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5MORPHOFUNCTIONAL CHANGES IN THE BREAST: INSIGHTS FROM CLINICAL, IMAGING, AND HISTOPATHOLOGICAL PERSPECTIVES FOLLOWING CHEMOTHERAPY AND RADIATION THERAPY IN WOMEN
1Madaminov S.M., 2Junaid Ali S., 3Kholmatov Sh,O., 4Zokirjonov D.Z.
1,2,3,4Ferghana Medical Institute of Public Health https://doi.org/10.5281/zenodo.10277898
Abstract. This review article delves into the intricate morphofunctional changes observed in the breast tissue of women after undergoing chemotherapy and radiation therapy. The study employs a comprehensive approach, integrating clinical assessments, advanced imaging techniques, and rigorous histopathological examinations to unravel the dynamic interplay between cellular adaptations and tissue architecture. Objective: This review aims to comprehensively examine the morphofunctional changes in the breast following chemotherapy and radiation therapy in women undergoing breast cancer treatment.
Keywords: Adjuvant therapy, early-stage breast cancer, chemotherapy, endocrine therapy, targeted therapy, predictive biomarkers, Post-mastectomy radiotherapy, automated breast density, breast carcinoma regression, breast density, mammography, SECRAB trial.
The purpose of this review is to provide a comprehensive exploration of morphofunctional changes in the breast subsequent to chemotherapy and radiation therapy in women with breast cancer.
Learning materials and Methods: The methodology employed in this review involves a comprehensive examination of peer-reviewed studies and relevant literature to synthesize insights into morphofunctional changes in the breast post-chemotherapy and radiation therapy. A systematic search was conducted across electronic databases, including PubMed, Web of Science, and relevant medical databases. Keywords such as "breast cancer," "chemotherapy," "radiation therapy," and "morphofunctional changes" were used to identify pertinent studies.
Learning results: The study conducted by Abram Recht, M.D., and team investigates the optimal sequencing of chemotherapy and radiation therapy in early-stage breast cancer patients undergoing breast-conserving therapy. In this randomized trial involving 244 patients at substantial risk for systemic metastases, the researchers explore the impact of a 12-week course of chemotherapy administered before or after radiation therapy. The findings reveal notable differences in the five-year actuarial rates of cancer recurrence and distant metastases between the two groups. Specifically, the group receiving chemotherapy before radiation therapy exhibits lower rates, suggesting a potential preference for this sequence in patients at substantial risk for systemic metastases. This study not only contributes valuable insights into refining breast cancer treatment strategies but also emphasizes the need to tailor treatment sequences for optimal efficacy. The work holds significance for clinicians and researchers alike, adding to the ongoing discourse on breast cancer treatment and providing critical information for enhancing patient outcomes. [ 1 ]
In a rare and intriguing case, Reza Matloob, MD, and colleagues present an unusual instance of partial breast necrosis following chemotherapy for recurrent ovarian cancer. Breast
necrosis is a seldom-seen occurrence owing to the breast's rich blood supply. This case, possibly the first of its kind, sheds light on breast necrosis as a systemic complication of chemotherapy, expanding our understanding of potential side effects. The 54-year-old patient, with a history of ovarian cancer and prior chemotherapy, developed breast discoloration and pain after initiating the BEP chemotherapy regimen. This led to partial breast necrosis, a condition where necrotic tissue eventually sloughed off after conservative management, followed by surgical repair.
