Pathologic response and residual tumor cellularity after neo-adjuvant chemotherapy predict prognosis in breast cancer patients

Gentile, Damiano; Sagona, Andrea; Carlo, Camilla De; Fernandes, Bethania; Barbieri, Erika; Grimaldi, Simone Di Maria; Jacobs, Flavia; Vatteroni, Giulia; Scardina, Lorenzo; Biondi, Ersilia; Vinci, Valeriano; Trimboli, Rubina Manuela; Bernardi, Daniele; Tinterri, Corrado

doi:10.1016/j.breast.2023.03.016

Cited by 23 publications

(8 citation statements)

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“…Secondly, NAT facilitates the in vivo evaluation of the tumor response to chemotherapy, which can inform treatment decisions post-surgery [ 4 , 5 ]. The response to NAT also holds prognostic significance, being closely linked to long-term oncological outcomes [ 4 , 6 , 7 , 8 , 9 ]. Furthermore, successful tumor reduction through NAT can minimize the extent of surgery required, eliminating the need for unnecessary axillary lymph node dissection (ALND) [ 10 , 11 ] and making breast-conserving surgery (BCS) possible for patients initially considered for mastectomy [ 12 , 13 , 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

De-Escalation Surgery in cT3-4 Breast Cancer Patients after Neoadjuvant Therapy: Predictors of Breast Conservation and Comparison of Long-Term Oncological Outcomes with Mastectomy

Tinterri,

Barbieri,

Sagona

et al. 2024

Cancers

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Background: Neoadjuvant therapy (NAT) has become increasingly employed for the treatment of cT3-4 breast cancer (BC), enabling breast-conserving surgery (BCS) in cases traditionally considered for mastectomy. This study aims to identify predictors for breast conservation post-NAT and to evaluate whether BCS influences long-term oncological outcomes. Methods: We retrospectively analyzed data from patients with cT3-4 BC who received NAT at the Breast Unit of IRCCS Humanitas Research Hospital, Milan, Italy, from October 2009 to April 2020. Surgical outcomes and long-term oncological results, such as disease-free survival (DFS), distant DFS (DDFS), overall survival (OS), and BC-specific survival (BCSS), were compared between the BCS and mastectomy groups. Results: Among 114 patients analyzed, 37 (32.5%) underwent BCS, and 77 (67.5%) had a mastectomy. The key predictors for opting for BCS included absence of vascular invasion, reduced tumor size post-NAT, and achieving ypT0 status. No significant differences in DFS, DDFS, OS, and BCSS were observed between the two surgical groups (log-ranks, p = 0.520, p = 0.789, p = 0.216, p = 0.559, respectively). Conclusions: BCS after NAT is a feasible and safe option for patients with cT3-4 BC, without adversely affecting long-term oncological outcomes. Identifying predictors of breast conservation can guide surgical decision-making, ensuring that patients receive optimal treatment.

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Section: Introductionmentioning

confidence: 99%

De-Escalation Surgery in cT3-4 Breast Cancer Patients after Neoadjuvant Therapy: Predictors of Breast Conservation and Comparison of Long-Term Oncological Outcomes with Mastectomy

Tinterri,

Barbieri,

Sagona

et al. 2024

Cancers

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“…Some novel targets, such as immune checkpoint inhibitors, have shown improved response rates when used in combination with anthracycline and taxane‐based chemotherapy. Nevertheless, early recurrence continues to significantly worsen patient prognosis 3,4 . Therefore, TNBC urgently requires innovative and more potent treatment strategies.…”

Section: Introductionmentioning

confidence: 99%

“…Nevertheless, early recurrence continues to significantly worsen patient prognosis. 3,4 Therefore, TNBC urgently requires innovative and more potent treatment strategies.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial dynamics as a novel treatment strategy for triple‐negative breast cancer

