Breast cancer is a heterogeneous disease and its molecular subtypes significantly influence tumor behavior, prognosis, and response to treatment. Accurate evaluation of these subtypes is crucial for determining appropriate treatment strategies. One such method is 18F-FDG PET/CT imaging, which measures metabolic activity through the maximum standardized uptake value (SUVmax). SUVmax has been proposed as a potential biomarker for assessing tumor aggressiveness and predicting therapeutic outcomes, particularly in the context of neoadjuvant chemotherapy (NACT) [1].

SUVmax has been shown to correlate with various molecular subtypes of breast cancer, including Luminal A, Luminal B, HER2-enriched, and Triple-Negative Breast Cancer (TNBC). Studies have demonstrated that these subtypes exhibit differing metabolic profiles on PET/CT scans, with TNBC and HER2-enriched subtypes typically showing higher SUVmax values, indicative of a more aggressive disease behavior [2,3]. For example, Luminal A subtypes generally display lower SUVmax values, which correlates with less aggressive tumor biology [4]. Moreover, SUVmax values have been found to correlate with the likelihood of achieving pathological complete response (pCR) after NACT, with higher SUVmax values often associated with better treatment response [5,6].

The prognostic significance of SUVmax is further supported by evidence that SUVmax can predict survival outcomes, particularly in patients with metastatic breast cancer. High SUVmax values in these cases have been linked to poorer survival, highlighting the importance of SUVmax as both a diagnostic and prognostic tool in clinical practice [7]. Given the heterogeneity in tumor response to treatment across molecular subtypes, this study aimed to explore the relationship between SUVmax and pCR across different breast cancer molecular subtypes to provide further insight into the utility of SUVmax as a predictive biomarker.

Study Design

This was a retrospective cohort study conducted at Vydehi Institute of Medical Sciences and Research Centre to evaluate the correlation between SUVmax measured by 18F-FDG PET/CT and the molecular subtypes of breast cancer. Additionally, the study aimed to assess the prognostic significance of SUVmax in predicting pathological complete response (pCR) to neoadjuvant chemotherapy (NACT). Ethical approval for the study was obtained from the Institutional Review Board (IRB) of Vydehi Institute of Medical Sciences and Research Centre, and patient consent was waived due to the retrospective nature of the study.

Patient Selection

A total of 107 breast cancer patients (median age, 51 years; range, 34–76 years) who underwent pretreatment 18F-FDG PET/CT imaging between 2023 and 2024 were included in the study. The inclusion criteria were patients with invasive breast cancer who received NACT and had complete clinical, pathological, and imaging data available. Patients were excluded if they had metastatic disease at the time of diagnosis, prior treatment with chemotherapy or radiation therapy, or incomplete data on the molecular subtypes or SUVmax measurements.

Molecular Subtype Classification

The molecular subtypes of breast cancer were determined based on immunohistochemical (IHC) analysis of tumor tissue. The following categories were used:

• Luminal A: ER-positive, PR-positive, HER2-negative, Ki67 < 14%
• Luminal B: ER-positive, PR-positive or negative, HER2-positive or negative, Ki67 ≥ 14%
• HER2-enriched: ER-negative, PR-negative, HER2-positive
• Triple-negative breast cancer (TNBC): ER-negative, PR-negative, HER2-negative

IHC assays were performed on the tumor samples using standard procedures, and the molecular subtypes were classified accordingly.

Imaging Protocol

All patients underwent pretreatment 18F-FDG PET/CT scans as part of their clinical management. The imaging protocol was standardized as shown in Figure 1.

• Preparation: Patients fasted for a minimum of 6 hours before the PET scan to reduce the impact of hyperglycemia on 18F-FDG
• Radiotracer: A dose of 15 mCi/kg of 18F-FDG was administered intravenously.
• Scan Timing: Scans were performed approximately 60 minutes after radiotracer injection.
• PET/CT Imaging: 18F-FDG PET/CT scans were acquired using a state-of-the-art PET/CT scanner (model specification). The maximum standardized uptake value (SUVmax) for each tumor was calculated based on the highest pixel value within a defined region of interest (ROI).

Figure 1: Representative 18F-FDG PET/CT axial slices in breast cancer patients prior to NACT.

Representative axial PET/CT cross-sectional images of breast tumors with varying metabolic activity are shown in Figure 2. These images illustrate the correlation between elevated FDG uptake and aggressive molecular subtypes (e.g., TNBC and HER2+). The highlighted lesions demonstrated high SUVmax values in responders who subsequently achieved pCR after NACT.

Pathological Complete Response (pCR)

A pathological complete response (pCR) was defined as the absence of invasive carcinoma in the breast and axillary lymph nodes following the completion of NACT. pCR was determined through histopathological evaluation of the surgically resected specimens. Patients were categorized as having achieved pCR if no invasive cancer was detected in the breast or axillary lymph nodes after the treatment.