The authors meticulously explore potential causes of breast necrosis, delving into existing literature on calciphylaxis, cardiac bypass surgery, warfarin-induced necrosis, and other reported cases. They highlight the scarcity of documented breast necrosis cases post-chemotherapy, emphasizing the need for heightened awareness among physicians. The absence of such reports for the BEP chemotherapy protocol adds a unique dimension to this study. This comprehensive case report not only contributes to the understanding of rare chemotherapy-related complications but also underscores the importance of recognizing and managing breast necrosis promptly. The authors conclude by advocating for increased awareness of potential causes of breast necrosis to facilitate timely intervention and appropriate management strategies. [2]
Another study led by Gabriel N. Hortobagyi, MD, the authors tackle the intricate management of Stage III Primary Breast Cancer employing a multimodal strategy involving primary chemotherapy, surgery, and radiation therapy. Conducted from March 1974 to March 1985, the research encompasses 191 eligible patients, distinguishing between Stage IIIA and Stage IIIB based on tumor characteristics, with the latter presenting challenges due to skin involvement, chest wall fixation, or node engagement. Highlighting the historical struggles in treating Stage III breast cancer, the authors note grim 5-year survival rates ranging from 10% to 45%. Traditionally, radical mastectomy and radiation therapy were the go-to treatments. The study pioneers a new approach by integrating primary chemotherapy to enhance outcomes. Results exhibit an impressive 87.4% overall response rate to the initial FAC chemotherapy cycles, rendering 96.5% of patient's disease-free post-local treatment. The study explores the correlation between clinical and radiographic remission and the absence of residual disease, emphasizing the efficacy of the multimodal protocol. Survival analysis reveals a median disease-free survival of 30 months for Stage IIIB and an encouraging 71% 5-year disease-free survival for Stage IIIA. Overall survival projections stand at 84% and 56% at 5 and 10 years for Stage IIIA, while Stage IIIB demonstrates a median survival of 48 months with 44% and 26% projected survival at 5 and 10 years. Examining additional factors such as age, BCG immunotherapy, and treatment program duration, the study provides a comprehensive evaluation of the multimodal approach's efficacy. Notably, despite the treatment's complexity, the authors report no significant increase in surgical complications. In summary, this study pioneers Stage III Primary Breast Cancer management, demonstrating the potential benefits of combining primary chemotherapy, surgery, and radiation therapy. The results underscore the significance of personalized, comprehensive strategies in improving outcomes for advanced breast cancer patients. [ 3 ]
The study led by Erika M.S. Negrao and team, the focus is on the impact of breast cancer phenotype on Magnetic Resonance Imaging (MRI) response evaluation following neoadjuvant chemotherapy (NAC). Neoadjuvant chemotherapy is standard for locally advanced breast cancer, offering benefits like increased eligibility for conservative surgical treatment. The research spans October 2014 to July 2017, involving 219 patients diagnosed with invasive breast carcinoma. MRI plays a crucial role in assessing tumor extent and treatment response, allowing classification of
breast cancer phenotypes. Despite MRI's sensitivity in evaluating tumor response after NAC, discrepancies with surgical pathology exist, with potential implications for the extent of surgery required. Pathologic complete response (pCR) after NAC is linked to better prognosis, particularly in aggressive subtypes. While breast MRI is generally accurate in assessing treatment response, factors influencing its accuracy, especially in detecting pCR, are not extensively explored. The study employs high-field MRI with contrast agent administration and thorough imaging protocols. Breast lesions are classified using BI-RADS® lexicon, and post-NAC MRI is compared with pathological outcomes. Results reveal an overall MRI accuracy of 80% in diagnosing pCR, with varying sensitivity and specificity across molecular subtypes. Luminal B/Her-2 negative subtype shows higher agreement rates among observers. Statistical analysis identifies a significant association between discordance rates and the presence of non-mass enhancement (NME) in pre-treatment MRI. Multivariate analysis confirms the influence of NME on MRI performance after NAC. [ 4 ]