Wang,

Harada‐Shoji,

Kitamura

et al. 2024

Cancer Medicine

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IntroductionTriple‐negative breast cancer (TNBC), recognized as the most heterogeneous type of breast cancer (BC), exhibits a worse prognosis than other subtypes. Mitochondria dynamics play a vital role as mediators in tumorigenesis by adjusting to the cell microenvironments. However, the relationship between mitochondrial dynamics and metabophenotype exhibits discrepancies and divergence across various research and BC models. Therefore, this study aims to explore the role of mitochondrial dynamics in TNBC drug resistance and tumorigenesis.MethodsThe Wst‐8 test was conducted to assess doxorubicin sensitivity in HCC38, MDA‐MB‐231 (TNBC), and MCF‐7 (luminal). Confocal microscopy and FACS were used to quantify the mitochondrial membrane potential (ΔφM), mitophagy, and reactive oxygen species (ROS) production. Agilent Seahorse XF Analyzer was utilized to measure metabolic characteristics. Dynamin‐related protein‐1 (DRP1), Parkin, and p62 immunohistochemistry staining were performed using samples from 107 primary patients with BC before and after neoadjuvant chemotherapy (NAC).ResultsMDA‐MB‐231, a TNBC cell line with reduced sensitivity to doxorubicin, reduced ΔφM, and enhanced mitophagy to maintain ROS production through oxidative phosphorylation (OXPHOS)‐based metabolism. HCC38, a doxorubicin‐sensitive cell line, exhibited no alterations in ΔφM or mitophagy. However, it demonstrated an increase in ROS production and glycolysis. Clinicopathological studies revealed that pretreatment (before NAC) expression of DRP1 was significant in TNBC, as was pretreatment expression of Parkin in the hormone receptor‐negative group. Furthermore, low p62 levels seem to be a risk factor for recurrence‐free survival.ConclusionOur findings indicated that the interplay between mitophagy, linked to a worse clinical prognosis, and OXPHOS metabolism promoted chemotherapy resistance in TNBC. Mitochondrial fission is prevalent in TNBC. These findings suggest that targeting the unique mitochondrial metabolism and dynamics in TNBC may offer a novel therapeutic strategy for patients with TNBC.

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“…TNBC, the most heterogeneous type of breast cancer, has a poor prognosis and a high risk of recurrence when compared to other types. A number of newly developed targeted therapies, such as immune checkpoint inhibitors, have improved initial response rates in addition to anthracycline and taxane-based chemotherapy; however, patients with residual disease could have a substantially poorer prognosis and frequently experienced early recurrence or metastasis (3,4). Therefore, individuals with TNBC urgently require novel and more potent therapeutic approaches.…”

Section: Introductionmentioning

confidence: 99%

Targeting DRP1 mediated mitochondrial metabolism as a novel treatment strategy for triple negative breast cancer (TNBC)

Wang

Harada-Shoji

Kitamura

et al. 2023

Preprint

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Background Triple-negative breast cancer (TNBC), the most heterogeneous type of breast cancer, has a high risk of recurrence and a shorter overall survival compared to the other subtypes. The ability of mitochondria to flexibly adapt to their microenvironment makes them crucial tumorigenesis mediators. in this study, we explored the role of mitochondrial dynamics in TNBC drug resistance and tumorigenesis.Methods The doxorubicin sensitivity of TNBC cell lines HCC38 and MDA-MB-231, as well as luminal cell line MCF-7, was determined using the Wst-8 test. Confocal microscopy and FACS were used to measure the mitochondrial membrane potential (ΔφM), mitophagy, and ROS generation of HCC38 and MDA-MB-231. Agilent Seahorse XF Analyzers measured metabolic characteristics of HCC38, MDA-MB 231and MCF-7. DRP1, Parkin, and p62 immunohistochemistry staining were performed by using both core needle biopsy samples and the samples removed at the surgery of 108 primary breast cancer patients who underwent surgery after neoadjuvant chemotherapy (NAC).Results MDA-MB-231, a doxorubicin resistant TNBC cell line, reduced ΔφM and enhanced mitophagy to maintain ROS production with OXPHOS-based metabolism. HCC38, a cell sensitive to doxorubicin, showed no change in ΔφM and mitophagy, with glycolysis as the primary metabolic characteristic and an uncontrolled rise in ROS production. Clinicopathological studies have found that DRP1 before NAC (pre-DRP1) was highly expressed in TNBC and groups with KI67 greater than 20% (p = 0.009, 0.016). Parkin was also highly expressed in HR- and high KI67 groups (p = 0.013 and 0.005) and the expression of p62 was higher only in high Ki67 groups (p = 0.003). There was a trend in the non-pCR group for DRP1 to decrease and p62 to increase after treatment, although the difference was not statistically significant.Conclusion Our findings showed that mitophagy, in association with OXPHOS metabolism, promoted chemotherapy resistance and tumor growth in TNBC. The lack of effective therapeutic options for patients with TNBC remains a major challenge, therefore, targeting unique mitochondria metabolic signatures within tumor cells can potentially offer another therapeutic strategy for this highly aggressive disease.

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Pathologic response and residual tumor cellularity after neo-adjuvant chemotherapy predict prognosis in breast cancer patients

Cited by 23 publications

References 30 publications

De-Escalation Surgery in cT3-4 Breast Cancer Patients after Neoadjuvant Therapy: Predictors of Breast Conservation and Comparison of Long-Term Oncological Outcomes with Mastectomy

De-Escalation Surgery in cT3-4 Breast Cancer Patients after Neoadjuvant Therapy: Predictors of Breast Conservation and Comparison of Long-Term Oncological Outcomes with Mastectomy

Mitochondrial dynamics as a novel treatment strategy for triple‐negative breast cancer

Targeting DRP1 mediated mitochondrial metabolism as a novel treatment strategy for triple negative breast cancer (TNBC)

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