Statistical Analysis

Descriptive statistics were used to summarize the baseline characteristics, including mean and standard deviation (SD) for continuous variables and frequencies for categorical variables. Shapiro-Wilk test for normality was performed to evaluate the distribution of SUVmax values. As the data were not normally distributed, non-parametric tests were used for comparison.

• The Mann-Whitney U test was used to compare SUVmax between HER2-enriched and hormone receptor-positive subtypes (Luminal A and B).
• The Kruskal-Wallis H test was used to assess the differences in SUVmax across all four molecular subtypes.
• Spearman’s rank correlation coefficient (ρ) was computed to evaluate the relationship between SUVmax and pCR as well as to assess the strength of the association between metabolic activity and response to treatment.

A significance level of p < 0.05 was used for all statistical tests. All statistical analyses were performed using SPSS version 22 (IBM Corp., Armonk, NY, USA).

Ethical Considerations

This study was approved by the Institutional Review Board (IRB) at [Institution Name]. Owing to the retrospective nature of the study, patient consent was waived, and all data were anonymized before analysis to protect patient confidentiality.

Limitations

The limitations of this study include its retrospective design, which may introduce a bias in patient selection. Additionally, the relatively small sample size, particularly in the Luminal A and TNBC subgroups, may limit the generalizability of the findings. Another limitation is the lack of standardization in defining pCR across institutions. Future prospective studies with larger multicenter cohorts and standardized criteria for pCR evaluation are required to validate these findings.

A total of 107 breast cancer patients who underwent pre-neoadjuvant chemotherapy (NACT) PET/CT imaging between 2023 and 2024 were retrospectively analyzed. The median age of the cohort was 51 years old. The mean maximum standardized uptake value (SUVmax) of the primary tumors was 7.94 (range: 4.3–14.4).

Distribution of Molecular Subtypes

Patients were classified into four molecular subtypes based on immunohistochemistry (IHC) profiles:

Table 1: SUVmax by Molecular Subtypes

Table 2: SUVmax and Pathological Complete Response (HPE)

SUVmax Distribution Across Subtypes

The SUVmax varied significantly among molecular subtypes:

• Triple-negative breast cancer (TNBC) showed the highest SUVmax (mean: 9.5, range: 6.2–14.4).
• HER2-enriched tumors followed (mean: 8.6, range: 5.4–13.2).
• Luminal B tumors showed moderate uptake (mean: 7.2, range: 4.8–11.7).
• Luminal A tumors had the lowest SUVmax (mean, 6.0; range: 4.3–8.1).

Table 3. Mean SUVmax by Molecular Subtypes

                        Visual comparison of SUVmax values is shown in Figure 2.

Figure 2 – Mean SUVmax by Molecular Subtype (PNG, 300 dpi)

Statistical Significance

• The Kruskal–Wallis H test revealed statistically significant differences in the SUVmax among all subtypes (p < 0.05).
• Pairwise Mann–Whitney U tests showed:
• TNBC vs. HR+ (Luminal A/B): SUVmax was significantly higher (p < 0.01).
• HER2-enriched vs HR+: also significantly higher (p < 0.05)

Correlation between SUVmax and Pathological Complete Response (pCR)

Linear regression analysis showed that higher SUVmax was associated with a greater likelihood of achieving pCR, particularly among TNBC and HER2-enriched patients. These subtypes demonstrated the strongest metabolic responses to NACT.

Table 4. Correlation Between SUVmax and pCR Across Molecular Subtypes

Interpretation:

• TNBC and HER2+ subtypes showed the strongest positive correlation between SUVmax and likelihood of achieving pCR.
• The correlation was weak and non-significant in Luminal A and marginal in Luminal B.
• The overall cohort showed a moderate positive correlation (ρ = 0.55, P < 0.01), supporting the hypothesis that a higher baseline SUVmax predicts a better treatment response to NACT.

literature suggesting that SUVmax on 18F-FDG PET/CT scans is a valuable biomarker for assessing metabolic activity in breast cancer and can be used to predict treatment response, especially in the context of neoadjuvant chemotherapy (NACT). Our findings demonstrated significant variability in SUVmax values across different molecular subtypes of breast cancer, with the highest values observed in Triple-Negative Breast Cancer (TNBC) and HER2-enriched subtypes. These subtypes are often

associated with a more aggressive tumor biology and poorer prognosis, which is reflected in their higher SUVmax values [1,2].

In contrast, luminal A displayed the lowest SUVmax values, which is consistent with its classification as a less aggressive subtype. Luminal B, while showing moderately elevated SUVmax values, still exhibited lower values than the HER2-enriched and TNBC subtypes. This aligns with previous studies that have demonstrated the metabolic heterogeneity of breast cancer subtypes and their association with prognosis [3,4].