The article by Funmilola A. Fisusia, and Emmanuel O. Akala explores the significance of molecular classifications, such as Basal-like, Luminal-A, Luminal-B, HER2-positive, and normallike tumors, in guiding therapeutic approaches. The review emphasizes the impact of intrinsic subtypes on prognosis, highlighting the aggressive nature of HER2-positive and basal-like subtypes. Adjuvant therapies, including endocrine therapy and immunotherapy (e.g., trastuzumab), have shown promising results in improving survival rates for specific BC subtypes. The focus then shifts to the role of combination therapy in BC management, encompassing neoadjuvant chemotherapy, surgery, radiotherapy, and adjuvant chemotherapy/endocrine therapy. Neoadjuvant therapy, particularly in early-stage BC, aims to make tumors operable and assess treatment response. The article delves into historical perspectives on combination chemotherapy, emphasizing its advantages in terms of efficacy, dose reduction, and decreased toxicity. The integration of taxanes, such as paclitaxel and docetaxel, into chemotherapy regimens for metastatic BC is discussed, highlighting their efficacy. The overview concludes by underscoring the importance of carefully selecting therapeutic combinations based on the molecular profile of BC. The goal is to maximize therapeutic benefits while minimizing unnecessary agents to optimize treatment outcomes for BC patients.[ 5 ]
Elena Provenzano's article, "Neoadjuvant Chemotherapy for Breast Cancer: Moving Beyond Pathological Complete Response in the Molecular Age," delves into the transformative landscape of neoadjuvant chemotherapy (NACT) for breast cancer, emphasizing its evolution from treating locally advanced cases to a pivotal role in managing biologically aggressive diseases. The article discusses the advantages of NACT, including its impact on surgical options, such as enabling breast conservation surgery, and its role in determining further adjuvant therapy based on treatment response. Provenzano explores the importance of accurately identifying pathological complete response (pCR) and the associated prognostic implications. The article provides a comprehensive analysis of predictors of response to NACT, focusing on molecular subtypes, including luminal, HER2+, and triple-negative breast cancer (TNBC). Additionally, it emphasizes the crucial role of pathologists in optimizing patient care, addressing issues such as specimen handling, size measurement, and assessing residual disease.
The review underscores the significance of adapting to the molecular age, where understanding tumor biology guides treatment decisions and where NACT not only influences immediate clinical outcomes but also serves as a platform for innovative trial designs and the rapid
integration of effective drugs into clinical practice. Overall, Provenzano's work contributes to the nuanced understanding of NACT's role in breast cancer management, emphasizing the need for tailored approaches and meticulous evaluation of treatment response for optimal patient outcomes.[ 6 ]
The article by Rebecca L. Read and Kathy Flitcroft delves into the underutilization of neoadjuvant chemotherapy (NAC) in operable breast cancer cases, despite its recommendation in recent guidelines. While initial trials failed to demonstrate a clear survival advantage, the analysis argues that advances in chemotherapy and understanding breast cancer subtypes make reevaluation timely. Emphasizing surgery's ongoing role, the article defines tumor response parameters, distinguishing clinical and pathological responses. It outlines potential drawbacks, including surgery delay in non-responsive cases and the loss of detailed pathology guiding multidisciplinary approaches. However, my reading suggests NAC's benefits outweigh these, allowing oncological outcome prediction, increasing breast-conserving and reconstructive surgery rates, enabling more timely treatment, downstaging the axilla, and fostering participation in novel therapeutic trials. The article underscores the need for personalized approaches and evidence-based resources to aid women in evaluating the nuanced benefits and drawbacks of NAC for their specific situations.[ 7 ]
Another research was conducted by Noam F. Pondé. The article explores advancements in adjuvant systemic therapy for early-stage breast cancer, acknowledging the substantial progress made in treatment options since the late 1970s. The primary focus lies on three systemic modalities: chemotherapy, endocrine therapy, and targeted therapy. Extended adjuvant endocrine therapy for ER+ cancer is examined, particularly in the context of late relapses, with a cautious approach to balance benefits and risks. The article discusses strategies like dose-dense chemotherapy, emphasizing the superior efficacy observed in certain subgroups, notably those with ER- disease. It evaluates the potential of capecitabine post-neoadjuvant chemotherapy, drawing insights from the CREATE X trial, although acknowledging associated risks and the need for further study. The integration of endocrine therapy with targeted therapies, such as CDK4/6 inhibitors and PI3K inhibitors, is explored. The piece underscores the evolving landscape, necessitating personalized approaches, consideration of patient characteristics, and the quest for predictive biomarkers. Overall, the article provides a critical assessment of recent developments, highlighting the complex balance between treatment escalation and de-escalation in the evolving field of early-stage breast cancer therapy.[ 8 ]
In Jacques Bernier's article, "Post-mastectomy radiotherapy after neoadjuvant chemotherapy in breast cancer patients: A review," the author addresses the complexities surrounding post-mastectomy radiotherapy (PMRT) in patients who have undergone neoadjuvant chemotherapy. The review delves into the challenges of determining the indications for PMRT, particularly in cases where pathologic complete response is achieved after neoadjuvant chemotherapy. Bernier emphasizes the importance of assessing risk factors, such as tumor size, lymphovascular invasion, and nodal involvement, to make informed decisions about PMRT. The article also explores the impact of response to neoadjuvant chemotherapy on local regional control. The author discusses the need for further studies, including large randomized trials, to refine the criteria for selecting patients who would benefit from PMRT. The review highlights the evolving landscape of radiotherapy technology and techniques, emphasizing the role of modern approaches like intensity-modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT)
in optimizing treatment outcomes and minimizing toxicity. Bernier concludes by underlining the ongoing challenges and unresolved issues in determining the exact role of PMRT in breast cancer patients treated with neoadjuvant chemotherapy and mastectomy.[ 9 ]
Another research, conducted by Si-Ye Chen and Guang-Yi Sun showed some important data. This retrospective analysis of a randomized controlled clinical trial involving 584 women with high-risk breast cancer investigated the impact of timing intervals on postmastectomy radiotherapy (PMRT) following adjuvant chemotherapy. Optimal cutoff values identified were SRI <210 days and CRI <42 days, indicating associations with improved overall survival. Patients with SRI >210 days faced a higher risk of distant metastasis and worse overall and disease-free survival. Similarly, CRI >42 days was linked to increased risks of distant metastasis and poorer overall and disease-free survival. Notably, moderate delays in SRI (180-210 days) did not significantly affect outcomes. The study underscores the importance of timely initiation of PMRT after chemotherapy in high-risk breast cancer, emphasizing the adverse impact of prolonged treatment intervals on crucial oncologic endpoints. [ 10 ]
In another comprehensive review, David Krug explores the evolving landscape of post-mastectomy radiotherapy (PMRT) and regional nodal irradiation (RNI) in breast cancer patients following neoadjuvant chemotherapy (NACT). Historically utilized for locally advanced, inoperable tumors, NACT's role expanded with growing chemotherapy indications. Krug emphasizes the challenge it poses to conventional radiotherapy decisions, as it alters pathologic parameters and adds prognostic information. While established guidelines recommend RNI and PMRT in high-risk cases, controversy surrounds intermediate-risk patients. The review underscores the lack of prospective data on adjuvant radiotherapy post-NACT, highlighting the reliance on retrospective studies. The paper synthesizes findings on individualizing RNI and PMRT based on treatment response, revealing a dearth of conclusive evidence. Ongoing randomized trials, such as NSABP B-51/RTOG 1304 and Alliance A11202, aim to address these knowledge gaps, emphasizing the critical need for tailored radiotherapy approaches in the rapidly evolving landscape of breast cancer treatment.[ 11 ]
Next important research was conducted by S. J. Bowden and the team also gives important data about the optimal sequencing of adjuvant chemotherapy and radiotherapy in early breast cancer treatment. Notably, there is a lack of consensus among clinicians regarding the ideal approach, with variations in practices observed. The timing of these treatments is crucial, as delaying radiotherapy beyond 8 weeks may significantly increase local relapse rates. Existing studies present inconsistent findings on the impact of delayed radiotherapy, complicating the determination of an optimal treatment timeline. Synchronous chemotherapy and radiotherapy, although avoiding delays, pose concerns due to potential increased toxicity, particularly with certain chemotherapy regimens. The text emphasizes ongoing efforts, such as the SECRAB trial, to provide more conclusive evidence on the most effective sequencing strategy. Until further evidence emerges, a cautious recommendation leans towards a sequential schedule for specific chemotherapy regimens, acknowledging potential toxicities associated with synchronous treatment.[ 12 ]
The study by Hak Jae Kim explores the sequencing of adjuvant chemotherapy and radiotherapy in the treatment of high-risk breast cancer patients following mastectomy. Historically, conventional practice involved administering chemotherapy before radiotherapy, aiming to capitalize on chemotherapy's potential to reduce metastatic spread. However, recent
trials have challenged this approach, suggesting potential survival benefits when radiotherapy is administered between chemotherapy cycles. The retrospective analysis, conducted between 1986 and 2000 on 275 patients, categorized them into groups based on the sequence of treatments: chemotherapy followed by radiotherapy (CTRT), radiotherapy followed by chemotherapy (RTCT), sandwich therapy, and concurrent chemoradiotherapy (CCRT). While no significant differences in overall and disease-free survival were observed among the groups, a subgroup analysis of patients with positive or close resection margins hinted at improved outcomes with early radiotherapy. The study adds valuable insights to the ongoing debate on the optimal sequencing of postmastectomy adjuvant therapies, emphasizing the need for further research in this critical aspect of breast cancer management.[ 13 ]
The study by Atsushi Fushimi and Rei Kudo investigates the potential of mammography in predicting pathologic complete response (pCR) after neoadjuvant chemotherapy for breast cancer. While MRI is typically more correlated with pathologic response evaluation, mammography's accuracy is hindered by the variable behavior of microcalcifications. Traditionally associated with necrosis, microcalcifications were expected to increase with neoadjuvant chemotherapy, yet the study observes cases where they decreased. The research aimed to identify characteristics of breast cancer patients showing a reduction in microcalcifications post-treatment to enhance clinical response evaluation through imaging analysis. The retrospective analysis, conducted from January 2013 to June 2017 on 70 patients, revealed that HER2 positivity was higher in cases with microcalcifications. Interestingly, among patients with microcalcifications, those exhibiting a decrease tended to have segmental or pleomorphic/linear microcalcifications without a mammographic mass. The sensitivity of decreased microcalcifications for predicting pCR was 28.6%, with high specificity (89.5%). The study suggests that neoadjuvant chemotherapy may selectively decrease malignant microcalcifications, especially segmental and pleomorphic/linear types, potentially providing valuable insights into treatment response. [ 14 ]
Similar research work was done by Lianhuang Li and his team, in which they explore the efficacy of label-free multiphoton imaging in evaluating breast carcinoma regression after preoperative chemotherapy. Focused on overcoming the limitations of existing diagnostic techniques, the study employs two-photon excited fluorescence (TPEF) and second-harmonic generation (SHG) imaging technologies. The multiphoton images vividly illustrate the distinct morphological features of breast carcinoma, allowing for precise categorization of tumor response levels—ranging from slight to significant and complete responses to neoadjuvant therapy. Through quantitative analysis, the research unveils significant differences in tumor cell density and collagen content, providing valuable insights into the effectiveness of preoperative treatment. The introduction of the Mandard classification system for grading pathological response enhances the diagnostic accuracy, promising a more comprehensive understanding of breast carcinoma regression. However, the study acknowledges challenges, such as the limited penetration depth of label-free multiphoton imaging, while emphasizing the transformative potential of this innovative approach in improving diagnostic precision for breast cancer patients.[ 15 ]
The study led by Jee Hyun Ahn focuses on predicting pathological response after neoadjuvant chemotherapy (NCT) in breast cancer patients through changes in automated mammographic breast density (MD). The research emphasizes the importance of identifying effective predictive factors for pathological complete response (pCR) beyond existing clinical and
pathological markers. The study examines volumetric breast density (Vbd) using the Quantra software, which provides automated measurements, enhancing objectivity and reproducibility.
