What Are Lobular and Ductal Breast Cancer? Differences and Treatment

Breast cancer is divided into several subtypes according to histological features; the most common include invasive lobular and invasive ductal breast cancer. These two subtypes differ in how cancer cells grow and spread within breast tissue.

The term "invasive" means that cancer cells can leave their original site and infiltrate surrounding tissues.

Invasive ductal breast cancer arises from the cells lining the milk ducts and is the most common type of breast cancer.

Invasive lobular breast cancer develops within the milk-producing glands (lobules) and is a less common type.

The two cancers have different clinical characteristics, patterns of treatment response, and disease courses.

The table below classifies breast cancer according to different characteristics. These features are considered when making treatment decisions.

This article examines how lobular breast cancer differs from the more common ductal breast cancer in its characteristics, disease course, and treatment approaches. Understanding these two histological subtypes, which are critically important in breast cancer treatment, plays a major role in disease management and improving patient care. We will explore the differences between lobular and ductal breast cancer, how these differences arise, and how treatment options are affected.

Lobular Breast Cancer

Lobular breast cancer is a relatively uncommon subtype that many oncologists do not fully understand.

Classic invasive lobular cancer is characterized by small, uniform-looking (monomorphic) cells with round nuclei and a noncohesive growth pattern, in which cells have lost their ability to adhere to one another and spread through breast tissue.

As lobular cancer gained recognition as a distinct tumor type in the 1970s and 1980s, cancer specialists began questioning whether it required different treatment from ductal cancer. Retrospective studies sought to improve understanding of this form of lobular cancer, but the first prospective investigation was not published until 2008.

Comparing Histological Subtypes by Survival

The International Breast Cancer Study Group (IBCSG) pooled results from 15 trials involving more than 13 thousand patients whose histology had been determined through central pathology review. Consistent with earlier retrospective studies, the IBCSG found that lobular cancers tended to occur at older ages, were associated with larger tumors, and led to more mastectomies than ductal cancers. A new observation also emerged: histological type had significant, time-dependent effects on disease-free and overall survival. Lobular cancers initially conferred an advantage, but this did not persist over the long term. At 6 years, patients with lobular cancer had significantly lower disease-free survival than those with ductal cancer, and after 10 years their overall survival was significantly lower.

Although late recurrences are known to be more common in patients with lobular cancer, most of whom are estrogen receptor-positive, this does not fully explain the different disease courses of lobular and ductal cancers. Similar survival-curve patterns in estrogen receptor-positive and -negative patients suggest that the time-dependent factors affecting the course of lobular cancers are independent of estrogen receptor status. This suggests that lobular cancers may have biological features different from ductal cancers that influence their course and response to treatment.

Differences in Recurrence Rates and Spread

The IBCSG study revealed another histology-related difference:

• Although local cancer recurrence rates were similar for lobular and ductal cancers,
• patients with ductal cancer experienced more regional recurrences, while
• patients with lobular cancer experienced more distant recurrences.

Metastatic disease showed different patterns: ductal cancers generally spread to bone, whereas lobular cancers tended to spread to sites such as the peritoneum (abdominal lining), ovaries, and gastrointestinal tract. Lung recurrence is less common in lobular cancers.

Risk Factors May Also Differ

Risk factors for lobular cancer may differ from those associated with ductal cancer. A meta-analysis of 25 observational studies of hormone exposure found stronger associations between lobular cancer and hormone replacement therapy, age at menarche (first menstruation), and age at menopause. Among past or current hormone replacement therapy users, the relative risk increase was 2-fold for lobular cancer versus 1.5 for ductal cancer; some individual studies reported a threefold increase in lobular cancer risk.

Despite increased use of magnetic resonance (MR) imaging in patients with lobular cancer, no marked improvement in surgical outcomes has been observed.

A particularly notable finding is that lobular carcinoma in situ (LCIS) is one of the strongest risk factors for lobular cancer. In other words, invasive lobular cancer tends to develop against a background of LCIS. Lobular carcinoma in situ shares the histological features of invasive lobular carcinoma, but its cells are confined to the terminal duct lobular units.

According to data from the US Surveillance, Epidemiology, and End Results (SEER) Program, after a diagnosis of lobular carcinoma in situ, patients have an 11% risk of developing breast cancer within the next ten years and a 20% risk within twenty years. These rates indicate an average annual risk increase of approximately 1%. Lobular carcinoma in situ is a risk factor for both ductal and lobular cancers; however, approximately 30% of cancers developing in this setting are pure lobular carcinomas or carcinomas with mixed ductal and lobular features.

A Closer Look at Phenotype and Genetics

Phenotype refers to the observable physical and biological characteristics of a living entity (tissue or organism) resulting from its genetic makeup and interactions with the environment.

Looking closely at the lobular breast cancer phenotype, pathologists have long known that its hallmark is loss of the cell-adhesion protein encoded by the CDH1 gene, E-cadherin. Loss of this protein produces the distinctive noncohesive growth pattern of lobular cancer cells, meaning they do not stick to one another.

Most lobular cancers have a luminal phenotype, usually the luminal A subtype (estrogen receptor-positive and HER2-negative), with a very low proliferation rate.

Below are details of breast cancer classification by biological characteristics and the luminal A subtype .

The Cancer Genome Atlas (TCGA) dataset was used to compare luminal A invasive lobular cancers with luminal A invasive ductal cancers. A "striking" difference was observed in the frequency of CDH1 mutations: 68% in lobular cancers versus 2% in ductal tumors .