In addition to the variation in SUVmax across molecular subtypes, our study also highlights the correlation between SUVmax and the likelihood of achieving pathological complete response (pCR) after NACT. In particular, TNBC and HER2-enriched subtypes showed the strongest positive correlation between SUVmax and pCR, with higher SUVmax values strongly associated with better treatment outcomes [5]. This result is consistent with earlier findings where higher SUVmax values were linked to an improved response to chemotherapy in patients with metastatic breast cancer [6]. The correlation between TNBC and HER2-enriched patients was especially pronounced, suggesting that SUVmax may serve as a powerful tool for predicting which patients are more likely to benefit from aggressive treatment regimens.

The correlation between SUVmax and pCR was weaker in the Luminal A and Luminal B subtypes, which is consistent with the literature indicating that these subtypes generally have a less robust response to chemotherapy [7]. Luminal A tumors, being hormonally driven, tend to respond less dramatically to chemotherapy, and Luminal B tumors, although more aggressive, still exhibit lower SUVmax values compared to their HER2-enriched and TNBC counterparts. This weaker correlation in these subtypes could indicate that SUVmax may be less predictive of response to NACT in hormone-receptor-positive cancers, further suggesting that the role of SUVmax as a prognostic marker may be subtype-specific [8].

Our study also supports the use of SUVmax as a prognostic marker of survival outcomes. High SUVmax values, particularly in TNBC and HER2-enriched subtypes, have been associated with a worse prognosis owing to the aggressive nature of these cancers [9]. However, these subtypes also exhibit a higher likelihood of achieving pCR, indicating that SUVmax not only reflects tumor aggressiveness, but also serves as an indicator of treatment responsiveness.

For example, TNBC and HER2-enriched subtypes, both of which are associated with aggressive behavior and poor prognosis, exhibited the highest SUVmax values in this study. These findings are consistent with previous research that identified high SUVmax as an indicator of more aggressive cancer phenotypes, which often correlates with increased glucose metabolism in malignant cells [10]. Notably, higher SUVmax values in TNBC and HER2-enriched tumors also correlated with a higher likelihood of achieving pathological complete response (pCR) following neoadjuvant chemotherapy. This positive correlation suggests that SUVmax could serve as a predictive biomarker for early treatment response, allowing clinicians to identify patients who are more likely to benefit from aggressive treatments, such as chemotherapy.

In contrast, Luminal A and Luminal B subtypes showed lower SUVmax values, which is consistent with their generally less aggressive nature and lower metabolic rate. Luminal A, characterized by estrogen and progesterone receptor positivity, often responds well to hormonal therapies, which may explain its relatively lower SUVmax values compared with TNBC or HER2-enriched subtypes [11]. Despite the lower SUVmax values, Luminal B subtypes exhibited slightly higher SUVmax values than Luminal A may reflect the more aggressive nature of this subtype, particularly in the context of hormone receptor expression and HER2 overexpression [12].

Interestingly, the correlation between SUVmax and pCR was weaker in Luminal A tumors, a finding that aligns with existing evidence suggesting that these tumors are less likely to achieve pCR following neoadjuvant chemotherapy. This weaker correlation in Luminal A due to the tumor’s lower metabolic activity and its responsiveness to endocrine therapy rather than chemotherapy. In contrast, Luminal B tumors, despite showing intermediate SUVmax values, exhibited a more favorable pCR rate than Luminal A tumors, indicating a greater sensitivity to chemotherapy.

Limitations

Despite these promising results, this study had several limitations. The sample size, particularly for certain subtypes such as Luminal A relatively small, and the retrospective nature of the study may have introduced biases in patient selection. Additionally, while we found correlations between SUVmax and pCR, causality could not be inferred from our analysis. Larger prospective studies with more diverse cohorts are needed to confirm these findings and to further evaluate the clinical utility of SUVmax in breast cancer treatment planning.

Moreover, while SUVmax is a valuable tool, it is important to consider other clinical and molecular factors when assessing the treatment response and prognosis. For example, hormonal receptor status and the expression of HER2 are crucial in predicting the response to specific therapies, and these factors should be integrated with metabolic imaging results to provide a more comprehensive assessment of the tumor.

In conclusion, SUVmax on 18F-FDG PET/CT is a promising prognostic marker in breast cancer, especially in predicting the response to NACT. Our findings suggest that higher SUVmax values are associated with a higher likelihood of achieving pCR, particularly in aggressive subtypes, such as TNBC and HER2-enriched cancers. While the correlation between SUVmax and pCR was weaker in hormone receptor-positive subtypes, these results underscore the need for personalized treatment strategies based on both molecular subtypes and metabolic imaging. Further research is warranted to explore the full potential of SUVmax as a predictive biomarker and refine its role in guiding breast cancer treatment.

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