Tumor biomarkers for diagnosis, prognosis and targeted therapy | Signal Transduction and Targeted Therapy
What Is Inflammatory Breast Cancer? Understanding Symptoms, Diagnosis, And Treatment
Dr Kirti notes, "IBC is sometimes mistaken for infections like mastitis due to its redness and swelling, particularly in younger women or breastfeeding mothers. However, its symptoms persist or worsen, underscoring the importance of thorough medical evaluation."
Also read: How Does Alcohol Consumption Increase The Risk Of Breast Cancer?
Diagnosing Inflammatory Breast CancerA timely and accurate diagnosis is essential to manage IBC effectively. Diagnosis typically involves:
Clinical Examination: A thorough physical examination of the breast.
Imaging Tests: Mammograms, ultrasounds, or MRIs to identify abnormalities.
Biopsy: Skin or tissue samples are taken to confirm the presence of cancer cells.
Staging Workup: PET scans or other imaging tests to check if the cancer has spread beyond the breast and lymph nodes.
Treatment Options for IBCDue to its aggressive nature, IBC requires a comprehensive treatment plan combining multiple therapies:
Neoadjuvant Chemotherapy: Administered before surgery to shrink the tumour and address potential spread.
Surgery: Typically, a mastectomy (removal of the entire breast) is performed along with lymph node removal. Breast-conserving surgery is not recommended for IBC.
Radiation Therapy: Used to target remaining cancer cells in the chest wall and surrounding lymph nodes.
Targeted Therapy: HER2-positive cancers may be treated with drugs like trastuzumab or pertuzumab.
Hormonal Therapy: Hormone receptor-positive cancers are managed with medications that block oestrogen or progesterone.
Immunotherapy: For triple-negative breast cancers, immunotherapy with pembrolizumab combined with chemotherapy can improve outcomes.
The prognosis for IBC is generally less favourable than for other breast cancers, primarily because it is often diagnosed at an advanced stage (Stage III or IV). However, modern treatment approaches are improving survival rates.
Dr Kirti emphasises, "The prognosis depends on factors like the stage at diagnosis, the tumour's response to treatment, and the cancer subtype. HER2-positive and hormone receptor-positive IBCs generally have more treatment options and better outcomes compared to triple-negative IBCs."
The Importance of Early RecognitionEarly detection and prompt treatment significantly improve outcomes for IBC patients. By spreading awareness of its symptoms and encouraging proactive medical care, lives can be saved.
Dr Kirti concludes, "While IBC is challenging to treat, advancements in cancer therapies are offering new hope to patients. Recognising symptoms early and seeking medical attention promptly are critical in improving survival rates."
Inflammatory Breast Cancer serves as a reminder of the importance of vigilance in breast health. Understanding its symptoms and acting quickly can make all the difference.
Top 10 Breast Cancer Breakthroughs In 2024
Here are the top 10 developments from the year.
3D rendering of breast cancer: © Giovanni Cancemi - stock.Adobe.Com
In 2024, several significant advancements in breast oncology were covered by Targeted OncologyTM. Here are the top 10 developments from the year:
FDA Approval of Inavolisib for Advanced Breast Cancer: The FDA approved inavolisib (Itovebi, previously GDC-0077) plus palbociclib (Ibrance) and fulvestrant for the treatment of hormone receptor–positive (HR+), HER2-negative (HER2-), PIK3CA-mutated breast cancer. Inavolisib is a PI3K inhibitor for the treatment of advanced HR+/HER2- breast cancer with PIK3CA mutations and its designation is supported by data from the phase 3 INAVO120 study (NCT04191499). This approval offers a new targeted therapy option for patients with this specific genetic profile.
Ribociclib Approved for Early High-Risk Breast Cancer: Ribociclib (Kisqali), a CDK4/6 inhibitor, received FDA approval for use in combination with an aromatase inhibitor for the adjuvant treatment of HR+/HER2- early breast cancer at high risk of recurrence, including patients with node-negative disease. Data from the phase 3 NATALEE trial (NCT03701334) support this approval as the combination led to an improvement in invasive disease-free survival vs endocrine therapy alone in this patient population.