More recently, FOXA1 alterations were found to be overrepresented in lobular cancers, and FOXA1 was found to have an important effect on estrogen receptor signaling in these cancers, potentially influencing treatment approaches.

These findings contribute to a better understanding of lobular cancers' molecular features and treatment response.

Imaging Considerations

Important imaging considerations play a critical role in determining disease extent and treatment approaches. In breast-conserving surgery , the appropriate size of margins—the boundary of healthy tissue around the tumor—and the role of preoperative treatment are important aspects of treatment planning.

Nodal (lymph node) management does not differ between lobular and ductal cancers. However, patients with lobular disease are more likely to have micrometastatic (very small, spread) nodal disease , and ultrasound-guided fine-needle aspiration may be less sensitive for these lesions.

Magnetic resonance imaging (MRI) stands out as the most effective method of determining tumor size. Its correlation coefficient is approximately 0.8, indicating greater accuracy than other imaging methods.

However, none of the currently available imaging methods is perfect. A Mayo Clinic series of 59 patients who underwent MRI evaluated agreement, underestimation, and overestimation between MRI tumor-size estimates and final pathological measurements. Notably, estimates obtained through clinical breast examination were the same as the MRI results. This indicates that our imaging methods need further improvement. Overall, preoperative MRI in the assessment of invasive breast cancer is known to increase mastectomy rates.

A meta-analysis evaluating preoperative MRI in invasive breast cancer, both lobular and ductal, included approximately 86 thousand patients and yielded important findings about surgical outcomes. MRI was associated with more mastectomies (breast removal surgery), but did not reduce positive margins—cancer cells at the surgical boundary—or the need for reoperation. It also nearly doubled prophylactic (preventive) mastectomy of the opposite breast.

In particular, a subgroup analysis of six studies limited to lobular cancers showed no increase in mastectomy use, unlike the main analysis. However, it also showed no reduction in reoperation rates among lobular cancer patients undergoing breast-conserving surgery.

Thus, despite increased MRI use in lobular cancer, it has not produced a marked improvement in surgical outcomes. These results raise important questions about MRI's effectiveness and its influence on surgical decisions in invasive breast cancer treatment.

Risk of Recurrence After Treatment

Studies published between 2004 and 2015 found quite low, "acceptable" local recurrence rates in patients with lobular cancer, as in those with ductal cancer. The most comprehensive, conducted by Galimberti and colleagues in 2011, found a local recurrence rate of 5.7% over a median follow-up of 8.4 years: 3.9% occurred at the original surgical site and 1.8% elsewhere. The study found no difference in locoregional (local and regional) recurrence among patients with "wider clear margins," meaning that recurrence rates did not differ when margin widths exceeded 10 mm.

Another study included 736 patients with lobular cancer treated at Brigham and Women's Hospital/Dana Farber between 1997 and 2007. Half underwent breast-conserving surgery, and all were followed for at least 5 years. Over a median follow-up of 72 months, local and regional recurrence did not differ between breast-conserving surgery and mastectomy, with rates below 5% for both treatments. Local and regional recurrence was associated with tumor size, grade, and final margin status, but not final margin width.

In conclusion, lobular cancer–specific measures are needed to better determine the course of disease in patients with lobular breast cancer. Such measures may make treatment approaches more precise and effective.

Below is a mind-map diagram summarizing the article so far:

Neoadjuvant Treatment Considerations

In patients with lobular cancer, pathologic complete response rates in published series range from 1% to 6% and are very low —lower than the 9% to 20% seen in estrogen receptor-positive ductal cancer.

Neoadjuvant chemotherapy response was assessed in the largest study by pooling nine German trials involving patients with estrogen receptor-positive tumors. Overall, among 1,051 patients with lobular cancer, the pathologic complete response rate was 6%, compared with 17% in ductal cancer (P < 0.001). Importantly, pathologic complete response was not associated with distant disease-free or overall survival in the lobular subgroup, whereas it affected subsequent outcomes in patients with nonlobular cancers.

Pathologic complete response is not predictive of the disease course in lobular cancer . With this in mind, genomic tests are important.

The most widely available commercial genomic tests for breast cancer have been shown to predict the course of lobular cancers. However, use of the Oncotype DX 21-gene Recurrence Score in this cancer is controversial; its usefulness in predicting chemotherapy benefit in this group has not yet been established.

One of the larger studies included 6,467 patients with early-stage lobular cancer and known Recurrence Scores; 19% received chemotherapy. For five-year breast cancer–specific survival, the Recurrence Score "stratified nicely" between low-intermediate and high-intermediate risk groups, but did not identify a subgroup benefiting from chemotherapy. This held true even in the high-risk group, although that subgroup comprised only 177 patients. It must also be acknowledged that HER2 status was unavailable for most patients.

Lobular and ductal breast cancers share similarities but also have many differences that are only now being understood. Tests tailored specifically to patients with lobular breast cancer are needed to better understand these differences and predict the course of the disease more accurately.

In this context, the newly developed LobSig multigene signature study represents a notable innovation. Using a set of 194 genes and integrating gene expression with DNA copy-number analyses, this system has the potential to address needs in lobular breast cancer treatment. LobSig has been shown to outperform all other currently available tests in predicting disease course, suggesting it will be used more widely in lobular breast cancer treatment in the future. Such innovations may help improve patient care by enabling more effective diagnosis and treatment of lobular cancers.

The diagram below highlights pathologic complete response rates in lobular and ductal breast cancer, response to neoadjuvant chemotherapy, genomic tests, and the importance of the LobSig multigene signature: