvement in DFS seen in the MA.20 and EORTC 22922/10925 trials,181,182 and the reduction in breast cancer mortality with 15-year follow-up of the EORTC 22922 patients,183 support the importance of RNI after BCS.
Clinical judgment is needed when determining inclusion of the internal mammary nodes during RNI. Therefore, the NCCN Panel no longer specifies the fields that should be included for RNI and refers to it as comprehensive RNI. According to the panel, patient selection should consider risks versus benefits, including long-term organ toxicities, comorbidities of the patient, age, and life expectancy. In including RT to the internal mammary nodes, meticulous treatment planning with normal tissue dose constraints is mandatory.
RNI After BCS for Node-Negative Disease
The NCCN Panel recommends consideration of comprehensive RNI in patients with central/medial tumors and in accordance with the MA.20 criteria-T3 tumors, as well as those with T2 tumors who have undergone limited axillary dissection and also have other risk factors, including high-grade histology, ER-negative disease, or extensive lymphovascular invasion.181
RNI After BCS for Node-Positive Disease
For those with 4 positive nodes, the NCCN Panel recommends comprehensive RNI with inclusion of any portion of the undissected axilla at risk .
RT After BCS in Older Adults With ER-Positive Tumors
Adjuvant RT After Mastectomy
Regimens Useful In Certain Circumstances For Therapy For Hr
Megestrol acetate,45,7173 estradiol74 androgens such as fluoxymesterone, and single agent abemaciclib have been listed as options useful in certain circumstances. The phase II MONARCH 1 trial evaluated the activity of abemaciclib as a single agent in patients with refractory HR-positive, HER2-negative metastatic breast cancer who had progressed on endocrine therapy and already received multiple systemic therapies .75 Ninety percent of patients had visceral disease, and 50.8% had more than 3 sites of metastases.75 Single-agent abemaciclib induced partial response in 26 and demonstrated an ORR of 19.7% .75 Median PFS was 6 months . At the final analysis, at 18 months, median OS was 22.3 months .75 Diarrhea was the most frequent adverse event, reported in 90.2% of patients. Other common adverse events were fatigue , nausea , and decreased appetite . Grade 3 and 4 neutropenia occurred in 26.9% of patients.75 The NCCN panel has included single-agent abemaciclib as an option for those with disease progression on prior endocrine therapy and prior chemotherapy in the metastatic setting.
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Management Of Recurrent Or Stage Iv Disease
From the time of diagnosis of recurrent/stage IV metastatic disease, patients should be offered appropriate supportive care and symptom-related interventions as a routine part of their care. NCCN believes that the best management of any patient with cancer is in a clinical trial. Patients should be encouraged to participate in clinical trials whenever clinical trials are available.
Systemic Therapy For Recurrent Or Stage Iv Hr
Women with stage IV or recurrent disease characterized by HR-positive, HER2-positive tumors have the option of receiving HER2-directed therapy as a component of their treatment plan. Options include treatment with a HER2-targeted therapy plus chemotherapy or endocrine therapy alone or in combination with HER2-targeted therapy. Endocrine therapy alone or in combination with HER2-targeted therapy is a less toxic approach compared with HER2-targeted therapy combined with chemotherapy. Premenopausal women treated with HER2-targeted therapy and endocrine therapy should receive ovarian suppression or ablation.
Adding trastuzumab or lapatinib to an AI has demonstrated a PFS advantage compared with AI alone in postmenopausal women with stage IV or recurrent HR-positive, HER2-positive tumors.
In the TAnDEM study, postmenopausal women with metastatic HR-positive and HER2-positive tumors were randomized to receive anastrozole alone or anastrozole plus trastuzumab.105 Compared with single-agent anastrozole, an improvement in PFS was seen with combination therapy . The combination was associated with a higher incidence of toxicities , fatigue , diarrhea , vomiting , and pyrexia serious toxicities were rare in both treatment arms.
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Treatment By Cancer Type
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