Olaparib Demonstrates Survival Benefit in Early Breast Cancer: Data from the phase 3 OlympiA trial (NCT02032823) showed that olaparib (Lynparza), a PARP inhibitor, significantly improved overall survival in patients with BRCA-mutated, HER2-negative early breast cancer. This marks the first PARP inhibitor to show such a benefit in this setting.
Precision Medicine Trial Improves Treatment by Tumor Subtype: The I-SPY 2.2 trial (NCT01042379) found that tailoring neoadjuvant therapy based on tumor subtype, including the use of antibody-drug conjugates and checkpoint inhibitors, improved outcomes in patients with early-stage breast cancer. Rebecca A. Shatsky, MD, I-SPY2.2 investigator and breast medical oncologist at the University of California San Diego Health, spoke with Targeted OncologyTM to discuss the trial, its novel design, and its implications for the treatment of patients with breast cancer.
TNBC Cancer Vaccine Research: Ongoing research into vaccines aimed at preventing triple-negative breast cancer has shown promising early results. Specifically, the investigational breast cancer vaccine for triple-negative breast cancer (TNBC) showed encouraging results, with over 70% of patients exhibiting protocol-defined immune responses. These findings come from a phase 1 trial (NCT04674306) presented at the Society for Immunotherapy of Cancer (SITC) 39th Annual Meeting.
FDA Approval of Tepylute for Breast and Ovarian Cancer: The FDA approved Tepylute (SH-105), a new formulation of an existing treatment, for use in patients with breast and ovarian adenocarcinoma. This approval provides an additional therapeutic option for these cancers.
Vepdegestrant Shows Clinical Activity in Combination Therapy: Early-phase clinical trials indicated that vepdegestrant (ARV-471), a novel selective estrogen receptor degrader, in combination with other agents, demonstrated clinical activity in patients with advanced breast cancer. In February 2024, the agent was granted fast track designation from the FDA as a monotherapy for the treatment of adult patients with ER+/HER2- locally advanced or metastatic breast cancer that received prior treatment with endocrine-based therapy.
Neoadjuvant/Adjuvant Pembrolizumab Improves Survival in Early-Stage TNBC: According to results from the phase 3 KEYNOTE-522 trial (NCT03036488) presented at the 2024 ESMO Congress, patients with early-stage TNBC had statistically significant improvements in overall survival with neoadjuvant pembrolizumab (Keytruda) plus chemotherapy, followed by adjuvant pembrolizumab, compared with neoadjuvant chemotherapy plus placebo, followed by adjuvant placebo.
Can GLP-1 Agonists Impact Breast Cancer Care?Recent trends have placed GLP-1 receptor agonists, such as semaglutide (Ozempic, Wegovy) and tirzepatide (Mounjaro, Zepbound), at the forefront of discussions on general weight loss. During the 2024 American Society of Clinical Oncology Annual Meeting, several presentations highlighted the potential role of GLP-1 agonists in weight management for patients with breast cancer.
T-DXd Shows Survival Benefit in HR+/HER2-Low Breast Cancer: In the primary population of the phase 3 DESTINY-Breast06 trial (NCT04494425), which consisted of patients with HR+/HER2-low, metastatic breast cancer following 1 or more lines of endocrine therapy when treated with fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd), a statistically significant and clinically meaningful improvement in progression-free survival was seen compared with those treated with standard-of-care chemotherapy.
These developments highlight the ongoing progress in breast oncology, with new therapies and strategies improving outcomes for patients across various stages and subtypes of breast cancer.
Understanding Genetics May Predict Treatment Response In Triple-Negative Breast Cancer
Several biomarkers may predict improved treatment responses and outcomes in patients with triple-negative breast cancer.
Several biomarkers were linked to improved outcomes in patients with high-risk, early-stage triple-negative breast cancer, with Keytruda plus chemotherapy.
Several biomarkers, including the T-cell inflamed 18-gene expression profile, were associated with improved pathologic complete response and event-free survival, both with and without Keytruda (pembrolizumab) therapy.
Results from an exploratory analysis of the KEYNOTE-522 study in high-risk, early triple-negative breast cancer were presented at 2024 San Antonio Breast Cancer Symposium.
Tumor mutational burden also correlated with improved event-free survival in the Keytruda plus chemotherapy arm, but not in the placebo plus chemotherapy arm. There were few patients with high tumor mutational burden in this patient population of those with triple-negative breast cancer.