The retrospective analysis includes 684 breast cancer patients treated with NCT, with 357 ultimately included in the study. The research explores the dynamics of MD before and after NCT, considering both qualitative and quantitative aspects. The AVbd% is calculated using the Quantra software, and patients are categorized based on changes in MD. The study investigates the association between AVbd% and various clinicopathological characteristics, shedding light on the clinical feasibility of AVbd% as a predictive marker for pathological responsiveness to NCT. Key findings indicate that the decreased AVbd% group, characterized by younger age, premenopausal status, and larger tumor size, is less likely to achieve pCR after NCT. The research underscores the significance of breast cancer subtype as a powerful predictor of pCR, with implications for personalized treatment strategies. Overall, the study contributes valuable insights into the potential use of automated MD changes as a predictive tool for treatment response in breast cancer patients undergoing NCT.[ 16 ]
Conclusion: In navigating the complex landscape of breast cancer treatment, this comprehensive review illuminates the morphofunctional changes occurring post-chemotherapy and radiation therapy. Integrating clinical, imaging, and histopathological perspectives, the study underscores the importance of tailored approaches. Notable contributions from diverse studies shed light on optimal sequencing, rare complications, multimodal strategies, and predictive factors. Collectively, these insights propel the discourse on refining breast cancer treatment, emphasizing the need for personalized, evidence-based interventions to enhance patient outcomes.
REFERENCES
1. "The Sequencing of Chemotherapy and Radiation Therapy after Conservative Surgery for Early-Stage Breast Cancer"Abram Recht, M.D., Steven E. Come, M.D., I. Craig Henderson, M.D., Rebecca S. Gelman, Ph.D., Barbara Silver, B.A., Daniel F. Hayes, M.D., Lawrence N. Shulman, M.D., and Jay R. Harris, M.D.
2. Title: Breast Necrosis after Chemotherapy for Recurrent Ovarian Cancer: Report of a Case and Review of the Literature. Authors: Reza Matloob, MD; Afsaneh Alikhasi, MD; Mohammad Shirkhoda, MD; Massoome Najafi, MD
3. Management of Stage III Primary Breast Cancer With Primary Chemotherapy, Surgery, and Radiation Therapy. Authors: GABRIEL N. HORTOBAGYI
4. Breast cancer phenotype influences MRI response evaluation after neoadjuvant chemotherapy. Erika M.S. Negrao
5. Drug Combinations in Breast Cancer Therapy. Funmilola A. Fisusia,b and Emmanuel O. Akalaa.
6. Neoadjuvant Chemotherapy for Breast Cancer: Moving Beyond Pathological Complete Response in the Molecular Age. Elena Provenzano
7. Utility of neoadjuvant chemotherapy in the treatment of operable breast cancer. Rebecca L. Read, Kathy Flitcroft, Kylie L.
8. Progress in adjuvant systemic therapy for breast cancer. Noam F. Ponde, Dimitrios Zardavas and Martine Piccart
9. "Post-mastectomy radiotherapy after neoadjuvant chemotherapy in breast cancer patients: A review," Jacques Bernier
10. Timing of postmastectomy radiotherapy following adjuvant chemotherapy for high-risk breast cancer: A post hoc analysis of a randomised controlled clinical trial. Si-Ye Chen and Guang-Yi Sun
11. Individualization of post-mastectomy radiotherapy and regional nodal irradiation based on treatment response after neoadjuvant chemotherapy for breast cancer. David Krug
12. Delaying Radiotherapy for the Delivery of Adjuvant Chemotherapy in the Combined Modality Treatment of Early Breast Cancer: Is It Disadvantageous and Could Combined Treatment be the Answer? S. J. Bowden
13. The sequencing of chemotherapy and radiotherapy in breast cancer patients after Mastectomy. Hak Jae Kim
14. Do Decreased Breast Microcalcifications After Neoadjuvant Chemotherapy Predict Pathologic Complete Response? Atsushi Fushimi, Rei Kudo
15. Evaluation of breast carcinoma regression after preoperative chemotherapy by label-free multiphoton imaging and image analysis. Lianhuang Li
16. Changes in Automated Mammographic Breast Density Can Predict Pathological Response After Neoadjuvant Chemotherapy in Breast Cancer. Jee Hyun Ahn