Further, the Keytruda/chemotherapy regimen offered an efficacy advantage compared with chemotherapy alone, regardless of subgroups defined by several biomarkers such as tumor mutational burden, T-cell inflamed 18-gene expression profile and more.
Glossary:T-cell inflamed 18-gene expression profile: a panel of 18 genes used to predict the response to immunotherapy in patients with cancer.
Pathologic complete response: the lack of all signs of cancer in tissue samples after treatment.
Event-free survival: the time after primary treatment when a patient is free from complications or events that treatment was meant to delay or prevent.
Tumor mutational burden: the total number of mutations in the DNA of cancer cells, which is information that may help with treatment plans. Patients with a high number of mutations may be more likely to respond to certain types of immunotherapy.
Neoadjuvant: the first treatment given to shrink a tumor before the main treatment like surgery.
Adjuvant: additional treatment for cancer given after the primary treatment to reduce the risk for cancer recurrence.
Overall survival: the time from diagnosis or treatment initiation when a patient with cancer is still alive.
Whole-exome sequencing: a laboratory method to learn how the building blocks of a person's DNA are organized, and can be used to find mutations in genes that may preclude a patient to disease.
RNA sequencing: a laboratory method to learn the exact order in which RNA molecules are situated in a cell, which helps care teams determine which genes are expressed in different types of cells.
PTEN loss signature: a gene that regulates cell growth and survival, and, when lost, can lead to uncontrolled cell growth and potentially tumor formation.
Proliferation: the process of cell division and growth.
Glycolysis: when glucose, or sugar, is broken down in cells via reactions that do not require oxygen, which is a way that cells produce energy.
About the KEYNOTE-522 Exploratory AnalysisThe phase 3 KEYNOTE-522 study sought to evaluate the combination of neoadjuvant Keytruda with chemotherapy and adjuvant Keytruda in patients with newly diagnosed, previously untreated, high-risk, early-stage triple-negative breast cancer. Previously reported findings have shown that neoadjuvant Keytruda with chemotherapy followed by adjuvant Keytruda significantly improved pathologic complete response, event-free survival and overall survival versus neoadjuvant placebo plus chemotherapy with adjuvant placebo in patients with high-risk, early triple-negative breast cancer.
In this exploratory biomarker analysis, the end points included evaluating the association of tumor mutational burden, T-cell inflamed 18-gene expression profile and a set of non-T-cell inflamed 18-gene expression profile consensus signatures with pathologic complete response and event-free survival. Secondary end points included evaluating RNA sequence-based molecular subtypes, BRCA/HRD status, HER2 gene expression/signature, and PTEN loss signature associations with pathologic complete response and event-free survival.
Patients with newly diagnosed, previously untreated, high-risk, early triple-negative breast cancer and evaluable pretreatment tumor samples were enrolled in the study. A total of 1,172 patients were randomly assigned and treated, including 783 in the Keytruda plus chemotherapy arm and 389 in the placebo and chemotherapy arm. There were 946 patients who had whole-exome sequencing data, with 641 who received Keytruda/chemotherapy and 305 given placebo/chemotherapy, and 904 had RNAseq data, consisting of 618 and 286 across the study arms.
Tumor mutational burden was assessed through whole-exome sequencing, while T-cell–inflamed 18-gene expression profile and non–T-cell-inflamed 18-gene expression profile consensus signatures were evaluated using RNA sequencing.
Additional FindingsAmong the non–T-cell-inflamed 18-gene expression profile consensus signatures, proliferation and glycolysis were positively associated with pathologic complete response in both arms but did not correlate with event-free survival.
For the secondary end points of the study, positive associations of PTEN loss signature and BRCA/HRD status with pathologic complete response were observed in both treatment arms. HER2 gene expression was linked with the T–cell-inflamed 18-gene expression profile; however, it did not show significant associations with pathologic complete response or event-free survival in the Keytruda/chemotherapy arm after adjustment for the T-cell–inflamed 18-gene expression profile.
Subgroup analyses of secondary biomarkers using prespecified cutoffs consistently confirmed the benefit of the Keytruda and chemotherapy combination over the chemotherapy and placebo combination.
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